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Main Rupatadine References
Contents:
Main Rupatadine References Pharmacodynamics / Pharmacokinetics

Dual effect of a new compound, rupatadine, on edema induced by platelet-activating
factor and histamine in dogs: Comparison with antihistamines and PAF antagonists.
Queralt M, Merlos M, Giral M, Puigdemont A. Drug Dev Res 1996; 39 (1): 12-8.
The antihistamine-H1 and antiplatelet activating factor (PAF) activities of seven compounds,
including rupatadine, a new antiallergic drug, were studied in healthy beagle dogs using a
new experimental model that allows simultaneous testing of PAF and histamine reactions in
the same animal. The method was based on the measurement of wheal area induced in
dogs' skin by intradermal injection of PAF (1.5 mug) or histamine (2.5 mug). Rupatadine and
the H1-antihistamine drugs cetirizine, levocabastine, and loratadine, administered orally at
doses of 1 or 10 mg/kg showed similar maximum potencies (75-85% of wheal inhibition) 4-
8 h after treatment. Levocabastine was the longest-acting compound (55% and 69%
inhibition 24 h after administration of 1 or 10 mg/kg, respectively). Rupatadine, loratadine,
and cetirizine behaved similarly, showing 34% and 58% inhibition at 24 h at the same doses.
Dual PAF and histamine antagonist SCH-37370 exhibited mild anti-H1 activity, the
maximum effect being 27% at 10 mg/kg. Pure PAF antagonists WEB-2086 and SR-27417
showed no effect against histamine-induced wheals.
Only rupatadine, SR-27417A, SCH-37370, and WEB-2086 showed PAF antagonist activity,
whereas pure antihistamines were inactive. The most potent PAF antagonist was SR-
27417A, with a maximum effect of 56% and 80% at 1 and 10 mg/kg, respectively.
Rupatadine and WEB-2086 antagonized PAF-induced wheal response, although they
showed less maximum effect and shorter duration of action than SR-27417A. SCH-37370
exhibited only slight PAF antagonist activity at 10mg/kg. Overall, the histamine- and PAF-
induced wheal model in dogs proved useful for independent evaluation of histamine and
PAF antagonist properties of the tested compounds, as pure antagonists blocked the effect
of only one of the mediators.
Rupatadine was the only one of the seven compounds studied that showed potent dual
activity against PAF and histamine.
Protective effect of rupatadine fumarate in experimental conjunctivitis in guinea pigs.
Ferrando R, Giral M, Balsa MD, Merlos M, Garcia Rafanell J, Forn J. Methods Find Exp Clin
Pharmacol 1996; 18 (Suppl B): 140. XX Congress of the Spanish Society of Pharmacology
and the IV Spanish-French Meeting on Pharmacology. Granada (Spain), September 18-20
1996.
The topical antiallergic activity of the novel histamine (H) and PAF antagonist rupatadine
fumarate (RF; UR-12592 fumarate) eyedrops was evaluated in comparison with loratidine
(LOR) in a model of H-, PAF-or ovalbumin (OVA)-induced conjunctivitis in guinea pigs. From
the results it was concluded that RF could be useful in the topical treatment of allergic
conjunctivitis. (conference abstract). Conjunctivitis was induced by topical application of H
(400 ug) or PAF (10 ug) in naive animals or OVA (140 ug) in actively sensitized guinea pigs.
Drugs were administered as eye-drops (20 ul) 15 min before agonist or antigen provocation.
Inflammation was scored (0-10 point scale) at 5, 15, 30, 60, 90, 120, and 150 min after
induction. RF (0.001-0.01 % w/v) strongly and dose-dependently inhibited H-induced
conjunctivitis, being about 20-fold more potent than LOR (IC50 values at 30 min were 0.0015
and 0.034% for RF and LOR, respectively). RF (0.05-0.2%) also inhibited PAF-and OVA-
induced conjunctivitis, e g. mean scores (at 30 min), PAF: 6.8 and 4.2 for control and 0.1%
RF, respectively; OVA: 7.2 and 3.8. LOR, at the same concentrations, inhibited OVA-, but
not PAF-induced conjunctivitis.
Main Rupatadine References Pharmacokinetics and dose linearity of rupatadine fumarate in healthy volunteers.
Izquierdo I, Nieto C, Ramis J, Cooper M, Dewland P, Forn J. Methods Find Exp Clin
Pharmacol 1997; 19 (Suppl A): 189. XXI Congress of the Spanish Society of Pharmacology.
Barcelona (Spain), November 11-14 1997. Sponsored by: Spanish Society of Pharmacology
(Sociedad Española de Farmacología).
The pharmacokinetics (PK) of single- and multiple dose rupatadine fumarate (RUP) and its
effect on the inhibition of intradermal histamine induced cutaneous flares were examined in
healthy male volunteers in 2 consecutive randomized, placebo (PL)-controlled, double blind
studies. The terminal half-life beta was influenced by the different doses administered.
Single and multiple doses of RUP were well tolerated and no serious adverse events were
noted. RUP showed after once daily administration, a high and long acting antihistamine
activity. (conference abstract).The single dose study was a randomized, double blind, 3-way
crossover involving 8 subjects. Each subject received a single dose of 10, 20 and 40 mg
RUP.
The multiple dose study was randomized, double blind, rising dose and PL controlled. 12
subjects received 20 and 40 mg, once daily for 7 days and only 3 subjects received PL. In
both studies there were at least 14 drug free days between dose periods. Blood samples for
determination of RUP were taken at different times on each study. Cutaneous flares were
also induced by i.d. injection of histamine to obtain a concentration effect relationship. Dose
linearity was demonstrated over the range 10-40 mg of RUP. The mean values of AUC0-
infinity were 8.68, 22.22 and 54.02 ng/ml/hr and mean values of Cmax were 2.33, 5.83 and
14.68 ng/ml. Within the doses administered the individual values indicated a relatively high
interindividual variation probably due to a varying degree of enterohepatic circulation.
Steady state was reached on days 3-5. Both the percentage and duration of flare inhibition
increased with dose. Mean inhibition of histamine reached a maximum of 69, 82 and 93%
with 10, 20 and 40 mg after single dose, respectively. After multiple dose the inhibition of
histamine flares rose rapidly after 1st dose and remained consistently high (70-90%)
throughout the dosing period. Inhibitory effect remained high (more than 60%) until 48 and
96 hr after the last dose.
Rupatadine, a new potent, orally active dual antagonist of histamine and platelet
activating factor (PAF).
Merlos M, Giral M, Balsa D, Ferrando R, Queralt M, Puigdemont A, Garcia Rafanell J, Forn
J. J Pharmacol Exp Ther 1997; 280 (1): 114-21.
Rupatadine (UR-12592, 8-chloro-6, 11-dihydro-11-[1-[(5-methyl3-pyridinyl) methyl]-4-
piperidinylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridine ) is a novel compound that inhibits
both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with
specific receptors (Ki(app) values against [3H]WEB-2086 binding to rabbit platelet
membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55
and 0.10 microM, respectively).
Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 =
9.29 +/- 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4
(LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit
platelets (WRP) (pA2 = 6.68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 =
0.68 microM), while not affecting ADP- or arachidonic acid-induced platelet aggregation.
Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats
(ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50
= 113 and 9.6 micrograms/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in
mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality
Main Rupatadine References in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine's duration of action was long,
as assessed by the histamine- and PAF-induced increase in vascular permeability test in
dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.).
Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor
prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects.
Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high
potency, the antihistamine properties being similar to or higher than those of loratadine,
whereas rupatadine's PAF antagonist effects were near those of WEB-2066. Rupatadine is
therefore a good candidate for further development in the treatment of allergic and
inflammatory conditions in which both PAF and histamine are implicated.
Effects of rupatadine on cardiovascular profile in rats and guinea pigs. Comparison
with other nonsedating antihistamines.
Giral M, Merlos M, Balsa D, Ferrando R, Garcia Rafanell J, Forn J. Allergy 1997; 52 (Suppl
37): 44-5. EAACI ' 97 Annual Meeting. Rhodes (Greece), June 1-4 1997.
The cardiovascular safety profile of i.v. infused rupatadine (RUP), a potent dual histamine
and PAF antagonist, was evaluated in rats and guinea pigs and compared with that of other
antihistmines. RUP and loratadine (LOR) produced minimal alterations in MABP and HR at
the highest dose. Terfenadine (TER) provoked a fall in MABP and HR, with severe
arrhythmias, and most animals died. No mortality was observed with when RUP or LOR. In
guinea pigs, RUP (i.v. bolus) did not alter either ECG or haemodinamic parameters. LOR,
however, produced a transient decrease followed by a prolonged increase in MABP,
accompanied with a significant increase in HR. TER and astemizole (AST) decreased HR
and MABP. From results obtained in guinea pigs it was suggested that RUP could have
lower risk of inducing cardiovascular adverse effects than LOR. (conference abstract). The
cardiovascular safety profile of rupatadine (RUP), a potent dual histamine and PAF
antagonist, has been evaluated in rats and guinea pigs and compared with that of other
antihistmines. Animals were anaesthetized and instrumental for the recording of mean
arterial blood pressure (MABP) and ECG derived parameters such as heart rate (HR) and
QT, PR and QRS intervals. RUP and loratadine (LOR) (3 - 30 mg/kg, intravenous infusion
of 1 min) produced minimal alterations in MABP and HR at the highest dose. ECG
parameters were not significantly modified. In contrast administration of 10 mg/kg
terfenadine (TER) provoked a fall in MABP and HR, with severe arrhythmias, and most
animals died within 4 min after administration. No mortality was observed when RUP or LOR
were administered at doses up to 30 mg/kg. In guinea pigs, RUP 30 mg/kg (intravenous
bolus) did not alter either ECG or haemodinamic parameters. LOR 30 mg/kg, however,
produced a transient decrease followed by a prolonged increase in MABP, accompanied
with a significant increase in HR. ECG intervals did not show any alteration. TER and
astemizole (AST) 10 mg /kg induced marked changes in haemodinamic (decrease of HR
and MABP) and ECG parameters: AST and TER increased PR (26% and 32% at 2 min,
respectively) and AST increased QRS (32% at 2 min). AST and TER 15 mg /kg also
produced QT prolongation and high mortality rate.
Main Rupatadine References Inhibition of rat peritoneal mast cell exocytosis by rupatadine fumarate: a study with
different secretagogues.
Merlos M, Balsa D, Giral M, Ferrando R, Garcia Rafanell J, Forn J. Methods Find Exp Clin
Pharmacol 1997; 19 (Suppl A): 148. XXI Congress of the Spanish Society of Pharmacology.
Barcelona (Spain), November 11-14 1997. Sponsored by: Spanish Society of
Pharmacology.
The ability of rupatadine fumarate (RUP), an orally active dual antagonist of histamine (HA)
and PAF, to inhibit rat mast cells (MC) exocytosis of inflammatory mediators induced by both
IgE dependent and -independent stimuli, was evaluated in comparison with loratadine
(LOR), a 2nd generation antihistamine. Both LOR and RUP inhibited HA and LTC4 release
from calcimycin (A-23187)-stimulated MC, but only RUP inhibited 48/80-induced HA
release. LOR and RUP also inhibited ex vivo A-23187-induced HA release after p.o. dosing.
In IgE- sensitized MC, both LOR and RUP inhibited antigen induced HA release. Effects
were calcium dependent. Thus, RUP has in vitro antiallergic properties that are thought to
be beyond its ability to block H1 and PAF receptors. The mechanism is still unclear, but it is
suggested that RUP may interfere with intracellular Ca2+ utilization (conference
abstract).Peritoneal MC from male Sprague Dawley rats were isolated in Tyrode solution.
MC were pre incubated in the absence or presence of products (0-10 min, 37 deg), then
secretagogue (0.5 uM A-23187, 1 ug /ml compound 48/80 and 2/10 ug/ml anti DNP IgE/DNP
albumin) was added and cells were further incubated (10-60 min, 37 deg). The released
mediators were extracted and quantified spectrofluorimetrically (HA) or by a commercially
available kit (LTC4). In the in vitro experiments, RUP and LOR were similarly effective in
inhibiting HA (55.5 and 50.2% at 10 uM, respectively) and LTC4 (IC50 = 5.6 and 5.8 uM)
release from A-23187-triggered MC. In 48/80-stimulated MC, only RUP (18.0%) reduced HA
release at 10 uM. Inhibitory behavior in the A-23187 and compound 48/80 assays varied
depending on Ca2+ concentration in the medium. RUP (IC50 = 73 uM) and LOR (IC50 =
288 u M) also inhibited HA release from IgE sensitized MC after antigen exposure. In the ex
vivo experiments, pretreatment with RUP and LOR (30 mg/kg, p.o.) similarly reduced A-
23187-induced HA exocytosis (32.2 and 27.3%).
Rupatadine inhibits the eosinophil recruitment in BAL fluid of ovalbumin-sensitized
guinea-pigs.
Merlos M, Giral M, Balsa D, Ferrando R, Garcia Rafanell J, Forn J. J Allergy Clin Immunol
1998; 101 (1 Pt.2): S218 AAAAI 54th Annual Meeting. Washington DC (USA), March 13-18
1998.
Female Dunkin-Hartley guinea pigs weighing 300-400 g were sensitized by administration
of 5% OVA (2 ml, i.p., 2 ml, s.c.). After 25-27 days, animals were challenged with an aerosol
of 0.5% OVA for 5 min. Adverse reactions showed by the animals (dyspnea, cyanosis, and
bronchospasm) were recorded. Rupatadine (RUP), loratadine (LOR), dexamethasone
(DEX) and cetirizine (CET) were administered (10 mg/kg, p.o.) 1 hr before challenge and
