| The
Desloratadine Secret X FILE !!!
El expediente Secreto X de la Desloratadinal
(Aerius) !!!
Data-Medicos
Dermagic/Express No. 4-(2) X file)
15 June 2.002 / 15 Junio 2.002
COMENTARIO ESPANOL
=================
ESTE DOCUMENTO es definitivamente APOCALIPTICO, como ustedes recordaran
todavia se discute SI LA DESLORATADINA es REALMENTE EFECTIVA O NO.
Encontre en el LADO CLARO DE LA RED este documento NADA MAS Y NADA MENOS
QUE EN LA FDA, podra usted sacar una CONCLUSION MAS PRECISA AL RESPECTO.
Traduzco literalmente los ultimos parrafos:
" La vida-media larga de la desloratadina se ha citado como una facililidad en la habilidad de que
el producto proporcione 24 horas llenas de efecto en comparacion con la vida-media más corta de
la loratadina; sin embargo, DATOS COMPARATIVOS EN PACIENTES CON
ENFERMEDAD ALERGICA NO EXISTEN. Se ha sugerido que la desloratadina puede ofrecer
ventajas terapéuticas encima de otros antihistaminicos no-sedantes para el tratamiento de la SAR
(rinitis alergica estacional) debido a sus propiedades de descongestionante.
NO HAY NINGUN
ESTUDIO CABEZA- A CABEZA QUE PRUEBE ESTA DEMANDA (PROPIEDAD).
Además, aunque hay ensayos inéditos que demuestran efectos significantes en la descongestión
nasal con desloratadina contra el placebo, EN 3 de los 4 ESTUDIOS CLINICOS de
multiples-dosis que fueron conducidos por la FDA en el proceso de aprovacion, LA
DESLORATADINA FALLO EN DIFERENCIARSE DEL PLACEBO en EL SINTOMA
promedio DE "CONGESTION /PESADEZ" nasal. Una determinacion FINAL DE
POTENCIALES ventajas clinicas para la desloratadina en TERMINOS DE INICIO de efectos,
DURACION, EFICACIA, (especialmente promedios de congestion nasal), y CALIDAD DE
VIDA, comparado CON LOS VIEJOS ANTIHISTAMINICOS DE SEGUNDA
GENERACION, ESPERAN LA REALIZACION DE ESTUDIOS CLINICOS CABEZA-A
CABEZA de los productos
Basados en los datos disponibles NO HAY SIGNIFICANCIA CLINICA O factores de
DIFERENCIACION SEGUROS (CONFIABLES), entre LA DESLORATADINA Y LOS
OTROS ANTIHISTAMINICOS NO SEDANTES, QUE EVITARIAN el estatus OTC (venta
libre) para la desloratadina. A pesar de que la FDA ya de hecho ha aprobado el ESTATUS DE
LA LORATADINA como un antihistaminico OTC. Nosotros RECOMENDAMOS que la
desloratadina SEA CONVERTIDA A ESTATUS OTC (venta libre) tan pronto como la FDA
tenga (adquiera) adecuados estudios naturalisticos para su uso."
PUBLICADO 15-17 ABRIL 2002 POR la FDA.
UNA VEZ MAS queda demostrado que DERMAGIC/EXPRESS tiene y siempre tuvo la RAZON
con respecto a esta droga que TODAVIA NO TERMINA DE convencernos como antihistaminico
con respecto a los otros del mercado, como Fexofenadina y Cetirizina.y la misma loratadina, su
predecesor.
Al final les presento un testimonial (solo en español) de los efectos secundarios provocados por la
DESLORATADINA EN una paciente ASMATICA y alergica a la ASPIRINA, e-mail que me llego
procedente de REPUBLICA DOMINICANA.
En las referencias, los hechos
saludos
Dr Jose Lapenta R.
ENGLISH COMMENT
=================
THIS DOCUMENT is definitively APOCALYPTIC, as you they remembered
still discusses IF THE DESLORATADINE is REALLY EFFECTIVE OR NOT.
