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`ISSN 0025 - 7656
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`Drugs of today. (IM)
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`v. 40, no. 5 (May 200-1)
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`Drugs of Today 2004, 40 (5): 415-421
`Copyright © 2004 PROUS SCIENCE
`CCC: 0025-7656/2004
`
`A new selective H, receptor antagonist for use in allergic disorders
`
`LEVOCETIFIIZINE
`
`James H. Day/7'2, Anne K. Ellis” and Elizabeth Flafeiro’
`
`‘Division of Allergy and Immunology, Kingston General Hospital;
`2Department of Medicine, Queen’s University, Kingston, Ontario, Canada
`
`CONTENTS
`
`415
`
`Summary ......................
`Introduction .....................
`
`Pharmacology ................
`Pharmacodynamics ............
`Pharmacokinetics ..............
`
`Therapeutic efficacy ..............
`Safety and side—effect profile ........
`Commentary ....................
`References .....................
`
`......................... 415
`......................... 416
`......................... 416
`......................... 417
`417
`418
`
`.........................
`
`......................... 419
`419
`
`Summary
`Levocetirizine is the active FI-enantiomer of ce-
`tirizine and represents a new second-generation
`histamine H1 antagonist. It has a high affinity and
`selectivity for H1 receptors. Comparative studies
`have shown evidence of superior H1 receptor bind-
`ing affinity over its racemate, cetirizine. Levocetiri-
`zine has a favorable pharmacokinetic profile;
`it is
`rapidly and extensively absorbed, minimally meta-
`bolized, and has a lower volume of distribution (Vd)
`than some other second-generation antihistamines.
`A number of studies using the histamine-induced
`wheal and flare model have repeatedly demon-
`
`——________—_)
`
`Correspondence: Dr. James H. Day, Division of Allergy
`& Immunology, Kingston General Hospital, 76 Stuart St,
`Kingston, ON, Canada K7L 2V7. Tel.: (613) 548-2336; FAX:
`(613) 546-3079; E—mail: dayj@kgh.kari.net
`
`strated marked suppressive effects for Ievocetiri-
`zine. Levocetirizine has also been found to be effec-
`tive in relieving symptoms of seasonal and peren-
`nial allergic rhinitis, including nasal congestion,
`and its side effects are minor. o 2004 Prous Scrence. All
`rights reserved.
`
`Introduction
`Levocetirizine is a newly developed selective
`H1 antagonist. It is the R—enantiomer or active isomer
`(eutomer) of the racemate cetirizine. a second-gen-
`eration antihistamine. The less active S—enantiomer,
`
`or distomer, is dextrocetirizine (Fig. 1). There is no
`evidence of chiral inversion (i.e., racemization) of le-
`vocetirizine in the body, a finding which is indicative
`of its stability (1, 2).
`Available in several countries in Europe and in
`
`Asia,
`
`levocetirizine is marketed mainly under the
`
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`416
`
`Levocetirizine
`
`
`
`
`(R)-|evocetirizine
`
`N/VOJCLOH
`NC)
`
`
`
`(S)-dextrocetirizine
`
`Fig. 1. Chemical structures of (Ff)-|evocetirizine and (S)-
`dextrocelirizine.
`
`trade names Xyzal® and Xusal® for the treatment
`of seasonal allergic rhinitis, perennial allergic rhini-
`tis and chronic idiopathic urticaria. This review will
`examine the pharmacology, therapeutic efficacy
`and safety of levocetirizine.
`
`Pharmacology
`
`Pharmacodynamics
`
`Receptor binding
`
`Levocetirizine is a competitive antagonist of
`histamine H1 receptors (3) and is at least 600 times
`more selective for H, histamine receptors than for
`a variety of other G-protein-coupled receptors (4).
`Binding studies using cloned human H1 receptors ex-
`pressed in Chinese hamster ovary cells have shown
`that levocetirizine has a twofold higher affinity for
`Hl receptors than cetirizine and an approximately
`30-fold higher affinity than its enantiomer dextroce-
`tirizine (5, 6). The carboxyl group of levocetirizine
`interacts strongly with the Lys1S1 residue of the hu-
`man H1 receptor, and this interaction is considered
`key to its long half-time of dissociation (6).