compared with sham and vehicle (VEH) groups. Mortality was only observed in the VEH
group (17%).
Rupatadine inhibited early symptoms and BAL eosinophil recruitment in a guinea pig model
of allergic asthma. (conference abstract).
Main Rupatadine References Inhibitory effects of rupatadine on mast cell histamine release and skin wheal
development induced by Ascaris suum in hypersensitive dogs.
Queralt M, Brazis P, Merlos M, Puigdemont A. Drug Dev Res 1998; 44 (2-3): 49-55.
In sensitized dogs, p.o. rupatadine (RU, 8-chloro 6,11-dihydro 11- ((5-methyl 3-pyridinyl)
methyl) 4-piperidinylidene) 5H benzo(5,6) cyclohepta(1,2-b) pyridine fumarate, Uriach), a
histamine and PAF antagonist, and p.o. loratadine (LO, Schering Plough), an H1 antagonist,
but not p.o. SR-27417A (SR, Sanofi), a PAF antagonist, inhibited wheal induced by
intradermal challenge with Ascaris suum extract (Greer). In vitro, histamine release from
passively sensitized dog mast cells on challenge with antigen (Greer) was inhibited by RU
and LO but not by SR. RU and LO were not cytotoxic in vitro; SR was. RU controls
inflammatory reactions in dog skin; the effect may partly be due to modulation of mast cell
degranulation, but not to PAF antagonism.5 Spontaneously hypersensitive male Beagle
dogs (14.2 kg) were fasted and given 10 ul 50 PNU/ml A. suum extract intradermally before
and after 0.1, 1 or 10 mg/kg drug. A. suum extract induced a wheal, the area of which was
maximally inhibited by 35%, 67% and 84%, respectively, by RU and 34%, 61% and 66%,
respectively, by LO; the peak effect was reached at 2-4 hr for both drugs.
SR was ineffective. Dog skin mast cells were passively sensitized by incubation with 15%
serum from A. suum sensitized dogs for 120 min. Drugs were incubated with cells for 10 min
before 30 min challenge with 1 mg/ml A. suum antigen. Antigen alone maximally released
12.3% of mast cell histamine. 15 And 40 min incubation with RU or LO at 10 mM - 30 uM
was not cytotoxic and showed no degranulating effects. SR 30 uM reduced cell viability to
65%. RU and LO dose dependently inhibited antigen induced histamine release; maximum
effects were 83.3% and 66.7%, respectively, at 30 uM; RU was the more potent (IC50 5.3
vs. 19 uM). SR was ineffective.
Effects of rupatadine, a new dual antagonist of histamine and platelet-activating
factor receptors, on human cardiac kv1.5 channels.
Caballero R, Valenzuela C, Longobardo M, Tamargo J, Delpon E. Br J Pharmacol 1999;
128 (5): 1071-81.
1. The effects of rupatadine, a new dual antagonist of both histamine H1 and platelet-
activating factor receptors, were studied on human cloned hKv1.5 channels expressed in
Ltk- cells using the whole-cell patch-clamp technique. 2. Rupatadine produced a use- and
concentration-dependent block of hKv1.5 channels
(KD=2.4+/-0.7 micronM) and slowed the deactivation of the tail currents, thus inducing the
'crossover' phenomenon. 3. Rupatadine-induced block was voltage-dependent increasing
in the voltage range for channel opening suggesting an open channel interaction. At
potentials positive to +10 mV the blockade decreased with a shallow voltage-dependence.
Moreover, rupatadine also modified the voltage-dependence of hKv1.5 channel activation,
which exhibited two components, the midpoint of the steeper component averaging -25. 2+/-
2.7 mV. 4. When the intracellular K+ concentration ([K+]i) was lowered to 25% the voltage-
dependent unblock observed at positive potentials was suppressed and the activation curve
in the presence of rupatadine did not exhibit two components even when the midpoint of the
activation curve was shifted to more negative potentials (-30. 3+/-1.3 mV). 5. On channels
mutated on the residue R485 (R485Y) which is located on the external entryway of the pore
the rupatadine-induced block did not decrease at potentials positive to +10 mV. In contrast,
on V512M channels rupatadine reproduced all the features of the blockade observed on wild
type channels. 6. All these results suggest that rupatadine blocks hKv1.5 channels binding
to an external and to an internal binding site but only at concentrations much higher than
therapeutic plasma levels in man. Efflux of K+ promotes the unbinding from the external site.
Main Rupatadine References Furthermore, rupatadine binds to an internal site and dramatically modifies the voltage-
dependence of channel opening.
In vitro inhibitory effect of rupatadine on histamine and TNF-alpha release from
dispersed canine skin mast cells and the human mast cell line HMC-1.
Queralt M, Brazis P, Merlos M, de Mora F, Puigdemont A. Inflamm Res 2000; 49 (7) : 355-
60.
Objective and design: To examine the inhibitory potential of rupatadine, a new H1-
antihistamine and anti-PAF agent, on histamine and TNF-alpha release. Comparison with
an H1-antihistamine (loratadine) and a PAF-antagonist (SR-27417A). Material: Dispersed
canine skin mast cells were used to assess the effect of the drugs tested on FcepsilonRI-
dependent and –independent histamine release; the human HMC-1 cell line was used to
study TNF-alpha release. Treatment and Methods: Before stimulation mast cell
populations were treated with increasing concentrations of rupatadine, loratadine and SR-
27417A. Histamine and TNF-alpha release were measured following 15-30 min and 3 h
activation, respectively. Results: The IC50 for rupatadine in A23187, concanavalin A and
anti-IgE induced histamine release was 0.7+/-0.4 microM, 3.2+/-0.7 microM and 1.5+/-0.4
microM, respectively whereas for loratadine the IC50 was 2.1+/-0.9 microM, 4.0+/-1.3 M and
1.7+/-0.5 microM. SR-27417A exhibited no inhibitory effect. Rupatadine, loratadine and SR-
27417A inhibited TNF-alpha release with IC50 2.0+/-0.9 microM, 2.1+/-1.1 M and 4.3+/-0.6
microM, respectively. Conclusions: Rupatadine and loratadine showed similar inhibitory
effect on histamine and TNF-alpha release, whereas SR-27417A only exhibited inhibitory
effect against TNF-alpha.
Effect of rupatadine on lymphocyte cytokine production
Barron S, Ramis I, Merlos M.
Allergy Clin Immunol Int: J World Allergy Org 2005; Suppl (1): 427 (Abs 1175) World Allergy
Congress: XIXth World Allergy Organization Congress – XXIVth Congress of the European
Academy of Allergology and Clinical Immunology (EAACI). Munich (Germany), June 26 -
July 1 2005.
Background: Rupatadine is a new anti-histamine and anti-PAF drug used in the treatment
of allergic rhinitis. Several studies have shown that rupatadinehas additional anti-
inflammatory properties besides the blockade of histamine and PAF receptor. Some second-
generation antihistamines (anti-H1) inhibit cytokine production by lymphocytes. The aims of
this study were to evaluate the inhibitory properties of rupatadine on human lymphocyte
cytokine production using different activation models and to compare this effect with that of
desloratadine. Methods: Lymphocytes were obtained from human peripheral blood with a
ficoll gradient followed by a negative selection using MACS(r) immunomagnetic beads.
Lymphocytes were activated with anti-CD3, anti-CD28 and IL-2 (activation A) or anti-CD3
and VCAM-1 (activation B). Anti-H1 were added 30 min before or simultaneously with
activation. Supernatants were collected after 4 days of incubation and cytokine levels were
measured by enzyme immunoassay technique.
Results: Pre-treatment with rupatadine followed by activation A inhibited IL-5, IL-6, GM-
CSF and TNF-a production in a concentration-dependent manner between 10-7 and 10-5
M. Desloratadine showed a similar pattern of cytokine inhibition for IL-6, GM-CSF and TNF-
a. Desloratadine, however, was not able to produce an inhibition of IL-5 higher than 30 % at
any proved concentration, whereas the inhibition elicited by rupatadine reached 60% at 10-
Main Rupatadine References 5M. In experiments where anti-H1 were added simultaneously with activation A, rupatadine
was still able to inhibit TNF-a production; desloratadine, however, fail to do so. The inhibition
of IL-5 production by rupatadine following activation B was significantly higher than that
obtained with desloratadine. Conclusion: Rupatadine inhibits the production of lymphocyte
inflammatory cytokines elicited by two different types of activation. Although desloratadine
is also effective, rupatadine showed a better inhibitory profile, particularly on the production
of Th2 cytokine IL-5 in all proved activation protocols.
This property may confer an advantage for rupatadine in the treatment of the allergic
inflammation.
Antihistaminic effects of rupatadine and PKPD modelling.
Peña J, Carbó M, Solans A, Nadal T, Izquierdo I, Merlos M. Eur J Drug Metab
Pharmacokinet April/June 2008; 33 (2): 107-116.
Rupatadine is a new oral antihistaminic agent used for the management of allergic
inflammatory conditions, such as rhinitis and chronic urticaria. The aim of the present study
was to develop a population pharmacokinetic/pharmacodynamics (PKPD) model for the
description of the effect of rupatadine and one of its active metabolites, desloratadine, on
the histamine-induced flare reaction and to predict the response to treatment after repeated
administrations of rupatadine. Both rupatadine and desloratadine were characterized by
two-compartmental kinetics.
For both compounds, covariates sex and weight had a significant effect on several
parameters. The pharmacodynamics were described by an indirect model for the inhibition
of flare formation that accounted for the contribution of both rupatadine and desloratadine
to the antihistaminic effect. The final PKPD model adequately described the original data.
The simulated response after repeated once-daily administrations of 10 mg rupatadine
showed a significant and maintained antihistaminic effect over time, between two
consecutive dosing intervals.
Rupatadine Inhibits Proinflammatory Mediator Secretion from Human
Mast Cells Triggered by Different Stimuli.
Vasiadi M, Kalogeromitros D, Kempuraj D, Clemons A, Zhang B, Chliva C, Makris M,
Wolfberg A, House M, Theoharides TC. Int Arch Allergy Immunol 2009; 151(1):38-45.
Background: Mast cells are involved in allergy and inflammation by secreting multiple
mediators including histamine, cytokines and platelet-activating factor. Certain histamine 1
receptor antagonists have been reported to inhibit histamine secretion, but the effect on
cytokine release from human mast cells triggered by allergic and other stimuli is not well
known. We investigated the ability of rupatadine, a potent histamine 1 receptor antagonist
that also blocks platelet-activating factor actions, to also inhibit mast cell mediator release.
Methods: Rupatadine (1-50 muM) was used before stimulation by: (1) interleukin (IL)-1 to
induce IL-6 from human leukemic mast cells (HMC-1 cells), (2) substance P for histamine,
IL-8 and vascular endothelial growth factor release from LAD2 cells, and (3) IgE/anti-IgE for
cytokine release from human cord blood-derived cultured mast cells. Mediators were
measured in the supernatant fluid by ELISA or by Milliplex microbead arrays.
Results: Rupatadine (10-50 muM) inhibited IL-6 release (80% at 50 muM) from HMC-1
cells, whether added 10 min or 24 h prior to stimulation. Rupatadine (10-50 muM for 10 min)
inhibited IL-8 (80%), vascular endothelial growth factor (73%) and histamine (88%) release
Main Rupatadine References from LAD2 cells, as well as IL-6, IL-8, IL-10, IL-13 and tumor necrosis factor release from
human cord blood-derived cultured mast cells.
Conclusion: Rupatadine can inhibit histamine and cytokine secretion from human mast
cells in response to allergic, immune and neuropeptide triggers. These actions endow
rupatadine with unique properties in treating allergic inflammation, especially perennial
rhinitis and idiopathic urticaria.
Efficacy and tolerability of rupatadine at four times the recommended dose against
histamine and PAF induced flares responses and ex vivo platelet aggregation in
healthy males.
Church MK Br J Dermatol 2010; 163(6): 1330-2
Background: European guidelines recommend increasing H1-antihistamine doses up to 4-
fold in poorly responding urticaria patients. Objectives: To assess the efficacy and tolerability
of high dose rupatadine (40 mg) against PAF and histamine-induced flare responses in
human skin and to verify its anti-PAF activity by assessing its inhibition of PAF-induced
platelet aggregation in the blood of subjects receiving 40 mg rupatadine. Methods: Flare
study: six male volunteers received a single dose of 40 mg rupatadine. Flares were induced
before dosing and up to 96 hours afterwards by intradermal PAF and histamine. Ex vivo
study: four male volunteers received an oral dose of 40 mg rupatadine and blood samples
taken 4 hours afterwards. Platelet aggregation was assessed in platelet-rich-plasma by
incubation for 5 minutes with PAF. Results: Rupatadine 40 mg reached maximal plasma
levels of 15.1±4.4 ng/ml at one hour and its metabolite, desloratadine, 5.2±0.9 ng/ml at two
hours. Neither was detectable by 12 hours. Inhibition of histamine- and PAF-induced flares
was significant within 2 hours, maximal at 6 hours (87.8±3.1% and 87.1±2.5% inhibitions,
P<0.0001) and still statistically significant at 72 hours. Rupatadine 40 mg inhibited PAF-
induced platelet aggregation ex vivo by 82±9% (P=0.023). A single oral dose of 40 mg
rupatadine was well tolerated with mild transient somnolence being reported. Conclusions:
A single dose of rupatadine at four times the recommended dose is well tolerated, highly
effective for up to 72 hours against PAF- and histamine-induced dermal flares and has
demonstrable PAF-receptor antagonism ex vivo.
Effect of Rupatadine on platelet-activating factor induced rhinitis in allergic
rhinitis patients.
Muñoz R, Valero A, Giralt J, Izquierdo I, Doménech A, Bartra J, Picado C, Mullol J
Allergy 2011; 66, Suppl 94: 132 (Abs 290) XXX Cong Eur Acad Allergy Clin Immunol
(EAACI), Istanbul, Turkey, 11-15 June 2011