I found in the CLEAR SIDE OF THE NET this document ANYTHING MORE AND
ANYTHING LESS THAT IN THE FDA, you can reach a CONCLUSION MORE
SPECIFIES in this respect: I translate the last paragraphs literally:
"The long half-life of desloratadine has been cited as facilitating the products ability to
provide a full 24 hours of effect as compared to loratadine's shorter half-life; however,
comparative data in patients with allergic disease does not exist. It has been suggested that
desloratadine may offer therapeutic advantages over other non-sedating antihistamines for
treatment of SAR due to its decongestant properties. There are no head-to-head studies to
substantiate this claim. Furthermore, although there are unpublished trials demonstrating
significant effects on nasal congestion with desloratadine versus placebo, in 3 out of the 4
multiple-dose clinical trials that were conducted for the FDA approval process, desloratadine
failed to differentiate from placebo in the "nasal congestion/stuffiness" symptom score. Final
determination of potential clinical advantages for desloratadine in terms of onset of effect,
duration of effect, efficacy (especially nasal congestion scores), and quality of life compared to
older second generation antihistamines awaits the performance of head-to-head trials of the
products.
Based on the available data, there are no significant clinical or safety differentiating
factors between desloratadine and the other non-sedating anti-histamines that would preclude
OTC status for desloratadine. Since the FDA has already approved the status of loratadine
as an OTC antihistamine, we recommend that desloratadine be converted to OTC status as
soon as the FDA acquires adequate naturalistic studies for its use."
PUBLISHED 15-17 APRIL 2.002 BY THE FDA
Once MORE are demonstrated that DERMAGIC/EXPRESS has and always had the REASON
with regard to this drug that doesn't STILL FINISH convincing us as antihistaminic
with regard to the other of the market, as Fexofenadine and Cetirizine.and the same loratadine, its
predecessor.
At the end I present you a testimonial one (alone in Spanish) of the secondary effects caused by the
DESLORATADINE IN an ASTHMATIC and allergic patient to the ASPIRIN, e-mail that I arrive
me coming from THE DOMINICAN REPUBLIC.
In the references, the facts
greetings
Dr José Lapenta R.
==================================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
==================================================================
1.) THE DESLORATADINE SECRET X FILE
2.) Testimonial EFECTOS SECUNDARIOS desloratadina (Republica Dominicana)
==================================================================
==================================================================
1.) THE DESLORATADINE SECRET X FILE
==================================================================
SOURCE: THE FDA
--------------------------------------------------------------------------------
21555 Oxnard Street
[f 1 9 9 `?? y$ 16 fk 9 y-7 Robert Seidman
Woodland Hills, CA 91367
Chief harmacy Officer
Tel (818) 234-4817
Pharmacy Department
Fax (818) 234-3011
email [email protected]
I April 152002
Food and Drug Administration
Center for Drug Evaluation and Research (HFA-305)
ATTN: Jenny Butler
5630 Fishers Lane
Rockville, MD 20857
Dear Ms. Butler:
The undersigned submits this petition under the Code of Federal Regulations, Food and Drug Administration,
Title-2 1, section 10.30. This regulation provides that drugs limited to prescription use under an NDA can be
exempted from that limitation if the Food and Drug Administration ("FDA") determines the prescription
requirements to be unnecessary for the protection of public health. By receipt of this letter, I am petitioning the
FDA to make the following exemption:
On October 26,1999, Schering-Plough Corporation filed its U.S. application for desloratadine for the treatment
of seasonal allergic rhinitis (SAR). Desloratadine, according to the submission, is a non-sedating, long-acting
antihistamine. Desloratadine is a metabolite of loratadineK%ritin@, also a Schering-Plough Corporation
pharmaceutical. Desloratadine, according to Schering- Plough Corporation's submission to the FDA, has a
safety profile identical to loratadine/Claritin@ and is natured in direct to
consumer (DTC) advertising as having side effects similar to a sugar pill. The clinical trials to date
(including ones evaluating SAR, SAR with concomitant asthma, perennial allergic rhinitis, and chronic
idiopathic urticaria) have reported similar incidences of adverse effects between desloratadine and placebo.
Loratadine/Claritin@ has been previously discussed with the FDA under
Title-2 1, section 10.30 in the Petition docket number 98P-061 O/CP 1 and has been deemed approvable by the
FDA to convert to over-the-counter (OTC) status.