`
`Histamine wheal and flare
`
`and nasal histamine challenge studies
`A number of studies have confirmed levocetiri-
`
`zine to be the active enantiomer of cetirizine, and
`dextrocetirizine the inactive enantiomer. One study
`
`compared levocetirizine (2.5 mg) with cetirizine
`(5.0 mg) and dextrocetirizine (2.5 mg) using the
`histamine-induced nasal response model (7). Both
`levocetirizine and cetirizine significantly reduced
`sneezing and inhibited the histamine-induced in-
`crease in nasal airway resistance by nearly 50%,
`which was not observed with dextrocetirizine or
`
`placebo. in a study by Devalia efaf. (8), the effects
`of these compounds were compared using the his-
`tamine-induced wheal and flare model in the skin. in
`
`this randomized, double-blind, crossover study us-
`
`ing healthy volunteers, both cetirizine and levocet-
`irizine produced a marked inhibition of histamine-
`induced wheal and flare, an effect not observed with
`dextrocetirizine. Inhibition by levocetirizine of both
`the wheal and flare responses was apparent in one
`hour, with inhibition of the wheal response lasting
`fora mean duration of 28.4 hours and with a max-
`
`imal inhibition of 83.8% at 6 hours post-treatment.
`inhibition of the flare response lasted a mean dura-
`tion of 26.0 hours, with a maximal inhibition of 83.6%
`
`at 6 hours. While cetirizine produced similar inhibito-
`ry effects on these parameters, levocetirizine pro-
`duced a greater effect than cetirizine on histamine-
`induced wheal from 0-32 hours postdose as cal-
`culated from the area under the curve (AUC, mean
`wheal area vs. time).
`The effects of levocetirizine 5 mg were com-
`pared to those of loratadine 10 mg and placebo in
`terms of the wheal and flare response to intrader-
`mai histamine injection as well as subjects’ self-rat-
`ing of skin itch at 4 hours postdose (9). Levocetiri-
`zine significantly reduced flare, wheai and itch by
`60%, 68% and 91%, respectively, while the effects
`of loratadine were variable and not significantly dif-
`ferent from those of placebo. Another histamine-in-
`duced wheal and flare study compared levoceti-
`rizine 5 mg, ebastine 10 mg, fexofenadine 180 mg,
`loratadine 10 mg, mizolastine 10 mg and placebo
`in single doses (10). The overall effect of each drug
`was evaluated by the AUC for inhibition of wheal
`and flare over 24 hours. In this study, levocetirizine
`produced the greatest suppression of wheal and
`flare surface areas, followed by ebastine, fexofe-
`nadine and mizolastine—all of which had compara-
`ble effects. Loratadine produced the least suppres-
`sion. A similar double-blind, randomized, crossover
`study involved 12 healthy volunteers who received
`a single dose of levocetirizine 5 mg, desloratadine
`5 mg or placebo. When the AUC versus time for
`the wheal and flare response over 24 hours were
`compared, levocetirizine suppressed skin reactivity
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`

`J.H. Day. A.K. Ellis and E. Rafeiro
`
`to histamine to a greater degree, more consistently
`and for a longer duration than desloratadine (11).
`Another comparison of these same treatments in t8
`healthy volunteers showed that levocetirizine and
`desloratadine were superior to placebo. and levo-
`cetirizine was superior to desloratadine.
`‘Total’
`wheal inhibition (295%) occurred only with levoce-
`tirizine, and the median duration of 70% wheal in-
`hibition with this compound was 21.4 hours (12).
`
`Antiallergic activity
`Two in vitro studies have shown evidence of anti-
`
`inflammatory activity for levocetirizine, Michel et al.
`(13), using the skin chamber technique, found pre-
`liminary evidence that levocetirizlne at therapeutic
`doses produces three main antiinflammatory effects:
`a decrease in eosinophil recruitment and a reduction
`in both soluble VCAM-t release and protein levels
`affecting vascular permeability. Levocetirizine has
`also been found to inhibit eotaxin-induced eosino-
`
`phil transendcthelial migration (14).
`
`Pharmacokinetics
`
`Absorption
`
`Levocetirizine undergoes rapid absorption, as
`evidenced by a maximal plasma concentration
`(0.27 i 0.04 ug/ml) at 0.75 hours (1mm) following
`administration of a single oral dose of 5 mg of the
`l"C-radiolabelled compound. its extensive absorp-
`tion is indicated by the recovery of 98.3% of the to-
`tal radioactivity in the urine and feces at 168 hours
`(7 days) (2).