Effects of Rupatadine on platelet activating factor (PAF) induced human mast
cell degranulation compared with Desloratadine and Levocetirizine.
Muñoz Cano R, Torres Atencio I, Ainsua E, Martin Andorra M, Sánchez Lopez J,
Bartra J, Picado C, Valera Santiago A. J Allergy Clin Immunol 2012; 129, 2 Suppl : AB122
(465). Am Acad Allergy Asthma Immunol (AAAAI) Annual Meeting 2012 Orlando, Florida,
March 2-6, 2012, USA.
Main Rupatadine References
Population pharmacokinetics of rupatadine in children 2-11 years of age with
allergic rhinitis.
Izquierdo I, Estévez J, Doménech A, Valle A. PAGE (Population Approach Group in Europe)
Annual Meeting 2012, 5 - 8 June, Venice, Italy, Abstr 2615



Clinical Efficacy


1. Adults


1.1. Allergic Rhinitis
A randomized, double-blind, parallel-group study, comparing the efficacy and safety
of rupatadine (20 and 10 mg), a new PAF and H (1) receptor-specific histamine
antagonist, to loratadine 10 mg in the treatment of seasonal allergic rhinitis.
Saint Martin F, Dumur JP, Pérez I, Izquierdo I. J Invest Allergol Clin Immunol 2004; 14 (1):
34-40.
Background: The main objective of this randomized, double-blind, parallel-group,
comparative study was to assess the efficacy and safety of rupatadine 10 mg (R10) and 20
mg (R20) administered once- daily for two weeks compared with those of loratadine 10 mg
(L10) in the treatment of seasonal allergic rhinitis (SAR). Methods: A total of 339 SAR
patients were randomized to receive R20 (111 patients), R10 (112 patients) or L10 (116
patients). The main efficacy variable was the mean total daily symptom score (mTDSS)
based on the daily subjective assessment of the severity of rhinitis symptoms - rhinorrhea,
sneezing, nasal itching, nasal obstruction, conjunctival itching, tearing and pharyngeal
itching - recorded by patients. Results: The mTDSS was significantly lower in the groups
treated with R20 (0.80 ± 0.46) and R10 (0.85 ± 0.52) than in the group treated with L10 (0.92
± 0.51) by protocol analysis (p=0.03) but not by intention-to-treat analysis. The secondary
variables used to assess efficacy (mDSS, DSSmax, CSS and TCSS) also showed
significantly milder symptoms in patients treated with R20 and R10, particularly in sneezing
and nasal itching. All treatments were well tolerated and no serious adverse events were
recorded. Headache was the most frequent non-serious adverse event, and these did not
show significant differences between treatments at similar dose levels. Somnolence was
more frequent in R20 than in the other two groups. Conclusions: The present results
suggest that rupatadine 10 mg a day may be a valuable and safe alternative for the
symptomatic treatment of seasonal allergic rhinitis.
Main Rupatadine References Rupatadine 10 mg and ebastine 10 mg in seasonal allergic rhinitis: a comparison
study.
Guadaño EM, Serra Batlles J, Meseguer J, Castillo JA, de Molina M, Valero A, Picado C.
Allergy 2004; 59 (7): 766-71.
Background: The aim of this study is to establish the efficacy and safety of rupatadine vs
ebastine and placebo in the treatment of seasonal allergic rhinitis (SAR). Rupatadine is a
new second generation H1-antihistamine with once-daily dosing that may provide better
control of symptoms than the currently used H1-receptor blockers because of its dual
pharmacol. profile (anti-PAF and anti-H1). Methods: In a multicentre study, 250 patients
with SAR were included in a double-blind, randomized, parallel-group and placebo-
controlled study. Patients received either rupatadine 10 mg, ebastine 10 mg or placebo once
daily for 2 wk. The main efficacy outcome was based on the patient's record of severity of
nasal symptoms (sneezing, nasal itching, runny nose and nasal obstruction) and nonnasal
symptoms (conjunctival itching, tearing and pharyngeal itching). The daily total symptom
score (DTSS) was the mean of the DSS recorded for each of the seven symptoms assessed,
and the mean DTSS (mDTSS) was the mean of the DTSS values for each study day.
Results: Significant differences in mDTSS were detected between rupatadine and placebo
(33% lower for rupatadine group; P = 0.005) after 2 wk of treatment. The TSS for rupatadine
were 22%, lower than for ebastine, although the differences were not statistically significant.
No serious adverse events were reported during the study period. Conclusions:
Rupatadine 10 mg once daily was clearly superior to placebo in alleviating the symptoms of
SAR over a 2-wk period. In comparison with ebastine, rupatadine shows a trend towards a
better profile as regard several secondary efficacy variables.
Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: a randomised,
double-blind parallel study.
Martinez Cocera C, De Molina M, Marti Guadaño E, Pola J, Conde J, Borja J, Pérez I, Arnaiz
E, Izquierdo I. J Investig Allergol Clin Immunol 2005; 15 (1): 22-9.
This randomised, double-blind, parallel-group, multicentre clinical trial evaluated the efficacy
and safety of rupatadine, a new antihistamine with antiplatelet-activating factor (PAF)
activity, and cetirizine in the treatment of patients with seasonal allergic rhinitis (SAR). A
total 249 patients were randomised to receive rupatadine 10 mg once daily (127 patients) or
cetirizine 10 mg (122 patients) for two weeks. The main efficacy variable was the mean total
daily symptom score (mTDSS) and was based on the daily subjective assessment of the
severity of each rhinitis symptom—nasal (runny nose, sneezing, nasal itching and nasal
obstruction) and non-nasal (conjunctival itching, tearing, and pharyngeal itching)--recorded
by patients in their diaries. The mTDSS was 0.7 for both treatment groups (intention to treat
analysis). In the investigator's global evaluation of efficacy at the seventh day, 93.3% and
83.7% patients in the rupatadine and cetirizine groups, respectively, showed some or great
improvement (p = 0.022). In the per protocol analysis (n = 181), runny nose at the seventh
day of treatment was absent or mild in 81.1% of patients in the rupatadine group and in
68.6% of patients in the cetirizine group (p = 0.029). In any case statistical significance was
not maintained at the second week. Overall, all treatments were well tolerated. Adverse
events (AEs) were similar in both treatment groups, i.e. headache, somnolence and
fatigue/asthenia as the most often reported. Somnolence was reported in 9.6% and 8.5% of
patients treated with rupatadine or cetirizine, respectively. The most reported AEs (67%)
were mild in intensity. Our results suggest that rupatadine 10 mg may be a valuable and
safe alternative for the symptomatic treatment of SAR.
Main Rupatadine References Effects of rupatadine vs placebo on allergen-induced symptoms in patients exposed
to aeroallergens in the Vienna Challenge Chamber.
Stübner P, Horak F, Zieglmayer R, Arnaiz E, Leuratti C, Pérez I, Izquierdo I. Ann Allergy
Asthma Immunol 2006; 96 (1): 37-44.
BACKGROUND: Rupatadine is a novel compound with potent dual antihistamine and
platelet-activating factor antagonist activities and no sedative effects. OBJECTIVE: To
evaluate the efficacy of rupatadine, 10 mg once daily, and placebo on allergen-induced
symptoms (including nasal congestion), nasal airflow, nasal secretion, and subjective
tolerability in response to grass pollen in a controlled allergen-exposure chamber. Methods:
In a randomized, double-blind, placebo-controlled, crossover trial, 45 patients with a history
of seasonal allergic rhinitis received rupatadine or placebo every morning for 8 days in 2
different periods separated by a 14-day washout interval. On day 8 of each crossover period,
patients underwent a 6-hour allergen exposure in the Vienna Challenge Chamber, where a
constant and homogeneous concentration of aeroallergens was maintained. Subjective and
objective assessments were performed online during the exposure. Results: Subjective
single and composite nasal and nonnasal symptoms were consistently less severe with
rupatadine use than with placebo use starting from the first evaluation at 15 minutes to the
end of the 6-hour Vienna Challenge Chamber challenge, with the most significant effects
seen for nasal rhinorrhea, nasal itching, sneezing attacks, and total nasal symptoms (P <
.001 for all). All the other symptoms (including nasal congestion, P < or = .005) were also
significantly reduced with active treatment compared with placebo use. Mean secretion
weights and overall feeling of complaint were significantly lower with rupatadine therapy than
with placebo use (P < or = .001). Overall, rupatadine treatment was well tolerated.
Conclusion: Rupatadine treatment is effective and well tolerated in patients with allergen-
induced symptoms exposed to aeroallergens in a controlled exposure chamber.
A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with
cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis.
Fantin S, Maspero J, Bisbal C, Agache I, Donado E, Borja J, Mola O, Izquierdo I. Allergy
2008; 63 (7): 924-931.
Objective: To investigate the efficacy of rupatadine, in controlling symptoms of PER over a
12-week period. Methods: A randomized, double blind, parallel-group, placebo-controlled
study was carried out in patients aged older than 12 years with PER. Main inclusion criteria
were: instantaneous total symptom score (i6TSS) =45, nasal obstruction score =12, and
overall assessment of PER =2 as moderate during the first visit. The primary efficacy
endpoint was the 12-week average change from baseline of the patients' i6TSS. Results:
In all, 736 patients were selected. Of them, 543 (73.8%) were randomized in three different
groups: placebo (n = 185), cetirizine (n = 175) and rupatadine (n = 183). Rupatadine (P =
0.008) but not cetirizine (P = 0.07) statistically reduced the baseline i6TSS vs placebo
(47.8%, 44.7% and 38.8%, respectively), after 12 weeks. Onset of action was observed at
the first 24 h for both treatments (rupatadine vs placebo, P = 0.013; cetirizine vs placebo, P
= 0.015). Furthermore, instantaneous total nasal symptoms score (iTNSS) (including nasal
blockage) mean change from baseline showed a significant reduction with rupatadine 10 mg
in comparison with placebo, along all treatment duration of 12 weeks. Study treatments were
well tolerated. Conclusion: Rupatadine significantly relieves symptoms of PER, providing a
rapid onset of action and maintains its effects over a long period of 12-weeks.
Main Rupatadine References Rupatadine 10 and 20 mg are effective and safe in the treatment of perennial allergic
rhinitis after 4 weeks of treatment: A randomized, double-blind, controlled trial with
loratadine and placebo.
Kowalski ML, Jukiewicz D, Kruszewski-J, Nowak D, Zietkowski Z, Spicakova M, Vernerova
E, Seberova E, Klenha K, Izquierdo I. Therapy 2009; 6(3): 417-25
Background and objectives: Allergic rhinitis is a global health concern of increasing
prevalence that can impact quality of life and work and school performance of affected
individuals. Antihistamines are recommended as the first-line treatment. This randomized,
controlled trial aimed to investigate the effects of rupatadine in adult subjects with perennial
allergic rhinitis. Methods: We randomly assigned 283 patients to receive placebo (n = 69),
loratadine 10 mg (n = 70), rupatadine 10 mg (n = 73) or rupatadine 20 mg (n = 71). The
study design was double blind and treatment was continued for 4 weeks. Subjective
assessment of symptoms (reflective evaluation) was recorded by patients in a diary card.
The primary end point was the percentage of days where the score of the most severe
symptom was less than or equal to one (Pdmax1). Furthermore, the change from baseline
in the severity of total symptom score and nasal symptom score were recorded, and the
investigator and patient global assessments were evaluated. Results: All 283 patients were
included in analyses (intention to treat); 265 (94%) patients completed the follow-up.
Rupatadine 20 mg significantly improved the Pdmax1 in comparison with placebo.
Significant reductions from baseline in total symptom score were achieved with rupatadine
10 mg (-4.00), rupatadine 20 mg (-3.96) and loratadine (-3.94) compared with placebo (p <
0.01). Similarly, all three active treatments significantly reduced the nasal symptom score
compared with placebo. No significant differences among groups in the incidence of overall
adverse events were observed and no clinically significant QTc enlargements were
detected. More patients receiving rupatadine complained of somnolence compared with
loratadine. Conclusion: Once-daily rupatadine (10 and 20 mg) is an efficacious and safe
treatment for the management of patients with perennial allergic rhinitis.
Reduction of Nasal Volume After Allergen-Induced Rhinitis in Patients Treated With
Rupatadine: A Randomized, Cross-Over, Double-Blind, Placebo-Controlled Study.
Valero A, Serrano C, Bartrá J, Izquierdo I, Muñoz-Cano R, Mullol J, Picado C. J Investig
Allergol Clin Immunol 2009; Vol. 19(6): 488-493.
OBJECTIVE: To measure the reduction in nasal obstruction using acoustic
rhinometry in patients with allergic rhinitis treated with rupatadine. Methods: We performed
a randomized, double-blind, cross-over, placebo-controlled clinical trial in asymptomatic
patients with allergic rhinitis. Patients received rupatadine 10 mg or placebo once daily for
3 days, in 2 subsequent periods separated by a washout interval of 14 days. We performed
a nasal allergen challenge during each period, and measured nasal volume using acoustic
rhinometry and nasal nitric oxide (nNO) at baseline, and at 2 hours and 24 hours after the
challenge. We also evaluated nasal symptoms (rhinorrhea, itching, obstruction, and
sneezing), as well as total symptom score (T4SS) at the same time points as for the primary
objective. Results: The study population comprised 30 outpatients with a mean (SD) age of
28 (10) years. Nasal airway blockage was significantly lower in the rupatadine group than in
the placebo group (47%, P < .05) at 2 hours postchallenge. nNO in the rupatadine-treated
patients remained unaltered, unlike in the placebo-treated group, where levels decreased at
2 hours. After treatment with rupatadine, patients showed a lower decrease in the mean total
symptoms score at 2 hours (3.6 [2.6]) compared with placebo (3.9 [2.9]), although these
differences did not achieve statistical significance. Overall, rupatadine was well tolerated
and no serious or unexpected adverse events were observed. Conclusions: Rupatadine
Main Rupatadine References 10 mg can reduce nasal obstruction assessed by objective measures and is well tolerated
in patients with allergic rhinitis.
ESTUDO FUTURA: Avaliação da eficácia e segurança do fumarato de rupatadina no
tratamento da rinite alérgica persistente.
Olavo de Godoy Mion, Regis A. Campos, Martti Antila, Priscila Bogar Rapoport, Nelson
Rosario João Ferreira de Mello Junior, Roberto Eustáquio Santos Guimarães, Marcos
Mocellin, Giovanni Di Gesu, Dirceu Solé , Luc Wexler, João Ferreira de Mello, Fábio Morato
Castro, Maria Letícia Chavarria. Braz J Otorhinolaryngol 2009; 75(5): 673-9.
Allergic rhinitis affects 10-30% of the population, negatively impacting one's quality of life
and productivity. It has been associated with sinusitis, otitis media, sleep disorders, and
asthma. Rupatadine is a second generation antihistamine with increased affinity to
histamine receptor H1; it is also a potent PAF (platelet- activating factor) antagonist. It starts
acting quite quickly, offers long lasting effect, and reduces the chronic effects of rhinitis. AIM:
This study aims to assess the efficacy and safety of rupatadine in the treatment of persistent
allergic rhinitis. MATERIALS AND METHOD: this is a multi-centric open prospective study.
This study included 241 patients from 13 centers in Brazil and was held between October of
2004 and August of 2005. Signs and symptoms of rhinitis and tolerance to medication were
analyzed after one and two weeks of treatment. Results: reduction on general scores from
8.65 to 3.21 on week 2 (p<0.001). All signs and symptoms improved significantly in the first
day of treatment (p<0.001), except for nasal congestion and secretion, which improved from
the second day of treatment (p<0.001). Adverse events occurred in 19.9% of the cases,
27.7% on week 1. Conclusion: rupatadine effectively controls persistent allergic rhinitis; it
is safe and presents low incidence of side effects.
Rupatadine and levocetirizine for seasonal allergic rhinitis: a comparative study of
efficacy and safety.
Maiti R, Rahman J, Jaida J, Allala U, Palani A. Arch Otolaryngol Head Neck Surg 2010;
136(8):796-800.
OBJECTIVE: To determine the better agent among rupatadine fumarate and levocetirizine
dihydrochloride for seasonal allergic rhinitis. Although treating and ensuring a decent quality
of life to patients is challenging, an increasing understanding of pathomechanisms has
revealed the potentiality of new-generation antihistamines in the treatment of seasonal
allergic rhinitis. DESIGN: A 2-week, single-center, randomized, open, parallel group
comparative clinical study between rupatadine and levocetirizine in patients with seasonal
allergic rhinitis. SETTING: A tertiary care center. PATIENTS: Following inclusion and
exclusion criteria, 60 patients were assigned to either the rupatadine or levocetirizine group.
INTERVENTIONS: Two-week treatment with rupatadine or levocetirizine. MAIN OUTCOME
MEASURES: After 2 weeks, all postdrug symptoms were listed, baseline laboratory
investigations (total and differential leukocyte count and IgE level) were repeated, and
clinical improvement was assessed in terms of change in Total Nasal Symptom Score,
Rhinoconjunctivitis Quality of Life Questionnaire score, and laboratory parameters. Results:
Differential count (P = .01) and absolute eosinophil count (P = .009) was significantly lowered
by both drugs, but rupatadine was found to be superior. In the rupatadine group there was
a significantly higher reduction (P = .004) in IgE level and Total Nasal Symptom Score (P <
.001) compared with the levocetirizine group. There was a decrease of 18.08% (P = .02) in
Rhinoconjunctivitis Quality of Life Questionnaire score in the rupatadine group, which was
Main Rupatadine References significantly greater compared with the levocetirizine group. Incidence of adverse effects
was less in the rupatadine group compared with the levocetirizine group. Conclusion:
Rupatadine is a better choice for seasonal allergic rhinitis compared with levocetirizine
because of its better efficacy and safety profile.
Rupatadine 10 mg in adolescent and adult symptom relief of perennial
allergic rhinitis.
Molina M, Pinto E, Cister A, Alamar Martínez R, Montero J, García González JJ, Serra J,
De La Torre F, Izquierdo I Therapy 2010; 7 (4): 429-436
Background & objectives: This randomized, double-blind clinical trial assessed the efficacy
and safety of rupatadine 10 mg administered once-daily for 4 weeks compared with placebo
and ebastine 10 mg in the management of symptoms of perennial allergic rhinitis (PAR).
Methods: We randomly assigned 223 patients to receive placebo (n = 73), ebastine 10 mg
(n = 79) or rupatadine 10 mg (n = 71). The efficacy and safety population analysis included
219 patients. The efficacy assessment was based on patients reflective assessment of the
severity of symptoms in a diary card. Symptoms of allergic rhinitis included rhinorrhea,
sneezing, nasal itching, nasal obstruction and ocular itching. The main variable of efficacy
was the percentage of days where the score of the most severe symptom was less than or
equal to one (Pdmax1). Furthermore, the change from baseline in the severity of total
symptom score (5TSS) and nasal symptom score (4TNSS) were measured, as well as
investigators and patients global assessment of efficacy. Results: Pdmax1 was
nonsignificantly lower for rupatadine 10 mg (49%) and ebastine 10 mg (51%) than for
placebo (42%) at the end of the study period. Both 5TSS and 4TNSS were significantly
improved for rupatadine 10 mg users compared with placebo (p = 0.019 and p = 0.025,
respectively). No significant differences were seen between active treatments. All treatments
were similarly safe and well tolerated, with headache (33%) and somnolence (17%) as the
most often reported adverse events in all treatment groups. Conclusions: Symptomatic
relief of PAR symptoms with rupatadine 10 mg was rapidly and effectively attained. A 4-
week treatment of patients suffering from PAR with rupatadine 10 mg is as effective and well
tolerated as ebastine 10 mg.
Rupatadine improves nasal symptoms, airflow and inflammation in patients with
persistent allergic rhinitis: a pilot study.
Ciprandi G, Cirillo I. J Biol Regul Homeost Agents 2010, 24 (2): 177-83.
Nasal obstruction is the main symptom in patients with allergic rhinitis and may be measured
by rhinomanometry. Rupatadine is a new antihistamine with potential antiallergic activities.
The aim of this pilot study is to evaluate nasal symptoms, nasal airflow and nasal mediators
in patients with persistent allergic rhinitis, before and after treatment with rupatadine. Twenty
patients with persistent allergic rhinitis were evaluated, 15 males and 5 females (mean age
35 +/- 9.1 years), all of whom received rupatadine (10 mg/daily) for 3 weeks. Nasal and
ocular symptoms (measured by VAS), rhinomanometry, and nasal mediators (ECP and
tryptase) were assessed in all subjects before and after treatment. Rupatadine treatment
induced significant symptom relief (both nasal and ocular, respectively p=0.005 and p
=0.0004), including obstruction (p=0.0015) and significant increase of nasal airflow
(p=0.0025). Moreover, there was a significant difference of nasal mediators. In conclusion,
this pilot study demonstrates the effectiveness of rupatadine treatment in: i) improving nasal
and ocular symptoms, ii) increasing nasal airflow, iii) exerting antiallergic activity in patients
Main Rupatadine References with persistent allergic rhinitis. These positive results could explain the effectiveness of
rupatadine in the treatment of persistent allergic rhinitis, as reported in a previous study.
Further controlled studies need to be conducted to confirm these preliminary findings.
Rupatadine Improves Nasal Symptoms, Quality of Life (ESPRINT-15), and Severity in
a Subanalysis of a Cohort of Spanish Allergic Rhinitis Patients.
Valero A, Izquierdo I, Giralt J, Bartra J, del Cuvillo A, Mullol J J Investig Allergol Clin Immunol
2011; 21(3): 229-235
Background: According to current guidelines, new second-generation oral H1-
antihistamines, as well as intranasal corticosteroids (ICSs), are recommended for the
treatment of allergic rhinitis (AR) in adults and children. Objective: To assess changes in AR
severity, in addition to nasal symptoms and health-related quality of life (HRQoL), after 4
weeks of treatment with rupatadine in a cohort of AR patients. Methods: A subanalysis of a
longitudinal, observational, prospective, multicenter Spanish study was carried out in spring-
summer 2007. Enrolled patients had a clinical diagnosis of AR of at least 2 years' evolution,
a total nasal symptom score (TNSS) of at least 5, and had not received antihistamines in
the previous week or ICSs in the previous 2 weeks. HRQoL (ESPRINT-15 questionnaire),
disease severity (using both the original and modified Allergic Rhinitis and its Impact on
Asthma [ARIA] classifications), and nasal symptoms (TNSS) were measured at baseline
and after 4 weeks of rupatadine treatment. Results: Data from a cohort of 360 patients
treated with rupatadine were analyzed (57.2% women, 42.5% with intermittent AR, 36.4%
with asthma, and 61.7% with conjunctivitis). After 4 weeks of treatment, the patients showed
a significantly lower mean (SD) TNSS (8.2 [1.9] vs 3.1 [2.1], P<.001), a significant
improvement in HRQoL (3.0 [1.2] vs 1.0 [0.9], P<.001) and significantly reduced AR severity
(P<.0001). Conclusions: In addition to an improvement in nasal symptoms and HRQoL,
rupatadine reduced AR severity after 4 weeks of treatment.
Morning and evening efficacy evaluation of rupatadine (10 and 20 mg), compared with
cetirizine 10 mg in perennial allergic rhinitis: a randomized, double-blind, placebo-
controlled trial.
Marmouz F, Giralt J, Izquierdo I, Rupatadine investigator's group J Asthma Allergy 2011;4 :
27–35
Background: A circadian rhythm of symptoms has been reported in allergic rhinitis (AR).
Severity of all major symptoms of AR, including runny nose, sneezing, and nasal congestion,
is typically at its peak in the morning. The objective of this study was to explore the efficacy
of the antihistamine and platelet activating factor (PAF) antagonist rupatadine in the morning
and evening and to evaluate whether rupatadine provides effective symptom relief
throughout the 24-hour dosing interval. Methods: A total of 308 patients ðd18 years of age
with PAR was randomly assigned to oncedaily rupatadine 10 mg, rupatadine 20 mg, or
cetirizine 10 mg for 4 weeks in a placebo-controlled, double-blind study. The main outcome
was the morning/evening reflective total symptom score (5TSS) over the treatment period.
Secondary endpoints included morning/evening reflective nasal total symptom score
(4NTSS), individual symptoms, Pdmax1 as percentage of days with daily severest symptom
score #1, and subject/investigator evaluation of therapeutic response. Results: All active
groups were significantly more effective than placebo in improving morning and evening
evaluations of 5TSS (P < 0.001) and 4NTSS (P < 0.001) at 2 or 4 weeks. At morning
evaluation, there was a significant reduction from baseline for 5TSS with rupatadine 10 mg
Main Rupatadine References (-36.8%, P < 0.01) and 20 mg (-46.3%, P < 0.01) compared with placebo. Similarly, 4NTSS
was reduced significantly more with rupatadine 10 mg (-34%, P < 0.05) and 20 mg (-41%,
P < 0.01) compared with placebo. In the cetirizine 10 mg group, the reduction was -32.7%
and -32.2% for 5TSS and 4NTSS, respectively, but this reduction was not significant
compared with placebo. The percentage reduction was greater at evening than at morning
evaluation. 5TSS reduction with rupatadine 10 mg (-40.7%, P < 0.05) and 20 mg (-49.9%,
P < 0.01) and cetirizine 10 mg (-40.1%, P < 0.05) was significantly better than with placebo.
4NTSS values for active groups were also significantly improved versus placebo. When
individual symptoms were assessed, statistically significant differences for rhinorrhea (P <
0.01), nasal itching (P < 0.01), and sneezing (P < 0.01) were shown in all active groups
compared with placebo at morning and evening evaluations. Pdmax1 index was significantly
improved for all active groups and the overall efficacy assessed by patients or investigators
showed a significant improvement (P < 0.01) versus placebo at 2 and 4 weeks. The
incidence of somnolence was significantly greater in all active groups versus placebo.
Conclusion: The sustained 24-hour action of rupatadine 10 mg provides an effective control
of morning and evening symptoms in patients with PAR treated for up to 4 weeks.
Morning and evening efficacy evaluation of rupatadine (10 and 20 mg), compared with
cetirizine 10 mg in perennial allergic rhinitis: a randomized, double-blind, placebo-
controlled trial [Corrigendum].
Marmouz F, Giralt J, Izquierdo I. Journal of Asthma and Allergy. 2011;4:27–35.