Patients are seeking greater ownership of their health care and often prefer to self medicate when feasible. Of all
the therapeutic classes of drugs available, the discrepancy in safety between the antihistamine and
antihistamine/decongestant combinations currently available OTC compared to desloratadine is most
pronounced. Based on the information provided by Schering-Plough
Corporation in their submission for desloratadine and supplemental information provided in this petition, please
expedite an OTC approval for desloratadine.
Currently, the FDA has authorized over 100 different antihistamine and antihistamine/decongestant
combinations for OTC sale. Although considered safe and effective by the FDA, all OTC antihistamine and
combination antihistamine/decongestant combinations are non-selective and have a more significant sedative
and anticholinergic effect than the three leading prescription antihistamine and antihistamine/decongestant
products. The safest antihistamine and antihistamine/decongestant combination medications are available only
by a prescription. Based on this information, desloratadine, the metabolite of loratadine/Claritin@, should also
be allowed to be available OTC.
The FDA approved loratadine/Claritin@ DTC advertising makes claims that the incidence of side effects with
loratadine/Claritin@ is no different than that obtained when ingesting a sugar pill. S@ce Schering-Plough
Corporation's NDA for desloratadine includes data illustrating a similar safety and efficacy profile foi that of
loratadine/Claritin@, it should be appropriate for desloratadine to be available OTC. Desloratidine (Aerius in
Canada) can already be purchased without a prescription in the Canadian provinces of Quebec and British
Columbia. It is our belief that Aerius (desloratadine) will be available OTC in all Canadian provinces in the near
future. Attached, please also find a review of the medical literature supporting the OTC status of desloratadine.
The undersigned certifies that, to the best lurowledge and belief of the undersigned, this amended Petition
includes all information and views on which the Petition relies, and that it includes representative data and
information known to the Petitioner which are
unfavorable to the Petition.
Chief Pharmacy Officer
WellPoint Health Networks
cc: Sandra Titus, FDA
Douglas Schur, WellPoint Health Networks
HMG Pharmacy Dep. Fax:1777855803 Rpr 17 2002 12:27 P.02
WELLPOINT
HEALTH NETWORKS*
(I ;j 1 6 "QZ j- ;`;7 1 -j I.." Ia; :;q
21555 Oxnard Str13at
Roben Seldman
Wwdland Hills, CA 91367
CRief Pharmacy Officer
Tel (818) 2w17
Pharmacy Department
Fax (818) 234-3011
email robertseldrnan 0 wellpoirkcom
April 17, 2002
Food and Drug Administration
ATTN: Jenny Butler
5630 Fishers Lane (HFA-305)
Rockville, MD 20857
Dear Ms. Butler:
Pursuant to Section 10.30, Section C of the Food and Drug Administration, we are
requesting an exception to provide an environmental assessment under Section 25.24
for the conversion of Clarinet (desloratadine) from prescription to over-the-counter
(OTC) status. Since Clarinex is a metabolite of a drug (ClaritinAoratadine) that is
already widely used, the conversion from prescription to OTC status will not result in the
introduction of any additional drug substances into the environment. We appreciate
your waiving of the environmental assessment provision for this important petition.
Respectfully,
e
WELLPOINT
HEALTHNETWORKS@
Non Sedating Antihistamines Literature Review
INTRODUCTION
The prevalence of allergic rhinitis has been increasing in the past two to three
decades.72 Approximately 9.3% to 30% of adults and up to 40% of children in the US have
allergic rhinitis.`173t74175
Allergic rhinitis is not a condition associated with mortality; however it
may impact an individual's quality of life, causing sleep and concentration disturbances, loss of
taste, and general discomfort. Allergic rhinitis has a significant cost impact, with an estimated
$I-$35 billion spent annually on the direct cost of disease and an additional $3.8~$5.2 billion in lost
productivity both at home and at work.73*76B77*78 Self management of allergic rhinitis through the use
of OTC antihistamines has already been approved by the FDA for a multitude of first generation
antihistamines and most recently for loratadine, a second generation antihistamine. The purpose of this
review is to provide clinical and safety data in support of the OTC status for desloratadine through an
amendment to petition docket 98P-061 OKPI.