`
`Distribution
`
`Volume of distribution (V) is a proportionality
`factor relating the drug concentration in the blood
`or plasma to the total amount of drug in the body. It
`has been determined that the higher the degree of
`drug distribution and binding to tissue, the lowerthe
`concentration in the plasma. and thus the greater
`the Vd. Levocetirizine has been shown to have a
`low apparent Vd which has been estimated at 0_3_.
`0.41 l/ltg (1.2) and is believed to be attributable to
`its relatively high plasma protein binding (912%)
`(15, 16). Levocetirizine’s Vd is lower than several
`other second-generation antihistamines, panicular-
`ly loratadine and ebastine, both of which have a Vl1
`estimated at >100 l/kg (17). A low Vd is desirable
`for medications in terms of both safety and efficacy
`since it indicates reduced exposure of organs which
`are not therapeutic targets to the circulating drug,
`
`417
`
`thereby minimizing toxicity. the potential for drug«-
`drug interactions and individual variations ln thera-
`peutic effect (16).
`Levocetirizlne's confinement to plasma is evi-
`denced by a whole blood to plasma ratio of 0.51—
`0.68 during the first 12 hours following a single
`dose of (‘4C]-levocetirizine, a finding indicative of
`minimal association with blood cells (2).
`
`Metabolism and elimination
`
`Levocetirizine is minimally metabolized; 85.8%
`of a single oral dose is excreted unchanged at 48
`hours postdosing, with only 2.4% of the total dose
`comprised of metabolites (2). Notably. levoceti-
`rizine is not metabolized by CYP 206, a specific
`P450 isozyme that is commonly involved in drug—
`drug interactions (1). CYP 3A4, another P450 iso-
`zyme, metabolizes antihistamines such as terfena-
`dine and astemizole. Co-administration of these anti—
`histamines with potent inhibitors of CYP 3A4 (e.g..
`ketoconazole, erythromycin) can lead to drug ac-
`cumulation and adverse events (18). CYP 3A4 is
`unlikely to play a significant role in levocetirizine’s
`restricted metabolism, but this has not been direct-
`ly evaluated.
`The half-life (tug) of levocetlrizine has been es-
`timated at 7.05—7.55 hours (1, 2). Levocetirizine is
`largely eliminated by renal excretion; single oral
`administration of 5 mg [MC]-levocetirizine to 4
`healthy volunteers resulted in 85.4% of the total
`dose being recovered in the urine, while 12.9%
`was recovered in faces at we hours (7' days) post-
`dose (2). Renal excretion of levocetirizine occurs
`by glomerular filtration and active tubular secretion,
`and renal clearance has been estimated at 29.2
`ml/min (or 350 ml/min when corrected for protein
`binding). The nonrenal clearance of levocetlrizine
`is relatively low (tie. 9.70 ml/min), which reduces its
`potential for metabolism-based drug interactions (t ).
`
`Therapeutic efficacy
`Levocelirizine has been investigated for its etfi-
`cacy in seasonal allergic rhinitis. Leynadier er al.
`(19) compared 2.5, 5 and 10 mg of levocetirizine
`and placebo administered once daily for 2 weeks
`during either grass or weed pollen season in France
`and Germany. In this study, 470 patients self-rated
`their symptoms of sneezing, rhinorrhea. nasal con—
`gestion, nasal pruritus and ocular pruritus on a scale
`from 0—3 each evening by means of diary evalua-
`tion cards. The total four-symptom score (T488) was
`calculated by adding each of the individual scores,
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`418
`
`Levocefirizine
`
`excluding nasal congestion. All three doses of lev-
`ocetirizine were superior to placebo in reducing the
`mean T488 as well as individual symptoms, with
`the exception of nasal congestion. There was a
`simple iinear relationship between levocetirizine
`dose and reduction of T488.
`
`In a randomized, double—blind, placebo-control-
`led, crossover study, 39 subjects with perennial rhini-
`tis and allergy to house dust mite were challenged
`with dust mite antigen in the Vienna Challenge Cham-
`ber, an indoor allergen challenge system (20), and
`response to a single dose of levocetirizine 5 mg.
`loratadine 10 mg or placebo was recorded (21).