A direct comparison of efficacy between desloratadine and rupatadine in seasonal
allergic rhinoconjunctivitis: a randomized, double-blind, placebo-controlled study.
Lukat KF, Rivas P, Roger A, Kowalski ML, Botzen U, Wessel F, Sanquer F, Agache I,
Izquierdo J Asthma Allergy 2013; 6: 31-9
Background: H1-antihistamines are recommended as the first-line symptomatic treatment
of allergic rhinitis. The objective of this study was to evaluate the effects of rupatadine (RUP)
versus desloratadine (DES) in subjects with seasonal allergic rhinitis (SAR).Method: To
assess the efficacy and safety of RUP in SAR in comparison with placebo (PL) and DES. A
randomized, double-blind, multicenter, international, and PL-controlled study was carried
out. The main selection criteria included SAR patients over 12 years old with a positive prick
test to a relevant seasonal allergen for the geographic area. Symptomatic patients at
screening with a nasal symptom sum score of $6 points (nasal discharge, nasal obstruction,
sneezing, and nasal pruritus), a non-nasal score of $3 points (ocular pruritus, ocular
redness, and tearing eyes), and a rhinorrhea score of $2 points with laboratory test results
and electrocardiography within acceptable limits were included in the study. Change from
baseline in the total symptom-score (T7SS) over the 4-week treatment period (reflective
evaluation) was considered the primary efficacy variable. Secondary efficacy measures
included total nasal symptom score (T4NSS) and conjunctival symptom score (T3NNSS),
both of which are reflective and instantaneous evaluations. Furthermore questions related
to quality of life (eg, sleep disturbances or impairment of daily activities) have also been
evaluated. Safety was assessed according to adverse events reported, as well as laboratory
and electrocardiography controls. Results: A total of 379 patients were randomized, of
which 356 were included and allocated to PL (n = 122), RUP (n = 117), or DES (n = 117).
Mean change of T7SS over the 4-week treatment period was significantly reduced in the
RUP (-46.1%, P = 0.03) and DES (-48.9%, P = 0.01) groups, compared with PL. Similarly,
Main Rupatadine References RUP and DES were comparable and significantly superior to PL for all secondary endpoints,
including nasal and conjunctival symptoms and patients' and investigator's overall clinical
opinions. Symptom score evaluation (both reflective and instantaneous evaluations)
throughout the treatment period showed a progressive and maintained significant
improvement with both treatments at day 7 (P = 0.01), day 14 (P = 0.007), and day 21 (P =
0.01) in comparison with PL. Adverse events were scarce and were similar in both treatment
groups. Electrocardiography (QTc) and lab test results did not show any relevant findings.
Conclusion: RUP is a very good choice for SAR due to its contribution to the improvement
of nasal (including obstruction) and non-nasal symptoms to a similar degree as DES.
Platelet-activating factor nasal challenge induces nasal congestion and reduces
nasal volume in both healthy volunteers and allergic rhinitis patients.
Rosa Muñoz-Cano, M.D., Antonio Valero, M.D., Ph.D., Jordi Roca-Ferrer, Ph.D., Joan
Bartra, M.D., Ph.D., Jaime Sanchez-Lopez, M.D., Joaquim Mullol, M.D., Ph.D., and Cesar
Picado, M.D., Ph.D. Am J Rhinol Allergy 27, e48–e52, 2013.
Background: Platelet-activating factor (PAF) is a lipid mediator produced by most
inflammatory cells. Clinical and experimental findings suggest that PAF participates in
allergic rhinitis (AR) pathogenesis. The aim was to assess the PAF ability to induce clinical
response in nasal airway after local stimulation. Method: Ten nonatopic healthy volunteers
(HVs) and 10 AR patients out of pollen season were enrolled. PAF increasing concentrations
(100, 200, and 400 nM) were instilled into both nasal cavities (0, 30, and 60 minutes,
respectively). Nasal symptoms (congestion, rhinorrhea, sneezing, itching, and total 4
symptom score and nasal volume between the 2nd and 5th cm (Vol2–5) using acoustic
rhinometry (AcR), were assessed at -30, 0, 30, 60, 90, 120, and 240 minutes. Result: PAF
increased individual and total nasal symptom score in both HVs and seasonal AR (SAR)
patients from 30 to 120 minutes (maximum score at 120', p < 0.05). Nasal obstruction was
the most relevant and lasting nasal symptom. PAF also induced a significant reduction of
Vol2–5 at 90' (27%), 120' (38.7%), and 240' (36.4%). No differences in the response to PAF
nasal challenge were observed between HVs and SAR subjects in either clinical symptoms
or AcR. Conclusion: This is the first description of PAF effects on human nasal mucosa
using a cumulative dose schedule and evaluated by both nasal symptoms and AcR. Nasal
provocation with PAF showed long-lasting effects on nasal symptoms and nasal obstruction
in HVs and in patients with SAR. Nasal challenge may be a useful tool to investigate the role
of PAF in AR and the potential role of anti-PAF drugs.
Evaluation of nasal symptoms induced by platelet activating factor, after nasal
challenge in both healthy and allergic rhinitis subjects pretreated with rupatadine,
levocetirizine or placebo in a cross-over study design.
Rosa Muñoz-Cano, Antonio Valero, Ignacio Izquierdo, Jaume Sánchez-López, Alejandro
Doménech, Joan Bartra, Joaquim Mullol and Cesar Picado Muñoz-Cano et al. Allergy,
Asthma & Clinical Immunology 2013, 9:43
Background: Platelet-activating factor (PAF) is produced by most inflammatory cells and it
is involved in inflammatory and allergic reactions. We aimed to assess the anti-PAF effects
of rupatadine and levocetirizine in the upper airways. Findings: Healthy volunteers (HV, N
= 10) and seasonal allergic rhinitis (SAR, N = 10) asymptomatic patients were treated out of
the pollen season with either rupatadine 20 mg, levocetirizine 10 mg, or placebo once a day
Main Rupatadine References during 5 days prior to the PAF nasal challenge. Total 4-nasal symptom score (T4SS) and
nasal patency (Vol2-5, by acoustic rhinometry) were assessed from 0 to 240 minutes after
a repeated PAF challenge. In SAR patients but not in HV, both rupatadine and levocetirizine
showed a trend to decrease PAF-induced T4SS from 60 to 120 minutes. Rupatadine but not
levocetirizine caused a significant reduction (p < 0.05) of T4SS area under the curve
compared to placebo. Rupatadine and levocetirizine caused no significant changes on nasal
patency compared to placebo. Conclusions: These results suggest that both rupatadine
and levocetirizine showed a tendency decrease toward nasal symptoms, but only rupatadine
significally reduces the overall nasal symptoms (AUC) induced by PAF in SAR patients.