Allergic rhinitis may be seasonal, caused by pollens, pollen fragments, or mold spores,
or perennial, due to allergens such as dust mites, mold, cockroaches, and animal dander.2 For both
seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), treatment is focused on alleviating the
nasal and ocular symptoms, including itching, tearing eyes, rhinorrhea, nasal itching and congestion,
sneezing, cough, headache, and throat irritation. Nonpharmacologic treatments-eliminating or reducing
allergen exposure, use of air conditioners and dehumidifiers, and saline nasal sprays-may be of some
benefit. However, for many patients, drug therapy is needed. Agents used in the treatment of allergic
rhinitis include topical and oral decongestants, intranasal corticosteroids, mast cell stabilizing agents,
topical antihistamines, and oral antihistamines. It should be mentioned that a number of recent analyses
have shown the nasal steroids to be superior to second generation antihistamines in the treatment of
allergic rhinitis and to be more cost effective.
Currently, there are four second generation antihistamines available in the US:
loratadine, fexofenadine, cetirizine, and desloratadine.
PHARMACOLOGY
All of the antihistamines exert their pharmacologic effects by competitively and
reversibly blocking the actions of histamine at the HI receptor.3 These agents do not inhibit the release of
histamine from mast cells, nor do they bind to histamine itself. HI receptors are found both centrally and
peripherally. First generation antihistamines (such as diphenhydramine, chlorpheniramine, and hydroxyzine)
are nonselective HI antagonists, binding
to central and peripheral HI receptors. This nonselectivity results in a higher incidence of
centrally-related adverse effects, including CNS depression or stimulation. The first generation
HI receptor antagonists also have stronger anticholinergic properties, exhibiting antiemetic
effects. In contrast, the second generation antihistamines (loratadine, desloratadine,
fexofenadine, and cetirizine) are selective for peripheral HI receptors, producing less centrally mediated
effects, such as sedation, with few anticholinergic effects. Of the second generation
antihistamines available, cetirizine is a piperazine derivative and is the active metabolite of
hydroxyzine, whereas fexofenadine, loratadine, and desloratadine are all piperidines.`*3V4
Table 1. Pharmacologic Effects of Second Generation Antihistamines3
Relative pharmacologic effects
Agent Sedative Antihistaminic Anticholinergic Antiemetic
Loratadine low to none moderate to high low to none N/A
Desloratadine low to none moderate to high low1 N/A
Fexofenadine low to none moderate to high low to none N/A
Cetirizine low to none moderate to high low to none N/A
DiphenhydramineL high low to moderate high moderate to high
N/A = not available; `Anticholinergic effects have been seen in some in vitro studies4'; * Included for
comparison of pharmacologic effects
In addition to their effect on histamine, a number of second generation agents appear to possess
anti-allergy effects that cannot be explained by blocking histamine receptors alone. The potential of these
agents to inhibit influx or activation of pro-inflammatory cells has been an area of intense research.36 A
large number of in vitro trials have been performed assessing the effect of various agents on mediator
release from inflammatory cells. While many of these studies use concentrations of drug that are hundreds
to thousands of times higher than those achievable in vivo, those using clinically achievable
concentrations found that available second generation antihistamines all possess some degree of
inhibitory effect on mediator release from cells.6936*38 In vivo studies have shown a multitude of
anti-inflammatory effects with these agents, perhaps most significantly with cetirizine and
desloratadine.36,54 However, the clinical relevance of these findings as well as the practical differences
between agents in not clear at this time.