`A significant improvement in symptom score was re-
`ported by 83.8% of subjects receiving levocetiri-
`zine, while only 66.7% of subjects responded to lo-
`ratadine.
`
`Another randomized, doublesblind, placebo-con-
`trolled evaluation of levocetirizine was undertaken
`
`with 294 dust mite-sensitive perennial allergic rhini-
`tis subjects at multiple centers in South Africa (22).
`Subjects received either levocetirizine 5 mg or
`placebo once daily for 6 weeks. Levocetirizine pro-
`duced an 86% improvement in T488 over the first
`week of treatment and a 47% improvement over
`the entire treatment period compared to placebo.
`Levocetirizine also produced an 83% improvement
`in nasal congestion at the completion of 6 weeks of
`treatment.
`
`Astudy using the Environmental Exposure Unit
`(EEU), an indoor pollen challenge system (23),
`compared the efficacy including the onset and du-
`ration of action of levocetirizine to that of deslo-
`
`in this double-blind, placebo-con-
`ratadine (24).
`trolled, parallel-group study, 373 ragweed-sensitive
`subjects were randomized to once-daily levocetiri-
`zine 5 mg, desloratadine 5 mg or placebo, and ex-
`posed to ragweed pollen on 2 consecutive days.
`Symptoms were self-rated every 30 minutes. On both
`days, levocetirizine produced a greater improvement
`in the major symptom complex score than deslo-
`ratadine; both were better than placebo. The onset
`of action of levocetirizine was 1 hour, compared to
`3 hours with desloratadine.
`
`Antihistamines have not traditionally been con-
`sidered efficacious in controlling nasal congestion
`(25, 26). Beginning in 2001, a number of studies
`specifically addressed the decongestant effects of
`desloratadine and have shown it to be effective for
`
`this symptom (27—32). Fexofenadine (30, 33-35),
`azeiastine (86, 37). ebastine (38) and cetirizine
`(39, 40) have also been shown to have deconges-
`
`tant effects. Recent studies of levocetirizine demon-
`
`strate that it too appears to possess this property.
`Potter’s evaluation (22) of levocetirizine showed
`that it provided significant relief of nasal congestion
`over 6 weeks of daily administration. A later study
`in the Environmental Exposure Unit showed that
`levocetirizine was not only superior to placebo in
`controlling nasal congestion on both treatment days
`but also better than desloratadine on the first treat-
`
`ment day (24). These findings suggest that further
`characterization of levocetirizine‘s decongestant
`properties is warranted.
`Levocetirizine has demonstrated beneficial ef-
`
`fects in chronic idiopathic urticaria and atopic der-
`matitis. in a large uncontrolled study, oral levoceti—
`rizine 5 mg once daily for 32 days was reported ef-
`fective in the treatment of both of these disorders
`
`in at least 80% of subjects at the end of the treat-
`ment period. Global assessments by subjects indi-
`cated efficacy ratings of either good or very good in
`over 80% of the subject population (41).
`
`Safety and side-effect profile
`Because of acknowledged sedative effects of
`first-generation antihistamines and to some extent
`with cetirizine (42—44), there have been several eval-
`uations of levocetirizine‘s effect on cognition and
`psychomotor performance. Verster et at. (45) com-
`pared the effects of levocetirizine 5 mg, diphenhy-
`dramine 50 mg and placebo administered once
`daily to 48 healthy volunteers. Memory and psycho-
`motor performance were assessed acutely (day 1)
`and subchronically (day 4). Levocetirizine did not
`alter memory, divided attention or tracking perfor-
`mance tests, but diphenhydramine significantly af-
`fected performance on tracking and divided atten-
`tion. The same study group found that diphenhy—
`dramine produced clinically relevant impairment of
`driving performance not evident with levocetirizine
`or placebo (46).
`The impact of levocetirizine 5 mg, diphenhy-
`dramine 50 mg and placebo on a different battery
`of psychometric tests (47) was studied with the
`treatments administered once daily for 5 consecu-
`tive days in a three-way crossover design. Levoce-
`tirizine did not modify cognitive and psychomotor
`function tests when compared with placebo, where—
`as diphenhydramine did. Decreased alertness was
`reported by subjects in the diphenhydramine group
`but not by those taking levocetirizine.
`The sedative/psychomotor effects of levoceti-
`rizine were also investigated by Hindmarch et al.