Rupatadine relieves allergic rhinitis: a prospective observational study.
Ph. Eloy, L. Tobback and J. Imschoot B-ENT, 2015, 11, 11-18
Background: Allergic rhinitis has reached epidemic levels for years in Belgium and
substantially impacts the quality of life of patients. Observational, non-interventional studies
can provide valuable data, supplementing findings from double blind trials, on the true value
of a drug therapy in daily practice. Rupatadine is a new, second-generation, selective oral
H1-antihistamine. The primary objective of this study was to evaluate the evolution of quality
of life in patients treated with rupatadine in clinical practice. The impact of rupatadine on the
severity of allergic rhinitis symptoms, the subject's evaluation of the treatment, and the safety
of rupatadine were also evaluated. Methods: This prospective, non-interventional,
observational, multicenter study included 2,838 adults aged over 18 years. The diagnosis of
moderate to severe allergic rhinitis was confirmed. Patients were assessed with validated
scales at baseline and after 6 weeks of treatment with rupatadine (10 mg, once daily).
Results: All outcome parameters improved significantly: mini-rhinoconjunctivitis quality of
life questionnaire (mini-RQLQ, p <0.001), total 5-symptom score (T5SS) severity (p <0.001),
visual analog scale (VAS) of symptom severity (p <0.001), and the allergic rhinitis and its
impact on asthma (ARIA) severity classification (p <0.001). Compliance was very good in
72.2% of patients, and only a few minor adverse effects were reported. The therapeutic
responses, evaluated by the patients, were complete relief in 21% and strong relief in 62%.
Conclusion: This study, which included a wide cohort of allergic-rhinitis patients, confirmed
the clinical benefit of rupatadine when prescribed in clinical practice, even for the most
severe symptoms, including nasal congestion.

Main Rupatadine References 1.2. Urticaria
Rupatadine in the treatment of chronic idiopathic urticaria: a double-blind,
randomized, placebo-controlled multicentre study.
Gimenez Arnau A, Pujol RM, Ianosi S, Kaszuba A, Malbran A, Poop G, Donado E, Pérez I,
Izquierdo I, Arnaiz E. Allergy 2007; 62 (5): 539-546.
Background: Chronic urticaria is one of the most common and disturbing cutaneous
condition. The treatment of chronic idiopathic urticaria (CIU) is still a challenge.
Antihistamines are recommended as first-line treatment. Rupatadine is a new potent
nonsedative anti-H1. Objective: To study rupatadine efficacy and safety for moderate to
severe CIU treatment. Methods: This randomized, double-blind, placebo-controlled,
parallel-group, multicentre, study was designed to assess primarily mean pruritus score
(MPS) reduction with rupatadine, 10 and 20 mg, administered once daily for 4 weeks. Three
hundred and thirty-three patients with active episodes of moderate-to-severe CIU were
included. Results: A 57.5% (P < 0.005) and 63.3% (P = 0.0001) significative MPS reduction
from baseline, was observed at week 4 with 10 and 20 mg rupatadine, respectively,
compared with placebo (44.9%). Both doses of rupatadine were not significantly different at
any time point, with respect to their effects on pruritus severity, number of wheals and total
symptoms scores. Rupatadine 10 mg had an overall better adverse event profile.
Conclusion: Rupatadine 10 mg is a fast, long-acting, efficacious and safe treatment option
for the management of patients with moderate-to-severe CIU.
Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a
randomised, double-blind, placebo-controlled study.
Dubertret L, Zalupca L, Cristodoulo T, Benea V, Medina I, Fantin S, Lahfa M, Pérez I,
Izquierdo I, Arnaiz E. Eur J Dermatol 2007; 17 (3): 223-228.
This randomised, double-blind, placebo-controlled, parallel-group, international, dose-
ranging study investigated the effect of treatment with rupatadine 5, 10 and 20 mg once daily
for 4 weeks on symptoms and interference with daily activities and sleep in 12-65 years-old
patients with moderate-to-severe chronic idiopathic urticaria (CIU). Rupatadine 10 and 20
mg significantly reduced pruritus severity by 62.05% and 71.87% respectively, from
baseline, over a period of 4 weeks compared to reduction with placebo by 46.59% (p < 0.05).
Linear trends were noted for reductions in mean number of wheals and interference with
daily activities and sleep with rupatadine 10 and 20 mg over the 4-week treatment period.
The two most frequently reported AEs were somnolence (2.90% for placebo, 4.29% for 5
mg-, 5.41% for 10 mg- and 21.43% for 20 mg-rupatadine-treated group) and headache
(4.35% for placebo, 2.86% for 5 mg-, 4.05% for 10 mg- and 4.29% for 20 mg-rupatadine-
treated group). These findings suggest that rupatadine 10 and 20 mg is a fast-acting,
efficacious and safe treatment for the management of patients with moderate-to-severe CIU.
Rupatadine decreased pruritus severity, in a dose- and time-dependent manner.
Main Rupatadine References Fast onset of action of Rupatadine 10- and 20 mg in the reduction of pruritus in
patients suffering from chronic urticaria.
Giménez Arnau A, Ianosi S, Kaszuba A, Zalupca L, Cristodoulo T, Pérez I, Arnaiz E 16th
Congress of the European Academy of Dermatology and Venereology (EADV). Vienna
(Austria), May 16-20 2007.
Aims: To evaluate at which time point did rupatadine 10 and 20 mg effectively relieves
pruritus following the first dose, in the treatment of moderate to severe
Chronic Urticaria or Chronic Idiopathic Urticaria (CIU). Methods: The pooled data from two
randomised, double-blind, placebo-controlled, 4-week multicentre studies were used for this
analyses. The first was a dose-ranging study comparing the efficacy and safety of
rupatadine 5mg, 10mg and 20 mg once daily in 248 CIU patients randomised to one of the
active arms or placebo. The second study compared the efficacy of rupatadine 10 mg and
20mg once daily with placebo in 334 CIU patients. Patients were included in the studies if
they had CIU, i.e. pruritus,episodes of hives of characteristic wheal and flare appearance,
occurring regularly (at least three times a week for a period of at least 6 weeks during the
previous 3 months), without an identifiable aethiology. Results: A 37.8% (p<0.01) and
42.17% (p<0.001) significative percentarges pruritus score reduction from baseline, was
observed after 12 hours drug intake) with 10 and 20 mg rupatadine respectively compared
with placebo (24.32%). A clear difference between 10- and 20 mg versus placebo was
observed (39.74% and p<0.01; 45.32 and p<0.001, respectively) after 24h treatment,
showing that rupatadine, at both dosages effectively relieved CIU symptoms after the first
dosage. This effect was maintained after 7 days of treatment and throughout the study
period (4-weeks). Conclusion: Rupatadine 10- and 20 mg shows a very fast onset of action
in reducing pruritus in patients with an active episode of CIU.
Fast onset of action of rupatadine in the reduction of pruritus in patients suffering
from chronic urticaria : pooled analysis
Gimenez-Arnau A; Donado E; Arnaiz E; Pérez I; Izquierdo I Allergy 2007; 62 Suppl 83:306
Abstract 848 XXVI Congress of the European Academy of Allergology and Clinical
Immunology (EAACI 2007). Göteborg (Sweden), June 9-13 2007.
Rationale: The roles of histamine and PAF (platelet activating factor) as important and
complementary mediators involved in the skin of patients with atopic dermatis and chronic
urticaria. It seems reasonable that a dual-blochage of histamine and PAF receptors may
provide special advantage over other classic antihistamines. Aims: To evaluate at which
time point did rupatadine 10- and 20 mg, a new histamine H1 receptor and PAF antagonist,
in the treatment of moderate to severe Chronic Idiopathic Urticaria (CIU). Methods: The
pooled data from two randomised, double-blind, placebo-controlled, 4-week multicentre
studies were used for this analyses. The first was a dose-ranging study comparing the
efficacy and safety of rupatadine 5-, 10-and 20 mg once daily or placebo in 248 CIU patients.
The second study compared the efficacy of rupatadine 10- and 20mg once daily with placebo
in 334 CIU patients. In both trials, patients were included if they had CIU, i.e. pruritus,
episodes of hives of characteristic wheal and flare appearance, occurring regularly (at least
three times a week for a period of at least 6 weeks during the previous 3 months), without
an identifiable aethiology. Results: A 37.8% (p<0.01) and 42. 2% (p<0.001) significative
percentarges pruritus score reduction from baseline, was observed after 12 hours drug
intake) with 10- and 20 mg rupatadine respectively compared with placebo (24.3%). A clear
difference between 10- and 20 mg versusplacebo was observed (39.7% and p<0.01; 45.3
and p<0.001, respectively) after 24h treatment, showing that rupatadine, at both dosages
effectively relieved CIU symptoms after the first dosage. This effect was maintained after 7
Main Rupatadine References days of treatment and throughout the study period (4-weeks). Conclusion: Rupatadine
shows a very fast onset of action after first administration in reducing pruritus in patients with
an active episode of moderatesevere CIU.
The use of a responder analysis to identify clinically meaningful differences in
chronic urticaria patients following placebo- controlled treatment with rupatadine 10
and 20 mg.
Giménez-Arnau A, Izquierdo I, Maurer M. J Eur Acad Dermatol Venereol 2009; 23(9): 1088-
91
Background According to the EAACI/GA(2)LEN/EDF guidelines for urticaria management,
modern non-sedating H1-antihistamines are the first-line symptomatic treatment for chronic
urticaria. Two previous randomized clinical trials demonstrated rupatadine efficacy and
safety in chronic urticaria treatment. However, a responder analysis to identify clinically
meaningful differences in patients with chronic urticaria has not yet been performed.
Methods This analysis includes the pooled data from two randomized, double-blind,
placebo-controlled, multicenter studies in which chronic urticaria patients were treated with
rupatadine at different doses. Responder rates were defined as the percentage of patients
after 4 weeks of treatment who exhibited a reduction of symptoms by at least 50% or 75%
as compared to baseline. The variables analysed were as follows: Mean Pruritus Score
(MPS), Mean Number of Wheals (MNW), and Mean Urticaria Activity Score (UAS). Results
A total of 538 patients were included. This responder analysis, using different response
levels, shows that the efficacy of rupatadine 10 mg and 20 mg is significantly better as
compared to placebo in the treatment of chronic urticaria patients. Notably, treatment with
rupatadine 20 mg daily resulted in a higher percentage of patients with response of 75%
symptom reduction or better than rupatadine 10 mg. Conclusion Our results support the
use of higher than standard doses of non sedating antihistamines in chronic urticaria. We
strongly recommend performing and reporting responder analyses for established and new
drugs used by patients with chronic urticaria.
Rupatadine and its effects on symptom control, stimulation time, and temperature
thresholds in patients with acquired cold urticaria.
Metz M, Scholz E, Ferran M, Izquierdo I, Giménez-Arnau A, Maurer M. Ann Allergy Asthma
Immunol 2010; 104: 86–92.
Background: Patients with acquired cold urticaria (ACU) show itchy wheals during cold
exposure. This disturbing condition involves histamine and platelet-activating factor in its
pathogenesis. Rupatadine is a dual antagonist of both histamine and platelet-activating
factor. OBJECTIVE: To assess rupatadine efficacy in preventing reactions to cold challenge
in patients with ACU. Methods: A crossover, randomized, double-blind, placebo-controlled
study in which 21 patients with ACU received rupatadine, 20 mg/d, or placebo for 1 week
each is presented. The main outcome was the critical stimulation time threshold (CSTT)
determined by ice cube challenge. Secondary outcomes included CSTT and the critical
temperature threshold assessed by a cold provocation device (TempTest 3.0), as well as
scores for wheal reactions, pruritus, burning sensations, and subjective complaints after cold
challenge. Results: After rupatadine treatment, 11 (52%) of 21 patients exhibited a complete
response (ie, no urticaria lesions after ice cube provocation). A significant improvement in
CSTT compared with placebo was observed after ice cube and TempTest 3.0 challenge (P
= .03 and P = .004, respectively). A significant reduction of critical temperature threshold (P
Main Rupatadine References < .001) and reduced scores for cold provocation-induced wheal reactions (P = .01), pruritus
(P = .005), burning sensation (P = .03), and subjective complaints (P = .03) after rupatadine
treatment were also found. Mild fatigue (n = 4), somnolence (n = 1), and moderate headache
(n = 1) were reported during active treatment. Conclusion: Rupatadine, 20 mg/d, shows
high efficacy and is well tolerated in the treatment of ACU symptoms.
Rupatadine and levocetirizine in chronic idiopathic urticaria: a comparative study of
efficacy and safety.
Maiti R, Jaida J, Raghavendra B, Goud P, Ahmed I, Palani A. J Drugs Dermatol. 2011 Dec
1;10(12):1444-50.
Background: Chronic Idiopathic Urticaria is difficult to treat due to its persistent debilitating
symptoms. New generation anti-histaminics are first line treatment for this condition. The
aim of this study is to compare efficacy and safety of rupatadine and levocetirizine in chronic
idiopathic urticaria. Methods: A randomized, single blinded, single-centred, parallel group
outdoor based clinical study was conducted in 70 patients of CIU to compare the two drugs.
After initial clinical assessment and baseline investigations, rupatadine was prescribed to 35
patients and levocetirizine to another 35 patients for 4 weeks. At follow-up, the patients were
re-evaluated and then compared using different statistical tools. Main outcome measures
were DC eosinophil, Absolute Eosinophil Count (AEC), serum IgE, Total Symptom Score,
Aerius Quality of Life Questionnaire score, and Global efficacy score. Results: Rupatadine
significantly improved patients' clinical condition including symptom score from baseline to
day 28. In rupatadine group, there was 27.9 percent decrease (P=0.027) in DC eosinophil,
35.6 percent decrease (P=0.036) in AEC, 15.3 percent decrease (P=0.024) in serum IgE,
28.2 percent decrease (P=0.02) in Total Symptom Scoring, and 27.3 percent decrease
(P=0.006) in Aerius Quality of Life Questionnaire score. Global efficacy score of rupatadine
was found to be significantly greater (P=0.009) than levocetirizine. The overall incidence of
adverse drug reactions was also found to be less in rupatadine group. Conclusion:
Rupatadine is a better choice in CIU in comparison to levocetirizine due to better efficacy
and safety profile.
Temperature Thresholds in Assessment of the Clinical Course of Acquired Cold
Contact Urticaria: A Prospective Observational One year Study
M. Estela MARTINEZ-ESCALA, Laia CURTO-BARREDO, Lluïsa CARNERO, Ramon M.
PUJOL and Ana M. GIMENEZ-ARNAU Acta Derm Venereol 2015; 95: 278–282
Cold contact urticaria is the second most common subtype of physical urticaria. Cold
stimulation standardized tests are mandatory to confirm the diagnosis. The aim of this study
is to define the utility of determining thresholds (critical time and temperature) in assessment
of the clinical course of typical acquired cold contact urticaria. Nineteen adult patients (10
women and 9 men; mean age 45 years) were included in the study and the diagnosis was
confirmed with the ice-cube test and TempTest® 3.0. Patients were treated continuously for
one year with 20 mg/day rupatadine (anti-H1). Thresholds measurements were made before
and after treatment. Improvements in temperature and critical time thresholds were found in
the study sample, demonstrating the efficacy of continuous treatment with rupatadine. In
most cases association with a clinical improvement was found. We propose an algorithm for
the management of acquired cold contact urticaria based on these results
Main Rupatadine References 1.3. Others – Allergy by mosquito bites