The relative potency of the second generation antihistamines is generally determined by their ability to
block intradermal histamine-induced wheal and flare reactions in the skin, although this is not necessarily
predictive of clinical efficacy. A recent double-blind, cross-over trial compared cetirizine, ebastine,
epinastine, fexofenadine, terfenadine, and loratadine with placebo on this measure. The rank order of
inhibitory effect was cetirizine, epinastine, terfenadine, ebastine, fexofenadine, loratadine, and placebo.3g
Comparative intradermal studies with desloratadine are not available. Based on the in vitro evaluation of
IC-50, desloratadine appears to be 14- fold more potent than loratadine at blocking the HA receptor? An
in vitro study in the Chinese hamster ovary model characterized desloratadine as having a relative potency
of 201 compared to 3.7, 1.2, and 1 .O for cetirizine, loratadine, and fexofenadine, respectively.70
Although the intradermal histamine-induced wheal and flare model is often used to
address onset of action in addition to potency, the onset of action of antihistamines in SAR
does not always correlate with this measure. Better measures of in vivo onset of action may be obtained
using other methods such as nasal challenge in environmental exposure units? In
one unpublished, controlled pollen challenge study of 28 patients with SAR, desloratadine 5mg was found
to have an onset of action of about 28 minutes.41 The onset of effect was defined as the time to a 28%
drop in nasal and non-nasal symptom scores. However, based on a pooled analysis of four
placebo-controlled seasonal allergic rhinitis trials, a 5mg dose of desloratadine offered an onset of action
between 75 minutes and 2 hours!' When fexofenadine 60mg, 120mg, or 180mg was compared with
loratadine 1 Omg using the intradermal histamine-induced wheal and flare model, the onset of action of
fexofenadine was `2 hours and was significantly faster than loratadine (p~O.05).~' Another study using
the same model showed significant inhibitory effects for loratadine were delayed up to 4 hours compared
to cetirizine, terfenadine, astemizole, and chlorpheniramine? When evaluating the onset of effect in seasonal
allergic rhinitis, clinical trials have shown loratadine to have significant efficacy starting 30 minutes after
ingestion. An environmental challenge unit study of terfenadine, astemizole, cetirizine, and loratadine
revealed cetirizine to have the quickest onset of definitive relief (2 hours 6 minutes)
2
followed by terfenadine (2 hours 17 minutes), loratadine (2 hours 37 minutes), and astemizole (2 hours
55 minutes) using survival analysis (p=0.01).7g As can be seen, the variety of study designs and outcome
measures used in these trials makes inter-study comparisons difficult.
Ill. PHARMACOKINETICS
The basic pharmacokinetic properties of the second generation antihistamines are given in Table 2.
Following oral administration, loratadine is rapidly absorbed and undergoes
extensive first-pass metabolism to an active metabolite (desloratadine) which represents 1% to 2% of the
dose? The parent compound and its metabolite are then metabolized by cytochrome P4503A4 and possibly
the P4502D6 isoenzymes and are subsequently excreted in the urine (42%) and feces (40%). Food has no
significant effect on the bioavailability of loratadine.3 Desloratadine is the active major metabolite of
loratadine? Following absorption, desloratadine is metabolized to 3-hydroxydesloratadine by unidentified
enzymes, followed by
glucuronidation.4,7 Eighty-seven percent of a dose of desloratadine has been found in the urine and feces
as metabolites. In 7% of individuals, the metabolism of desloratadine is slow and systemic exposure to the
drug is higher than in those who are not slow metabolizers. The
frequency of slow metabolism is higher in some ethnic groups (e.g. 20% in blacks).4 The
bioavailability of desloratadine is unaffected by food.4s,4 The absolute bioavailability of
fexofenadine is unknown, however, the drug is rapidly absorbed.' Only about 5% of a total
dose is thought to be metabolized, with most of the drug excreted unchanged in the urine (80%) and
feces (11%). Administration with food does not have a clinically significant effect on the rate or extent of
absorption of fexofenadine.70 For cetirizine, most of the drug is eliminated unchanged in the urine (70%),
with only a small amount found as catabolites.g Although hepatic metabolism is not a major route of
elimination for cetirizine, studies suggest that a lower dose may be required in patients with hepatic
dysfunction, as well as for patients with renal impairment. Food also has no effect on the bioavailability of
cetirizine.7'
Table 2. Pharmacokinetics of Second Generation Antihistamines3p4
Agent Time to maximum Elimination Usual dosing interval % protein
CYP450
concentration Cr,,) half-life (t X) binding metabolism
Loratadine 1.3-2.5 h 8.4-28 h1 24 h 97%L Yes
Desloratadine 3h 27 h 24 h 82%-89% No
Fexofenadine 2.6 h 14.4 h 12 h (24 h for the SR preparation) 60-70% No
Cetirizine Ih 8.3 h 24 h 93% No
`For parent compound and active metabolite. *Not measured with plain tablets, only with D products.
IV. CLINICAL EFFICACY
Allergic Rhinitis A number of comparative trials have been conducted between the older
second generation antihistamines. Overall, similar efficacy has been seen between agents. In
general, these agents are most effective in providing relief from rhinorrhea, sneezing, and itching.