`
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`

`J.H. Day, A.K. Ellis and E. Rafeiro
`
`(48). In this double-blind, randomized, crossover stu-
`dy, 20 healthy volunteers received levocetirizine 5
`mg, cetirizine 10 mg, loratadine 10 mg, prometha-
`zine 30 mg or placebo once daily for 4 days. Psy-
`chometric evaluation and histamine-induced skin
`
`prick testing were performed at baseline and at 1,
`2, 3, 4, 6, B, 10 and 12 hours postdosing on days 1
`and 4. Promethazine (a sedating phenothiazine
`antiemetic) served as a positive control and veri-
`fied the sensitivity of the test battery. Both acute
`(single-dose) and subchronic (4-day) promethazine
`produced a deleterious impact on all psychometric
`tests. The effects of levocetirizine, cetirizine and to—
`
`ratadine were indistinguishable from those of place-
`bo for all objective and subjective tests at all time
`points on both test days. Both cetirizine and levoce-
`tirizine produced potent inhibition of histamine wheat
`and flare compared to placebo, whereas promet-
`hazine and loratadine had lesser inhibitory effects.
`The lack of significant adverse effects of levo-
`cetirizine treatment are suggested in the study by
`Potter (22) that involved a 6-week administration of
`a 5 mg dose once daily, the longest reported treat-
`ment period using levocetirizine. Subjects taking
`levocetirizine or placebo had a similar incidence of
`adverse events, with 60.0% and 68.1% reporting at
`least one adverse event, respectively. The most fre-
`quently reported adverse events for both levoceti-
`rizine and placebo groups, respectively, were head-
`ache (34.7% and 34.7%), influenza-like symptoms
`(16.7% and 13.9%) and upper respiratory tract in—
`fections (6.7% and 9.0%). The most common ad-
`verse events judged to be related to treatment were
`headache and somnolence. The incidence of som-
`nolence was 6.0% for levocetirizine and 2.8% for
`placebo. One subject experienced an increase in
`alanine aminotransferase (ALT) that was consid-
`ered to be drug-related; it resolved spontaneously
`after 9 days. No cases of increases in QTc intervals
`on electrocardiograms were reported.
`Although sedation has been reported for levo-
`cetirizine, significant impairment of memory or psy-
`chomotor performance has not been demonstrat-
`ed. These findings, along with the minimal side-ef-
`fect profile, indicate levocetirizine to be safe for
`patients on a daily dosing program. Dose adjust-
`ment is recommended for patients with renal or
`hepatic impairment (49).
`
`Commentary
`Levocetirizine is a recently developed second
`generation H1 antihistamine available for the treat-
`
`419
`
`ment of allergic rhinitis and urticaria. It has demon-
`strated clinical efficacy for the relief of allergic rhini-
`tis symptoms including improvement of nasal con-
`gestion. It has been suggested that levocetirizine is
`a “me too" drug—that it is simply the active enan-
`tiomer of cetirizine offering no new benefits over the
`parent compound (50). However, based on phar-
`macokinetic and pharmacodynamic properties, a
`rationale has been offered for the chiral switch from
`the racemate to levocetirizine (16). These proper-
`ties include chiral stability, a higher affinity for H1
`receptors and a lower Vd compared to cetirizine.
`There is insufficient evidence to draw conclusions
`on the clinical relevance of these findings, but in-
`formation available to date is reason for further in-
`
`vestigation.
`
`References
`
`1.Baltes, E., Coupez, R., Giezek, H., Voss, G.,
`Meyerhoff, C., Strolin, B. M. Absorption and dis-
`position of levocetirizine, the eutomer of cetiri-
`zine, administered alone or as cetirizine to
`healthy volunteers. Fundam Clin Pharmacol
`2001, 15: 269-77.
`2. Benedetti M. 8., Plisnier, M. Kaise, J. et at.
`Absorption distribution, metabolism and excre-
`tion of [’4C]levocetirizine, the R enantiomer of
`cetirizine, in healthy volunteers Eur J Clin Phar-
`macol 2001 57: 571— 82.
`3 Christophe, B. Cartier, B, Gillard, M, Chate-
`lain, P. Peck M., Massingham R. Histamine
`H receptor antagonism by cetirizme in isolated
`guinea pig tissues. Influence of receptor re-
`serve and dissociation kinetics Eur J Pharma-
`col 2003, 470: 87- 94.