Treatment of mosquito-bite allergy with rupatadine.
Karppinen A, Brummer Korvenkontio H, Reunala T. Allergy 2008; 63 (Suppl 88): 82
(Abs184). XXVIIth Congress of the European Academy of Allergology and Clinical
Immunology (EAACI). Barcelona (Spain), June 7-11 2008.
This double-blind, placebo-controlled, crossover study was performed with rupatadine and
matched placebo in 30 mosquito-bite-sensitive adults. Rupatadine reduced the size of bite
reaction and the accompanying pruritus. There was no difference in the adverse events
under rupatadine and placebo. This study in mosquito-bite-sensitive adults shows that
prophylactically given rupatadine is an effective treatment for the mosquito-bite whealing
and accompanying pruritus. (conference abstract: 27th Congress of the European Academy
of Allergology and Clinical Immunology, Barcelona, Spain, 07/06/2008-11 /06/2008).
Methods: A double-blind, placebo-controlled, crossover study was performed with
rupatadine 10 mg and matched placebo in 30 mosquito-bite- sensitive adults (mean age 37
yr). The subjects had suffered from harmful mosquito bite reactions for a mean of 15 yr.
Either rupatadine or placebo was taken at 8.00 hr for 4 days, followed by a 5-day washout
period and then alternative treatment was given for 4 days. On day 3, in both drug periods,
the subjects received 2 Aedes aegypti mosquito-bites on the forearm. The size of 2 15-mm
bite lesions and intensity of accompanying pruritus were measured. Results: 26 Subjects
were analyzed for the efficacy. The size of the 15-mm bite reaction was under placebo 106
sq.mm and rupatadine 55 sq.mm. This decrease (48%) was significant. The accompanying
pruritus decreased from 60 (VAS; median) under placebo to 47.5 under rupatadine, which
also was a significant difference. There was no significant difference in the adverse events
under rupatadine and placebo.
Rupatadine 10 mg in the treatment of immediate mosquito-bite allergy.
Karppinen A, Brummer-Korvenkontio H, Reunala T, Izquierdo I. J Eur Acad Dermatol
Venereol. 2012 Jul;26(7):919-22.
Background People frequently experience wealing and delayed papules from mosquito
bites. Wealing is mediated by antisaliva IgE antibodies and histamine. Rupatadine is a new
antihistamine effective in allergic rhinitis and urticaria, but the effect on mosquito-bite allergy
is not known. Objective? To determine the effectiveness of rupatadine in inmediate
mosquito-bite allergy-confirmed adult patients. Methods A double-blind, placebo-controlled,
cross-over study was performed with rupatadine 10mg and matched placebo in 30
mosquito-bite-sensitive adults. The mean age was 37years and the subjects had suffered
from harmful mosquito bites for a mean of 15 years. Either rupatadine or placebo was taken
at 08:00 am for 4 days, followed by a 5 day wash out period and then alternative treatment
was given for 4?days. On day 3, in both drug periods the subjects received two Aedes
aegypti mosquito-bites on the forearm. The size of lesions and intensity of pruritus [visual
analogue scale (VAS)] were measured after 15 min bite reaction. Results Twenty-six
subjects were analysed for efficacy. The size of the 15 min bite reaction under placebo was
of 106 mm (2) and under rupatadine, of 55 mm(2) . This is a significant decrease (48%; P =
0.0003). The accompanying pruritus decreased from 60 (VAS; median) under placebo to
47.5 under rupatadine, which also is a significant (P = 0.019) difference. There was no
significant (P = 0.263) difference in adverse events under rupatadine and placebo.
Conclusion The present placebo-controlled study in mosquito-bite-sensitive adults shows
that rupatadine 10 mg prophylactically given is an effective treatment for the mosquito-bite
wealing and skin pruritus.
Main Rupatadine References 2. Children

2.1. Allergic Rhinitis

Rupatadine in children aged 6-11 years with allergic rhinitis: a proof of concept
evaluation by a 4 weeks treatment follow-up study. Rupatadine oral solution, in
children aged 6-11 with allergic rhinitis: a proof of concept evaluation and 4 weeks
treatment follow-up efficacy and safety study.
Izquierdo I, Cranswick N, McCreanor J, Antonijoan R, Gich I, Barbanoj MJ. Pediatr Allergy
Immunol 2009; 20 (Suppl. 20): 2. Abstracts of the EAACI Pediatric Allergy and Asthma
Meeting. Venice (Italy), Novembrer 12-14 2009. 3 – Poster Symposium.

Rupatadine oral solution in children with persistent allergic rhinitis: A randomized,
double-blind, placebo-controlled study.
Potter P, Maspero JF, Vermeulen J, Barkai L, Németh I, Baillieau RA, Garde JM, Giralt J,
Doménech A, Izquierdo I, Nieto A. Pediatr Allergy Immunol. 2013; 24(3) 144-50.
Background: Allergic rhinitis (AR) is one of the most common chronic diseases in childhood.
No large, multicentre clinical trials in children with persistent allergic rhinitis (PER) have
previously been performed. Rupatadine, a newer second-generation antihistamine, effective
and safe in adults, is a promising treatment for children with AR. The aim of the present
study was to evaluate the efficacy and safety of a new rupatadine oral solution in children
aged 6-11 yr with PER. Methods: A multicenter, randomized, double-blind, placebo-
controlled study was carried out worldwide. Patients between 6 and 11 yr with a diagnosis
of PER according to ARIA criteria were randomized to receive either rupatadine oral solution
(1 mg/ml) or placebo over 6 wk. The primary efficacy end-point was the change from
baseline of the total nasal symptoms score (T4SS) after 4 wk of treatment. Results: A total
of 360 patients were randomized to rupatadine (n = 180) or placebo (n = 180) treatment.
Rupatadine showed statistically significant differences vs. placebo for the T4SS reduction
both at 4 (-2.5 ± 1.9 vs. -3.1 ± 2.1; p = 0.018) and 6 wk (-2.7 ± 1.9 vs. -3.3 ± 2.1; p = 0.048).
Rupatadine also showed a statistically better improvement in the children's quality of life
compared with placebo. Adverse reactions were rare and non-serious in both treatment
groups. No QTc or laboratory test abnormalities were reported. Conclusions: Rupatadine
oral solution (1 mg/ml) was significantly more effective than placebo in reducing nasal
symptoms at 4 and 6 wk and was well tolerated overall. This is the first large clinical report
on the efficacy of an H1 receptor antagonist in children with PER in both symptoms and
quality of life.
Main Rupatadine References 2.2. Urticaria

Rupatadine is effective in the treatment of chronic spontaneous urticaria in children
aged 2–11 years.
Paul Potter, Essack Mitha, László Barkai, Györgyi Mezei, Eva Santamaría, Iñaki Izquierdo,
Marcus Maurer. Pediatric Allergy and Immunology 27 (2016) 55–61 2015 John Wiley & Sons
A/S.
Background: Recommendations in current guidelines for the treatment of chronic
spontaneous urticaria (CSU) in infants and children are mostly based on extrapolation of
data obtained in adults. This study reports the efficacy and safety of rupatadine, a modern
H1 and PAF antagonist recently authorized in Europe for children with allergic rhinitis and
CSU. Methods: A double-blind, randomized, parallel-group, multicentre, placebo-controlled
compared study to desloratadine was carried out in children aged 2–11 years with CSU,
with or without angio-edema. Patients received either rupatadine (1 mg/ml), or desloratadine
(0.5 mg/ml) or placebo once daily over 6 weeks. A modified 7-day cumulative Urticaria
Activity Score (UAS7) was employed as the primary end-point. Results: The absolute
change of UAS7 at 42 days showed statistically significant differences between active
treatments vs. placebo (-5.5 ± 7.5 placebo, -11.8 ± 8.7 rupatadine and -10.6 ± 9.6
desloratadine; p < 0.001) and without differences between antihistamines compounds.
There was a 55.8% decrease for rupatadine followed by desloratadine (-48.4%) and placebo
(-30.3%). Rupatadine but not desloratadine was statistically superior to placebo in reduction
of pruritus (-57%). Active treatments also showed a statistically better improvement in
children's quality of life compared to placebo. Adverse events were uncommon and non-
serious in both active groups. Conclusion: Rupatadine is effective and well tolerated in the
relief of urticaria symptoms, improving quality of life over 6 weeks in children with CSU. This
is the first study using a modified UAS to assess severity and efficacy outcome in CSU in
children.
Main Rupatadine References Clinical Safety

1. General
Safety of rupatadine administered over a period of 1 year in the treatment of persistent
allergic rhinitis: a multicentre, open-label study in Spain.
Valero A, de la Torre F, Castillo JA, Rivas P, del Cuvillo A, Antepara I, Borja J, Donado E,
Mola O, Izquierdo I Drug Saf 2009; 32(1): 33-42
Background: Rupatadine (Rupafin), a novel antihistamine approved recently in Europe for
the treatment of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged>or=12
years, has been shown to be highly efficacious, and as safe and well tolerated as other
commonly employed antihistamines in the treatment of allergic disease. There are, however,
few data on the long-term safety of these antihistamines derived in accordance with the
clinical safety recommendations of the European Agency for the Evaluation of Medicinal
Products (EMEA) and the International Conference on Harmonisation (ICH) of Technical
Requirements for Registration of Pharmaceuticals for Human Use Guideline. OBJECTIVE:
To assess the safety and tolerability of treatment with rupatadine 10 mg/day for 12 months
in subjects with persistent AR (PER). Methods: A multicentre, open-label, phase IV study
in patients recruited from 33 centres in Spain, from September 2002 to November 2005. The
study enrolled 324 male and female patients (aged 12-70 years) with a medical history of
PER for at least 12 months and a documented positive skin-prick test to an appropriate
allergen. On 4 of the 7 days prior to start of treatment, the patients were required to have a
minimum total nasal symptom score (TNSS (for sneezing, rhinorrhoea, nasal obstruction
/congestion and nasal itching)) of >or=5. Of the 324 eligible patients starting treatment, 120
needed to be treated for more than 6 months and were followed up until the end of 12
months. All patients received rupatadine 10 mg/day and were allowed to continue their
normal concomitant medication for all conditions, other than rhinitis, for up to 6 or 12 months.
Safety was assessed by means of adverse events (AEs) reported by patients or detected
by investigators, scheduled centralized ECG with special attention to Bazzet corrected QT
interval (QTcB) and standard laboratory investigations. Results: Assessment of treatment
compliance rates indicated 90% and 83% of patients to be compliant during the 1-6 months
and 1-12 months treatment periods, respectively, with compliance rates>80% being
associated with the majority of the study population reporting at least one AE. Overall, 74.1%
and 65.8% of the patients reported at least one AE during the 1-6 months and 1-12 months
treatment periods, respectively, compared with 20.4% and 10.8% of patients reporting at
least one treatment-related AE during these periods. Disorders of the nervous system and
respiratory thoracic and mediastinal system, in particular headache, somnolence and
catarrh, were the three most common AEs reported by >5% of the patients during both
treatment periods. Detailed ECG assessments demonstrated no clinically relevant abnormal
ECG findings, nor any QTcB increases >60 msec or QTcB values>470 msec for any patient
at any time during treatment. Serious AEs were reported in seven patients, of whom six were
considered as unlikely to be related to rupatadine treatment, whereas one involving
increased blood enzyme levels was considered as possibly related to rupatadine treatment.
Conclusion: This study confirmed the good long-term safety and tolerability of rupatadine
at the therapeutic dose of 10 mg/day in patients with PER.
Main Rupatadine References 2. Cardiac Safety
Cardiac safety of rupatadine according to the new ICH guideline: a "thorough QT/QTc
study".
Donado E, García O, Pérez I, Barbanoj MJ, Antonijoan R, Peña J, Solans A, Izquierdo I,
Morganroth J. XXV Congress of the European Academy of Allergology and Clinical
Immunology (EAACI 2006). Vienna (Austria), June 10-14 2006. Abstract Book: 216 (Abs
760).
Background: A delay in cardiac repolarization, measured by a prolongation of QTc interval,
increases the risk of torsade de pointes, an arrhythmia that can degenerate into a fatal
ventricular fibrillation, as reported previously by some antihistamines such as terfenadine or
astemizole. Objective: We aimed to evaluate the effects of rupatadine, a new once-daily
non-sedating H1-antihistamine with platelet activating factor (PAF) antagonist activity, on
the QTc interval, according to the recommendations of EMEA and ICH Guidelines (ICH
E14): a "Thorough QT/QTc study" Methods: This randomized, blinded (volunteers and ECG
analysis), parallel, placebo and moxifloxacin controlled clinical trial was conducted in 160
healthy volunteers (gender balanced) randomized in four treatment groups: rupatadine
therapeutic dose: 10mg/day or supratherapeutic dose: 100mg/day (RU 100), placebo or
moxifloxacin 400 mg/day. RU was dosed to steady state. A centralized ECG lab was used
to evaluate the ECG digital date: 3 ECGs around each of 13 scheduled time points, after
single dose and again after steady state. The primary analysis was based on individual
subject corrected QT (QTcI) prolongation. Treatment effects (change from baseline) were
assessed using the largest time-matched mean difference on QTcI between the drug and
placebo. Per ICH E14, the study was considered negative if the upper bound of the 95%
one sided confidence interval for the largest time-matched mean effect of the drug on the
QTc excludes 10 ms. Outlier analyses were performed to complete the cardiac safety profile
of rupatadine. Results: The validity of the trial was demonstrated by the fact that
moxifloxacin, the positive control group, demonstrated the expected change in QTc duration.
The ECG data for rupatadine at both 10 and 100 mg showed no signal of any effects on the
ECG. There was no gender effect, pharmacodynamic-kinetic relationship of rupatadine and
main metabolites, or imbalance in outliers, which also confirmed the lack of any signal of RU
especially on QTc duration. No serious or unexpected adverse events were recorded.
Conclusions: This thorough ECG trial has demonstrated that rupatadine, up to 10 times
therapeutic dose, does not have any proarrhythmic potential and hence raises no cardiac
safety concerns for this novel antihistamine.
Heart Rhythm Disturbances Associated With Rupatadine: A Case Series From the
Spanish and Portuguese Pharmacovigilance Systems.
Carvajal A, Macias D, Salado I, Sainz M, Ortega S, Campo C, Garcia del Pozo J, Martin
Arias L, Velasco A, Gonçalves S, Pombal R, Carmona R. Clin Pharmacol Ther 2009; 85(5):
481-4.
We searched the Spanish and Portuguese pharmacovigilance databases for spontaneous
case reports of heart rhythm disturbances associated with rupatadine and other new H1
antihistamines. Five cases were found involving patients treated with rupatadine (13.9% of
all reports relating to this drug). In all five cases, the reaction started after exposure and
resolved when the drug was discontinued. In two cases, rupatadine was the only medication
being taken by the patient, and no other condition that could explain the heart rhythm
disturbances was diagnosed. The reporting odds ratio was 3.2 (95% confidence interval,
Main Rupatadine References 1.0-10.5). The reporting rate was 2 cases per 100,000 patients treated per year (95%
confidence interval, 0.4-6.0). These results suggest a causal relationship between
rupatadine and heart rhythm disturbances.
No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results
from a 'thorough QT/QTc study' performed according to ICH guidelines.
Donado E, Izquierdo I, Pérez I, García O, Antonijoan RM, Gich I, Solans A, Peña J,
Morganroth J, Barbanoj MJ. Br J Clin Pharmacol 2010; 69(4):401-10.
AIMS: To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on
cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according
to International Conference on Harmonization guidelines. Methods: This was a randomized
(gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10
and 100 mg day(-1), and placebo were administered single-blind for 5 days, whilst
moxifloxacin 400 mg day(-1) was given on days 1 and 5 in open-label fashion. ECGs were
recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment
days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were
analysed independently. The primary analysis of QTc was based on individually corrected
QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean
difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A
negative 'thorough QT/QTc study' is one where the main variable is around < or =5 ms, with
a one-sided 95% confidence interval that excludes an effect >10 ms. Results: The validity
of the trial was confirmed by the fact that the moxifloxacin-positive control group produced
the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both
10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated
administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender
effects or clinically relevant changes in ECG waveform outliers were observed. No deaths
or serious or unexpected adverse events were reported. Conclusions: This 'thorough
QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had
no proarrhythmic potential and raised no concerns regarding its cardiac safety.