`4.Gillard, M., van der Perren, C., Moguilevsky, N.,
`Massingham, R., Chatelain, P. Binding charac-
`teristics of cetirizine and levocetirizine lo hu-
`man H(t) histamine receptors: Contribution of
`Lys(191) and Thr(194). Mol Pharmacol 2002,
`61: 391-9.
`
`5. Gillard, M., van der Perren, C., Massingham, H.,
`Chatelain, P. Binding characteristics of PHjlev-
`ocetirizine to cloned human H 1-histamine-re-
`
`ceptors expressed in CHO cells. Inflamm Res
`2002, 51 (Suppl. 1): 877—878.
`6. Gillard, M., van der Perren, C., Moguilevsky, N.,
`Massingham, R., Chatelain, P. Major role for
`the carboxylic function of cetirizine and levoce-
`tirizine in their binding characteristics to human
`Ht-histamine-receptors, Inflamm Res 2002, 51
`(Suppl. 1): 879-880.
`
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`420
`
`Levocetirizine
`
`7.Wang, D.Y., Hanotte, F., De Vos, G.. Clement,
`P. Effect of cetirizine, tevocetirizine, and dextro-
`cetirizine on histamine-induced nasal response
`in healthy adult volunteers. Allergy 2001, 56:
`339-48.
`
`8. Devalia, J.L., De Vos, (3., Hanotte, F., Baltes. E.
`A randomized, double-blind, crossover compar-
`ison among celirizine,
`ievocetirizine, and ucb
`28557 on histamine—induced cutaneous re-
`
`sponses in healthy adult volunteers. Allergy
`2001, 56: 50-7.
`9. Clough, GE, Boutsiouki, P., Church, M.K. Com~
`parison of the effects of tevocetirizine and lo-
`ratadine on histamine-induced wheat, flare, and
`itch in human skin. Allergy 2001, 56: 985-8.
`10. Grant, J.A., Ftiethulsen,
`.J.M., Moulaer’t, B.,
`DeVos. C. A doubtenbiind, randomized, single-
`dose, crossover comparison of levocetirizine
`with ebastine, fexofenadine, loratadine, mizo-
`lastine, and placebo: Suppression of histamine-
`induceo‘ wheat-and-flare response during 24
`hours in healthy male subjects. Ann Allergy
`Asthma Immunol 2002, 88: 190—7.
`11. Denham, K.J., Boutsiouki, P., Clough, G.F.,
`Church, M.K. Comparison of the effects of des-
`tcratadine and levocetirizine on histamine-in-
`duced wheat, flare and itch in human skin. In-
`flamm Flee 2003, 52: 424-7.
`12. Purohit, A., Melac, M., Pauli, G.. Frossard, N.
`Twenty-four-hour activity and consistency of
`activity of levocetirizine and desioratadine in
`the skin. Br J Clin Pharmacol 2003, 56: 388—94.
`13. Michel, L., Jean-Louis, F., Dubertret, L. Pharma-
`cological study of levocetirizine in tg-E depen-
`dent hypersensitivity cutaneous reaction in
`grass pollen allergic volunteers: Demonstration
`of mediator release and eosinophit recruitment
`modulation by tevocetirizine. Allergy 2001, 56:
`150-1.
`
`14. Thomson, L., Blaylock, M.G., Sexton, D.W..
`Campbell, A., Walsh, GM. Cetirizine and levoce-
`tirizine inhibit eotaxin-induced eosinophit trans-
`endothetial migration through human dermal or
`lung microvascular endothelial cells. Clin Exp
`Allergy 2002, 32: 1187-92.
`15.Bree. F., Thiault, L., Gautiers, G. et al. Blood
`distribution of levocetirizine, a new non-sedating
`histamine Hl-receptor antagonist.
`in humans.
`Fundam Clin Pharmacol 2002, 16: 471-8.
`16.Ti|lement, J.P., Tests, 5., Bree, F. Compared
`pharmacological characteristics in humans of
`racemic ceiirizine and levocetirtzine. two his-
`
`tamine Ht-receptor antagonists. Blochem Phar-
`macol 2003, 66: 1123-6.
`17.Tillement, J.P. A low distribution volume as a
`determinant of efficacy and safety for histamine
`(H1) antagonists. Allergy 1995, 50: 126.
`18.Renwick, A.G. The metabolism of antihis-
`tamines and drug interactions: The role of cyto-
`chrome P450 enzymes. Clin Exp Allergy 1999,
`29 (Suppl. 3): 116-24.
`19. Leynadier, F., Mees, K., Arendt, G.. Pinelli, ME.
`Efficacy and safety of levocetirizine in seasonal
`allergic rhinitis. Acta Otorhinolaryngol Belg 2001,
`55: 305-12.
`20.Horak, F., Jager, S. The Vienna Challenge
`Chamber (VCC): A new method for allergen ex-
`position tests. Wien Klin Wochenschr 1987, 99:
`509-10.
`21.Horak, F., Stubner. P.. Zieglmayer, Ft. et al.
`Effect of levocetirizine and toratadine on symp-
`tom relief in house-dust-mite allergic patients
`exposed to allergen in the Vienna Challenge
`Chamber. Allergy 2001, 56: 201-2 [Abst].
`22. Potter, RC. Levocetirizine is effective for symp~
`tom relief including nasal congestion in adoles-
`cent and adult (PAR) sensitized to house dust
`mites. Allergy 2003, 58: 893-9.
`23. Day, J.H.. Briscoe, MP. Environmental Expo-
`sure Unit: A system to test anti-allergic treat-
`ment. Ann Allergy Asthma Immunol 1999, 83:
`8349.
`
`24. Day, J.H., Briscoe, M.P., Rateiro, E., Ratz J.D.
`Comparative clinical efficacy, onset, and dura-
`tion of action of tevocetirizine anct destoratadine
`
`for symptoms of seasonal allergic rhinitis in
`subjects evaluated in the Environmental Expo»
`sure Unit (EEU).
`Int .J Clin Practice 2004, 58:
`109-18.
`in-
`25.Weiner, J.M., Abramson, M.J., Puy, BM.
`trenasat corticosteroids versus oral H1 receptor
`antagonists in allergic rhinitis: Systematic re-
`view of randomised controlled trials. BMJ 1998,
`317: 1624-9.
`
`26. Passalacque, G., Canonica, G.W., Bousquet, J.
`Structure and classification of H,-antthista-
`mines and overview of their activities. Clin AI-
`
`Iergy Immunol 2002, 17: 65—100.
`27. Bachert. C. Decongestant efficacy of desiorata-
`dine in patients with seasonal allergic rhinitis.
`Allergy 2001, 56 (Suppl. 65): 14-20.
`28.Berger, W.E., Schenkel. E.J., Mansfield, L.E.
`Safety and efficacy of desloratadine 5 mg in
`
`UCB Biopharma SPRL (IPR2019-00400)
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2028 Page 8
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`

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`J.H. Day. A.K. Ellis and E. Rafeiro
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`asthma patients with seasonal allergic rhinitis
`and nasal congestion. Ann Allergy Asthma Im-
`munol 2002, 89: 485-91.
`
`Nayak, A.S., Schenkel, E. Des/oratadine re-
`duces nasal congestion in patients with intermit-
`tent allergic rhinitis. Allergy 2001, 56: 1077-80.
`Wilson, A.M., Haggart, K., Sims, E.J., Lipworth,
`B.J. Effects of fexofenadine and desloratadine
`
`on subjective and objective measures of nasal
`congestion in seasonal allergic rhinitis. Clin Exp
`Allergy 2002, 32: 1504-9.
`Horak, F., Stubner, U.P., Zieglmeyer, FL, Harris,
`A.G. Effect of desloratadine versus placebo on
`nasal airflow and subjective measures of nasal
`obstruction in subjects with grass pollen-in-
`duced allergic rhinitis in an allergen-exposure
`unit. J Allergy Clin Immunol 2002, 109: 956-61.
`Horak, F., Stubner, P., Zieglmeyer, R., Harris,
`A.G. Comparison of the effects of desloratadine
`5-mg daily and placebo on nasal airflow and
`seasonal allergic rhinitis symptoms induced by
`grass pollen exposure. Allergy 2003, 58: 481—5.
`Ciprandi, G., Cosenlino, C., Milanese, M., Mon-
`dino, G., Canonica, G.W. Fexofenadine reduces
`nasal congestion in perennial allergic rhinitis.
`Allergy 2001, 56: 1068-70.