Main Rupatadine References 3. CNS Effects
Central and peripheral evaluation of rupatadine, a new antihistamine/platelet
activating factor antagonist, at different doses in healthy volunteers.
Barbanoj MJ, Garcia-Gea C, Morte A, Izquierdo I, Pérez I, Jane F. Neuropsychobiology.
2004; 50 (4): 311-21.
AIMS: To assess peripheral anti-H1 and central nervous system (CNS) activity of single
increasing doses of rupatidine fumarate (RU), a new antihistamine/platelet-activating factor
antagonist compound, in comparison with hydroxyzine and placebo. Methods: Eighteen
healthy young subjects of both sexes took part in a crossover, randomised, double-blind,
placebo-controlled study. Treatments tested were: RU 10, 20, 40 and 80 mg and
hydroxyzine 25 mg, as a positive standard. Before and several times after drug intake,
peripheral anti-H1 activity was appraised by the skin reactivity to intradermal injection of
histamine. CNS effects were also obtained by objective tests of psychomotor performance
and subjective mood scales. Results: All active treatments showed a significant reduction
of the wheal and flare reaction in relation to placebo, RU displaying a potent dose-dependent
inhibition pattern. The global nonparametric Friedman test to changes from placebo in 15
objective variables from psychomotor performance showed a significant impairment of
similar magnitude after hydroxyzine 25 mg (p = 0.01) and RU 80 mg (p = 0.02), but this was
slower in development and recovery after the latter. After RU 40 mg, a smaller impairment
was also obtained (p = 0.04). Activity (p = 0.01) and drowsiness (p = 0.02) scales showed
significant changes, the subjects feeling less active and more drowsy after all active
treatments. Conclusion: RU presents a potent dose-dependent peripheral anti-H1 activity,
displaying psychomotor impairment activity only at the highest dose (80 mg), while
therapeutically relevant lower doses (10 and 20 mg) were similar to placebo.
Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine,
hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers.
Barbanoj MJ, Garcia-Gea C, Antonijoan R, Izquierdo I, Donado E, Pérez I, Solans A,
Jane F. Hum Psychopharmacol Clin Exp 2006; 21 (1): 13-26.
INTRODUCTION: The Central Nervous System (CNS) impairment induced by moderate
alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously.
Rupatadine (RUP) is a new H (1)-antihistamine which also inhibits platelet activating factor
(PAF) release in inflammatory reactions. OBJECTIVE: The main aim of the study was to
assess the effects of ALC 0.8 g/Kg on RUP (10 mg and 20 mg) CNS effects. An evaluation
of alcohol and RUP pharmacokinetics was also attained. Methods: Eighteen healthy young
volunteers of both sexes participated in a phase I, randomised, crossover, double-blind,
placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo
(PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25 mg (HYD), (d)
cetirizine 10 mg (CET), (e) RUP 10 mg or (f) RUP 20 mg. At baseline and several times
thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills,
nystagmus, temporal estimation, critical-flicker-fusion frequency, 'd2' cancellation, simple
reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness,
clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and
extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures
to each variable together with a multivariate non-parametric approach were applied. Plasma
concentrations of alcohol, and of RUP and its metabolites, were quantified by validated
immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all
Main Rupatadine References compounds were analysed by means of model-independent methods. Results: The
combination of alcohol with HYD, CET and RUP 20 mg produced more cognitive and
psychomotor impairment as compared to alcohol alone, being the combination of alcohol
and HYD the one which induced the greatest deterioration. The combination of alcohol and
RUP 10 mg could not be differentiated from ALC alone. Subjective self-reports reflect effects
on metacognition after the combination of alcohol with HYD and CET i.e. the increased
objective impairment observed was not subjectively perceived by the subjects. No significant
differences were obtained when comparing alcohol plasma concentrations assessed after
the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20 mg with
a higher exposition to both metabolites assayed. Conclusions: Present results showed that
single oral doses of rupatadine 10 mg in combination with alcohol do not produce more
cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in
combination with alcohol, may induce cognitive and psychomotor deterioration as
hydroxyzine and cetirizine at therapeutic doses.
Lack of effects between rupatadine 10 mg and placebo on actual driving performance
of healthy volunteers.
Vuurman E, Theunissen E, van Oers A, van Leeuwen C, Jolles J. Hum Psychopharmacol
Clin Exp 2007; 22 (5): 289-97. 27
Introduction: Rupatadine fumarate is a potent, selective, histamine H(1)-receptor
antagonist and PAF inhibitor with demonstrated efficacy for the relief of allergic rhinitis.
Rupatadine does not easily cross the blood-brain barrier and is believed to be non-sedating
at therapeutic doses. Consequently, rupatadine should show no impairment on car driving.
OBJECTIVE: This study compared the acute effects of rupatadine, relative to placebo and
hydroxyzine (as an active control), on healthy subjects' driving performance. Methods:
Twenty subjects received a single dose of rupatadine 10 mg, hydroxyzine 50 mg, or placebo
in each period of this randomized, double-blind, three-way crossover study. Two hours
postdosing, subjects operated a specially instrumented vehicle in tests designed to measure
their driving ability. Before and after the driving tests ratings of sedation were recorded.
Results: There was no significant difference between rupatadine and placebo in the primary
outcome variable: standard deviation of lateral position (SDLP); however, hydroxyzine
treatment significantly increased SDLP (p < 0.001 for both comparisons). Objective
(Stanford sleepiness scale) and subjective sedation ratings (Visual Analogue Scales)
showed similar results: subjects reported negative effects after hydroxyzine but not after
rupatadine. Conclusion: Rupatadine 10 mg is not sedating and does not impair driving
performance.
Rupatadine does not potentiate the depressant CNS effects of lorazepam:
randomized, double-blind, crossover, repeated dose, placebo-controlled study (p ).
García-Gea C, Ballester MR, Martínez J, Antonijoan RM, Donado E, Izquierdo I, Barbanoj
MJ Br J Clin Pharmacol 2010 ,69(6): 663-74.
Although one defining characteristic of second generation H-1-antihistamines is their lack of
CNS effects, it has been proved that some compounds of this group are not devoid of such
effects.center dot There is evidence that second generation H-1-antihistamine compounds
without relevant CNS effects at therapeutic doses could increase the behavioural
impairment produced by sedating drugs when both are taken concomitantly.center dot The
evaluation of possible drug interactions is crucial, especially when both compounds could
Main Rupatadine References have CNS effects, due to the possible consequences at the patient safety level.WHAT THIS
STUDY ADDS The study demonstrates the lack of CNS effects after repeated administration
at therapeutic doses of the unique second generation H-1-antihistamine with anti-PAF
activity.center dot The study demonstrates the lack of interaction between repeated
administration of rupatadine 10 mg and a single oral dose of lorazepam 2 mg.center dot The
study presents a useful design to evaluate the interaction between two compounds saving
time and the exposure of the volunteers to medication. AIM The main objective was to
assess whether benzodiazepine intake when rupatadine plasma concentrations were at
steady-state would increase the CNS depressant effects. Rupatadine is a new H-1-
antihistamine which also inhibits platelet activating factor (PAF) release and has been shown
to be clinically effective at doses of 10 mg. Methods Sixteen healthy young volunteers took
part in a crossover,randomized, double-blind, placebo controlled trial comprising two
experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as
single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to
a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS
effects were evaluated on these days by seven objective tests of psychomotor performance
and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug
intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2
mg and rupatadine 10 mg + lorazepam 2 mg. Results Significant CNS effects, either
impairment of psychomotor performance or subjective sedation, were observed when
lorazepam was administered, either alone or in combination with steady state concentrations
of rupatadine. No significant differences were found between these two conditions. In
addition, rupatadine was not different from placebo. All treatments were well tolerated.
Conclusion Repeated doses of rupatadine (10 mg orally) did not enhance the CNS
depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor
tasks or in subjective evaluations.


4. Drug Interactions
Influence of food on the oral bioavailability of rupatadine tablets in healthy
volunteers: a single-dose, randomized, open-label, two-way crossover study.
Solans A, Carbó M, Peña J, Nadal T, Izquierdo I, Merlos M. Clin Ther 2007; 29 (5): 900-8.
BACKGROUND: Rupatadine is an oral active antihistamine for the management of
diseases with allergic inflammatory conditions, such as perennial and seasonal rhinitis and
chronic idiopathic urticaria. Oral rupatadine has been approved for the treatment of allergic
rhinitis and chronic urticaria in adults and adolescents in several European countries.
OBJECTIVE: The purpose of this study was to describe the effect of the concomitant intake
of food on the pharmacokinetic profile and bioavailability of a single dose of rupatadine.
Methods: This was a single-dose, randomized, open-label, 2-way crossover study in which
healthy male and female volunteers received a single, 20-mg oral dose of rupatadine under
fed and fasting conditions. Blood samples were collected and plasma concentrations of
rupatadine and its active metabolites desloratadine and 3-hydroxydesloratadine were
determined by liquid chromatography tandem mass spectrometry. Tolerability was based on
the recording of adverse events (AEs), physical examinations, electrocardiograms, and
laboratory tolerability tests immediately before each treatment period and at the final visit of
the study. Results: Twenty-four volunteers (12 males; mean [SD] age, 25.4 [5.3] years
[range, 18-34 years]; mean [SD] weight, 71.2 [4.3] kg [range, 64-77 kg]; 12 females; mean
[SD] age, 26.8 [6.5] years [range, 18-38 years]; mean [SD] weight, 58.4 [6.8] kg, [range 50-
Main Rupatadine References 69 kg]) were enrolled and randomized with equal distribution of sex. A significant increase
in AUC from drug administration to the final quantifiable sample (AUC(0-t)) and AUC from
drug administration to infinity (AUC(0-infinity)) values of rupatadine was seen under fed
conditions without affecting C(max). The ratios (90% CI) of the mean log-transformed
AUC(0-t) and AUC(0-infinity) for rupatadine revealed a significant increase in AUC(0-t) (ratio
131%; 90% CI, 111%-154%) and AUC(0-infinity) (ratio 133%; 90% CI, 113%-156%),
whereas C(max) remained unaltered (ratio 97%; 90% CI, 80%-116%). Plasma
concentration-time profiles of desloratadine and 3-hydroxydesloratadine were similar with
and without food, and no differences were seen for AUC(0-t), AUC(0-infinity), or C(max).
Seven (28%) subjects reported > or =1 AE. All AEs were mild, resolved spontaneously, and
did not affect the outcome of the study. Conclusions: The results of this study indicate that
concomitant intake of food with a single 20-mg oral dose of rupatadine exhibits a significant
increase in rupatadine bioavailability. Despite the absence of bioequivalence, the drug was
well tolerated under fed and fasting conditions, and no major changes in severity and/or
prevalence of AEs were reported.
Pharmacokinetic and safety profile of rupatadine when coadministered with
azithromycin at steady-state levels: a randomized, open-label, two-way, crossover,
Phase I study.
Solans A, Izquierdo I, Donado E, Antonijoan R, Peña J, Nadal T, Carbo M, Merlos M,
Barbanoj M. Clin Ther 2008; 30 (9): 1639-50.
Background: Rupatadine is an oral active antihistamine and platelet- activating factor
antagonist indicated for the management of allergic rhinitis and chronic urticaria in Europe.
OBJECTIVE: The purpose of this study was to describe the effect of the concomitant
administration of azithromycin and rupatadine on the pharmacokinetics of rupatadine and
its metabolites after repeated doses. Methods: This was a multiple-dose, randomized,
open-label, 2-way, crossover, Phase I study in which healthy male and female volunteers
received rupatadine 10 mg once a day for 6 days either alone or with azithromycin 500 mg
on day 2 and 250 mg from day 3 to day 6. Treatments were administered after a fasting
period of 10 hours with 240 mL of water, and fasting conditions were kept until 3 hours
postmedication. A washout period of at least 21 days between the 2 active periods was
observed. Blood samples were collected and plasma concentrations of rupatadine and its
metabolites desloratadine and 3- hydroxydesloratadine were determined by liquid
chromatography tandem mass spectrometry. Tolerability was based on the recording of
adverse events (AEs), physical examination, electrocardiograms, and laboratory screen
controls at baseline and the final study visit. Results: Twenty-four healthy volunteers (15
males, 9 females; mean (SD) age, 25.67 (5.58) years; weight, 65.96 (8.57) kg) completed
the study. Except for maximum observed concentration during a dosing interval (Cmax, ss)
of 3-hydroxydesloratadine, on average, there were no statistically significant differences in
mean plasma concentrations in any of the main pharmacokinetic parameters of rupatadine,
desloratadine, and 3-hydroxydesloratadine when administered in combination with
azithromycin or alone. The Cmax, ss ratio was 111 (90% CI, 91-136) and area under the
plasma concentration-time curve during a dosing interval (AUC0-tau) ratio had a value of
103 (90% CI, 91-117). The corresponding ratios for the rupatadine metabolites were 109
(90% CI, 100-120) for Cmax, ss and 103 (90% CI, 96-110) for AUC0-tau for desloratadine
and 109 (90% CI, 103-115) for Cmax, ss and 104 (90% CI, 100-108) for AUC0-tau for 3-
hydroxydesloratadine. Point estimates for Cmax, ss ratios using paired data were 111% for
rupatadine, 109% for desloratadine, and 109% for 3-hydroxydesloratadine. The 90% CIs
were included in the interval 80% to 125% for desloratadine and 3-hydroxydesloratadine,
Main Rupatadine References whereas 90% CI for rupatadine was shifted to the right of the interval used for comparing
bioavailability of the drugs. A total of 5 subjects reported 9 AEs; 5 of these were thought to
be related to the drug administration and all were categorized as mild or moderate. The
reported AEs were somnolence (1/24 in the rupatadine group and 1 /24 in the rupatadine
plus azithromycin group), diarrhea (1/24 in the rupatadine plus azithromycin group), and
gastric discomfort (2/24 in the rupatadine plus azithromycin group). Four AEs were
considered not to be related (2 episodes of headache, 1 anemia, 1 cheilitis). All were
resolved spontaneously. No serious AEs were reported. Conclusions: The results of this
study in these healthy volunteers found no significant differences in pharmacokinetic
parameters other than Cmax, ss of 3-hydroxydesloratadine between rupatadine 10 mg
administered alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6.
The administration of rupatadine compared with rupatadine plus azithromycin met the
regulatory definition of bioequivalence in terms of exposure and rate parameters; however,
Cmax, ss of rupatadine was outside the conventional confidence interval.