`Horak, F., Stubner, P., Zieglmeyer, R. et al.
`Controlled comparison of the efficacy and safe-
`ty of cetirizine 10 mg o.d. and fexofenadine 120
`mg o.d. in reducing symptoms of seasonal ai-
`lergic rhinitis. Int Arch Allergy Immunol 2001,
`125: 73-9.
`
`Van Cauwenberge, P., Juniper, E.F. Comparison
`of the efficacy, safety and quality of life provid-
`ed by fexofenadine hydrochloride 120 mg, lora-
`tadine 10 mg and placebo administered once
`daily for the treatment of seasonal allergic rhini-
`tis. Clin Exp Allergy 2000, 30: 891-9.
`Golden, S.J., Craig, T.J. Efficacy and safety of
`azelastine nasal spray for the treatment of al-
`lergic rhinltis. J Am Osteopath Assoc 1999, 99:
`87-12.
`
`Grossrnan, J., Halverson, P.C., Meltzer, E.O. et
`al. Double-blind assessment of azelastine in
`
`the treatment of perennial allergic rhinitis. Ann
`Allergy 1994, 73: 141-6.
`Rather, P., Hampel, F., Jr., Gispert, J. Efficacy
`of ebastine in the control of nasal congestion
`associated with allergic rhinitis. Methods Find
`Exp Clln Pharmacol 2003, 25: 111-5.
`
`421
`
`39. Aaronson, D.W. Evaluation of cetirizine in pa-
`tients with allergic rhinitis and perennial asthma.
`Ann Allergy Asthma Immunol 1996, 76: 440-6.
`40. Lai, D.S., Lue, K.H., Hsieh, J.C., Lin, K.L., Lee,
`H.S. The comparison of the efficacy and safety
`of cetirizine, oxatomide, ketotifen, and a place-
`bo for the treatment of childhood perennial al-
`lergic rhinitis. Ann Allergy Asthma Immunol
`2002, 89: 589-98.
`41.8cheinfeld, N. The new antihistamines—desta-
`ratadine and levocetirizine: A review. J Drugs
`Dermatol 2002, 3: 311-6.
`42. Falliers, C.J., Brandon, M.L., Bushman, E. et al.
`Double-blind comparison of cetirizine and place-
`bo in the treatment of seasonal rhinitis. Ann
`
`Allergy 1991, 66: 257-62.
`43. Bonifazi, F., Provinciali, L., Antonicelli, L. et al.
`Comparative study of ten‘enadine and cetirizine
`in hay fever: Assessment of efficacy and central
`nervous system effects. J Investig Allergol Clin
`immunol 1995, 5: 40-6.
`44. Horak, F., Stubner, U.P. Comparative tolerability
`of second generation antihistamines. Drug Saf
`1999, 20: 385-401.
`45.Verster, J.C., Volkerts, E.R., van Oosterwijck,
`A.W. et al. Acute and subchronic effects of lev-
`ocetirizine and diphenhydramine on memory
`functioning, psychomotor performance, and
`mood. J Allergy Clin Immunol 2003, 111: 623-7.
`46. Verster, J.C., De Weert, A.M., Bijtjes, S.|. et al.
`Driving ability after acute and sub-chronic ad-
`ministration of levocetlrizine and dlphenhy-
`dramine: A randomized, double—blind, placebo-
`controlled trial. Psychopharmaoology 2003, 169:
`84-90.
`
`47. Gandon, J.M., Allain, H. Lack of effect of single
`and repeated doses of levocetirizine, a new an-
`tihistamine drug, on cognitive and psychomotor
`functions in healthy volunteers. Br J Clin Phar-
`macol 2002, 54: 51-8.
`48. Hindmarch, |., Johnson, 8., Meadows, FL, Kirk-
`patrick, T., Shamsi. Z. The acute and sub-
`chronic effects of levocelirizlne, cetirizine, lora-
`
`tadine, promethazine and placebo on cognitive
`function, psychomotor performance, and weal
`and flare. Curr Med Res Opin 2001, 17: 241-55.
`49. Xyzal Product Monograph. UCB Pharma |nc.,
`Brussels, Belgium 2001.
`50. Levocetirizine: New preparation. Me-too: Simply
`the active enantiomer of cetirizine. Prescrire Int
`
`2003,12: 171-2.
`
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`Exhi