Review Articles

Rupatadine: A new selective histamine H (1) receptor and platelet-activating factor
(PAF) antagonist. A review of pharmacological profile and clinical management of
allergic rhinitis.
Izquierdo I, Merlos M, Garcia-Rafanell J. Drugs Today 2003; 39 (6): 451-68.
Rupatadine is a new agent for the management of diseases with allergic inflammatory
conditions, such as seasonal and perennial rhinitis. The pharmacological profile of
rupatadine offers particular benefits in terms of a strong antagonist activity towards both
histamine H(1) receptors and platelet-activating factor (PAF) receptors. Rupatadine has a
rapid onset of action, and its long-lasting effect (> 24 h) permits once-daily dosing.
Rupatadine should not be used in combination with the cytochrome P450 inhibitors, such as
erythromycin or ketoconazole, due to an increase in AUC and C(max) for rupatadine,
although no clinically relevant adverse events have been reported. In addition, rupatadine,
at the recommended dose of 10 mg, has been shown to be free of sedative effects and not
to cause significant changes in the corrected QT interval in special populations, including
the elderly, nor when coadministered with erythromycin or ketoconazole. Preclinical data
have also shown that rupatadine and its main active metabolites did not interfere with cloned
human HERG channel and did not affect in vitro isolated dog Purkinje fibers at
concentrations at least 2000 times greater than those obtained with therapeutic doses in
humans. Rupatadine is clinically effective in relieving symptoms in patients with seasonal
and perennial allergic rhinitis. Newly published data on its efficacy and safety suggest that
this compound may improve the nasal and non-nasal symptoms in comparison to other
currently available second generation H(1) receptor antihistamines.
Main Rupatadine References Rupatadine: pharmacological profile and its use in the treatment of allergic disorders.
Picado C. Expert Opin Pharmacother 2006; 7 (14): 1989-2001.
Rupatadine is a once-daily, non-sedating, selective and long-acting new drug with a strong
antagonist activity towards both histamine H1 receptors and platelet-activating factor
receptors. The use of rupatadine is indicated in adult and adolescent patients (> 12 years of
age) suffering from intermittent and persistent allergic rhinitis and chronic idiopathic urticaria.
In the treatment of these diseases, rupatadine is at least as effective as ebastine, cetirizine,
loratadine and desloratadine. A very good safety profile of rupatadine has been evidenced
in various studies, including a long-term (1-yr) safety study. Rupatadine does not present
drug-drug interactions with azithromycin, fluoxetine and lorazepam, but should not be
administered concomitantly with known CYP3A4 inhibitors.
Rupatadine: a review of its use in the management of allergic disorders.
Keam SJ, Plosker GL. Drugs. 2007; 67 (3): 457-74.
Rupatadine (Rupafin((R)), Rinialer((R)), Rupax((R)), Alergoliber((R))) is a selective oral
histamine H(1)-receptor antagonist that has also been shown to have platelet-activating
factor (PAF) antagonist activity in vitro. It is indicated for use in seasonal allergic rhinitis
(SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU) in patients aged
>/=12 years.Clinical trials show that rupatadine is an effective and generally well tolerated
treatment for allergic rhinitis and CIU. It has a rapid onset of action and a prolonged duration
of activity. Importantly, it has no significant effect on cognition, psychomotor function or the
cardiovascular system. Once-daily rupatadine significantly improves allergic rhinitis
symptoms in patients with SAR, PAR or persistent allergic rhinitis (PER) compared with
placebo, and provides similar symptom control to that of loratadine, desloratadine, cetirizine
or ebastine. In patients with CIU, longer-term use of rupatadine improves CIU symptoms to
a greater extent than placebo. It is as well tolerated as other commonly used second-
generation H(1)-receptor antagonists. Thus, the introduction of rupatadine extends the
range of oral agents available for the treatment of allergic disorders, including allergic rhinitis
and CIU.
Rupatadine in allergic rhinitis and chronic urticaria.
Mullol J, Bousquet J, Bachert C, Canonica WG, Gimenez-Arnau A, Kowalski ML, Martí-
Guadaño E, Maurer M, Picado C, Scadding G, Van Cauwenberge P. Allergy 2008: 63
(Suppl. 87): 5-28.
Histamine is the primary mediator involved the pathophysiology of allergic rhinitis and
chronic urticaria, and this explains the prominent role that histamine
H1-receptor antagonists have in the treatment of these disorders. However, histamine is
clearly not the only mediator involved in the inflammatory cascade. There is an emerging
view that drugs which can inhibit a broader range of inflammatory processes may prove to
be more effective in providing symptomatic relief in both allergic rhinitis and chronic urticaria.
This is an important consideration of the Allergic Rhinitis and its Impact on Asthma (ARIA)
initiative which provides a scientific basis for defining what are the desirable properties of an
ideal antihistamine. In this review of rupatadine, a newer dual inhibitor of histamine H1- and
PAF-receptors, we evaluate the evidence for a mechanism of action which includes anti-
inflammatory effects in addition to a powerful inhibition of H1- and PAF-receptors. We
assess this in relation to the clinical efficacy (particularly the speed of onset of action) and
safety of rupatadine, and importantly its longer term utility in everyday life. In clinical trials,
Main Rupatadine References rupatadine has been shown to be an effective and well-tolerated treatment for allergic rhinitis
and chronic idiopathic urticaria (CIU). It has a fast onset of action, producing rapid
symptomatic relief, and it also has an extended duration of clinical activity which allows once-
daily administration. In comparative clinical trials rupatadine was shown to be at least as
effective as drugs such as loratadine, cetirizine, desloratadine and ebastine in reducing
allergic symptoms in adult/adolescent patients with seasonal, perennial or persistent allergic
rhinitis. Importantly, rupatadine demonstrated no adverse cardiovascular effects in
preclinical or extensive clinical testing, nor negative significant effects on cognition or
psychomotor performance (including a practical driving study). It improved the overall well-
being of patients with allergic rhinitis or CIU based on findings from quality of life
questionnaires and patient global rating scores in clinical trials. Thus, rupatadine is a
recently introduced dual inhibitor of histamine H1- and PAF-receptors, which has been
shown to be an effective and generally well-tolerated treatment for allergic rhinitis and
chronic urticaria. It possesses a broader profile of anti-inflammatory properties inhibiting
both inflammatory cells and a range of mediators involved in the early- and late-phase
inflammatory response, but the clinical relevance of these effects remain to be clarified.
Pharmacological profile, efficacy and safety of rupatadine in allergic rhinitis.
Katiyar S, Prakash S. Prim Care Respir J 2009; 18(2): 57-68.
Allergic rhinitis (AR) is a disease with high prevalence. In AR, exposure to airborne allergens
elicits an allergic response which involves epithelial accumulation of effector cells - e.g. mast
cells and basophils - and subsequent inflammation. During the early response in AR,
histamine has been found to be the most abundant mediator and it is associated with many
symptoms of this disease mediated through the histamine H1 receptor. Therefore, anti-
histamines have a role to play in the management of AR. However, the available
antihistamines have certain well-known side effects like sedation and potential pro-arrythmic
effects owing to their interactions with other drugs, as well as having poor or no effect on
platelet activating factor (PAF) which also plays an important role in AR. This article is a
qualitative systematic literature review on the pharmacological profile of rupatadine in order
to evaluate its safety and efficacy in AR as compared to other anti-histamines. Rupatadine
is a once-daily non-sedative, selective, long-acting H1 anti-histamine with antagonistic PAF
effects through its interaction with specific receptors. Rupatadine significantly improves
nasal symptoms in patients with AR. It has a good safety profile and is devoid of
arrythmogenic effects. These properties make rupatadine a suitable first line anti-histamine
for the treatment of AR.
Rupatadine for the treatment of allergic rhinitis and urticaria.
Metz M, Maurer M. Expert Rev Clin Immunol 2011; 7(1):15-20.
Allergies are a widespread group of diseases of civilization and most patients are still
undertreated. Since histamine is considered to be the most important mediator in allergies
such as allergic rhinitis and urticaria, the most commonly used drugs to treat these disorders
are antihistamines acting on the histamine 1 (H1) receptor. The currently available
antihistamines, however, have significant differences in their effects and safety profiles.
Furthermore, the Allergic Rhinitis and its Impact on Asthma initiative calls for additional
desirable properties of antihistamines. Here, we review the profile of rupatadine, a new dual
platelet-activating factor and H1-receptor antagonist that fulfils these criteria and therefore
offers an excellent option for the treatment of allergic diseases.
Main Rupatadine References Rupatadine: a novel second-generation antihistamine.
Grzelewska-Rzymowska I, Górski P Post Dermatol Alergol 2011, 28(6): 480–488
Histamine is the primary mediator involved in the pathogenesis of allergic rhinitis and chronic
idiopathic urticaria. Platelet-activating factor (PAF) is also a mediator which plays a key role
in the allergic reaction. Rupatadine is a novel antihistamine of the second generation
approved recently in Europe for the treatment of allergic rhinitis and chronic idiopathic
urticaria in patients aged = 12 years. Rupatadine shows both antihistamine and anti-PAF
effects because it presents hybrid molecule. One unit of this molecule has high affinity to H1
receptor, and the second one blocks the receptor for PAF. Relative potency of rupatadine is
much higher than that of other second generation antihistamines. Rupatadine also has anti-
allergic and anti-inflammatory activity. The drug blocked the release of histamine from mast
cells and other proinflammatory cytokines such as IL-5, IL-6, IL-8, TNF-α and GM-CSF from
activating human lymphocytes. It also blocked in vitro chemotaxis of human eosinophils to
eotaxin, and neutrophils to PAF and LTB4. Anti-allergic and anti-inflammatory activity of
rupatadine results from blocking NFκβ. Clinical trials have indicated that rupatadine is
significantly more effective than placebo and equally effective as other antihistamines of the
second generation. Rupatadine is well tolerated, and side effects are mild and moderate,
the most common ones were headache and somnolence. The drug is safe, not cardiotoxic,
does not impair psychomotor or cognitive activity.
Positioning of antihistamines in the Allergic Rhinitis and its Impact on Asthma (ARIA)
guidelines.
Mullol J Clin Exp Allergy Rev 2012, 12:17-26
Allergic rhinitis (AR) is a major health problem with high and ever-increasing prevalence
worldwide. At least one-fifth of adults in industrialized countries are estimated to have AR,
defined as nasal and eye symptoms that are sufficiently severe to have a substantial
negative impact on the quality of life (QoL). The former classification of AR comprised
seasonal AR (SAR) and perennial AR (PAR), which did not adequately reflect the
presentation and clinical course of the disease. The Allergic Rhinitis and its Impact on
Asthma (ARIA) classification is based on the duration of symptoms and the disease severity.
Both intermittent AR (IAR: symptoms _ 4 days/week or _ 4 consecutive weeks) and
persistent AR (PER: symptoms > 4 days/week and > 4 consecutive weeks) may be mild,
moderate, or severe based on the QOL impairment (sleep, daily activities/leisure, work
productivity/ school performance) and bothersome symptoms. Despite its disabling effects,
AR remains a condition where affected individuals do not seek appropriate treatment, are
undertreated and do not adhere well to treatment, which all lead tolow disease control and
high societal costs. The four pillars of AR treatment are allergen and pollutant avoidance,
patient education, pharmacotherapy and allergen-specific immunotherapy. Oral
antihistamines, together with intranasal corticosteroids and leucotriene antagonists,
constitute important pharmacological options for the treatment of AR at all levels of severity.
New secondgeneration antihistamines are H1-receptor antagonists with high efficacy (rapid
onset of action for AR symptoms, sometimes even on nasal congestion, improvement of
QoL and additional anti-allergic effects) and safety (low sedation rates). Although new
antihistamines have been studied and approved for SAR and PAR, only some of them have
been reported to show efficacy and safety for treatment of AR under the ARIA classification:
levocetirizine (high efficacy) and rupatadine (dual antihistamine and anti-PAF effects) for
PER, and desloratadine (high safety) for both IAR and PER.
Main Rupatadine References Rupatadine for allergic rhinoconjunctivitis: metanalysis of randomised, double-blind,
placebo-controlled studies.
Compalati E, Anthi R, Braido F, Canonica GW XXXI Cong Eur Acad Allergy Clin Immunol
(EAACI), Geneva, Switzerland, 16-20 June 2012 (Abtr 862)

Rupatadine (Rupafin), symptomatic treatment of allergic rhinitis and urticaria in
adults and adolescents
Bijl D. Geneesmiddelenbulletin 2012, 46(3) 29-31

Update on rupatadine in the management of allergic disorders
J. Mullol, J. Bousquet, C. Bachert, G. W. Canonica, A. Giménez-Arnau, M. L. Kowalski, F.
E. R. Simons, M. Maurer, D. Ryan & G. Scadding Allergy 70 Suppl. 100 (2015) 1–24 2014
John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
In a review of rupatadine published in 2008, the primary focus was on its role as an
antihistamine, with a thorough evaluation of its pharmacology and interaction with histamine
H1-receptors. At the time, however, evidence was already emerging of a broader
mechanism of action for rupatadine involving other mediators implicated in the inflammatory
cascade. Over the past few years, the role of platelet-activating factor (PAF) as a potent
mediator involved in the hypersensitivity-type allergic reaction has gained greater
recognition. Rupatadine has dual affinity for histamine H1-receptors and PAF receptors. In
view of the Al ergic Rhinitis and its Impact on Asthma group's call for oral antihistamines to
exhibit additive anti-allergic/anti-inflammatory properties, further exploration of rupatadine's
anti-PAF effects was a logical step forward. New studies have demonstrated that rupatadine
inhibits PAF effects in nasal airways and produces a greater reduction in nasal symptoms
than levocetirizine. A metaanalysis involving more than 2500 patients has consolidated the
clinical evidence for rupatadine in allergic rhinoconjunctivitis in adults and children (level of
evidence Ia, recommendation A). Other recent advances include observational studies of
rupatadine in everyday clinical practice situations and approval of a new formulation (1
mg/ml oral solution) for use in children. In this reappraisal, we revisit some key properties
and pivotal clinical studies of rupatadine and examine new clinical data in more detail
including studies that measured healthrelated quality of life and studies that investigated the
efficacy and safety of rupatadine in other indications such as acquired cold urticaria,
mosquito bite allergy and mastocytosis.

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