Their efficacy in relief of nasal congestion is more variable. Table 3 reviews selected comparative
trials between agents.
Table 3. Clinical Trials of Second Generation Antihistamines for Allergic
Rhinitis""*
Reference 1 # ptslduration 1 Regimen I Outcomes
Loratadine
Al-Muhaimeed 84 pts Loratadine 10mg or Mean nasal symptoms scores were & in
both groups and were similar between txs
1997 (1 wk) astemizole 1 Omg (except for runny nose scores, which favored
astemizole [p=.OO8]). The % of pts
daily rated as good or excellent by global assessment were ? with
astemizole (87% vs
62%) as were the % of pts who were sx-free (54% vs 39%);
however, statistical
analyses were not given.
Chervinsky 167 pts Loratadine IOmg or Both agents were effective in 4 total, nasal,
and nonnasal sxs scores from baseline
et al 1994 (8 wks) astemizole 1 Omg w/no sig diff between the 2 tx groups. Loratadine
was favored for improvements in
daily ocular symptoms (tearing and redness, pc.04). MD and pt
assessments indicated
earlier response w/loratadine, with improvements noted at 1
week. The 2 txs were
equivalent at later time points.
Day et al 1997 111 pts (Single Loratadine 1 Omg, Onset to time of relief was fastest
wicetirizine; however, the differences were not sig
dose following astemizole 1 Omg, between the active tx groups. The % of pts
w/clinically important relief was similar
allergen cetirizine 1 Omg, between the tx groups. Cetirizine was ranked highest
on global assessments for time
challenge) terfenadine 60mg, or to relief and relative efficacy.
olacebo
Crawford 14 pts (8 wks- Loratadine 1 Omg, Overall efficacy scores, patient-reported
symptoms, and pseudoephedrine use were
et al 1998 2 wk crossover terfenadine 120mg, similar between the tx groups. All 4 txs
improved sxs from baseline as assessed by
trial) astemizole 1 Omg, MD nasal-exam scores; however astemizole was rated
sig ? than loratadine (pc.05).
chlorpheniramine
16mg per day
Carlsen 76 pts Loratadine 1Omg or Both txs associated with sig ? from baseline in
sxs. 78% of loratadine- and 80% of
et al 1993 (4 wks) terfenadine 120mg terfenadine-treated pts were considered
responders. All 7 pts who did not respond to
per day terfenadine improved with loratadine, while only 419 pts
who did not respond to
loratadine responded to terfenadine.
Del Carpio 317 pts Loratadine 1 Omg, Both active txs were ? effective in improving
nasal and non-nasal allergy sx severity
et al 1989 (2 wks) Terfenadine 120mg, scores. However, only loratadine reached sig in
comparison to placebo at end of the
or placebo per day study. 58% of loratadine-tx and 51% of terfenadine-tx
pts had good or excellent
response to tx as compared to 27% of the placebo group
(pc.01).
Cetirizine
Lackey 1 311 pt 1 Cetirizine IOmg, At 1 week, cetirizine resulted in sig ? in total sx
scores as compared to terfenadine or
et al 1996 (2 wks) terfenadine 120mg, or placebo (p=.OOl); however no difference was seen
between the 3 groups at 2 wks
placebo daily
Renton 60 pts Cetirizine 10mg or Both txs were = effective in relieving sxs based
on investigator scores; however
et al 1991 (6 wks; 3 wk terfenadine 120mg cetirizine was more effective in relieving sxs of
rhinorrhea. There was no difference
crossover trial) daily in pt scored symptoms between the 2 treatments.
Lobaton 30 pts Cetirizine 10mg or Both cetirizine and astemizole were effective in
improving nasal sxs with no sig
et al 1990 (12 wks; 4 wk astemizole 1 Omg differences btx the 2 groups based on
investigators assessments. However, pt
crossover trial) dailv assessments rated improvements with cetirizine higher
(p=.OOOl).
Meltzer 279 pts Cetirizine 1 Omg, Cetirizine produced sig ? reductions in mean sx
complex scores during 3 of the4 time
et al 1996 (2 days) loratadine lOmg, or periods evaluated. However, changes with
loratadine similar to those seen with
placebo placebo. Total sx complex severity scores were sig better
with cetirizine at each time
period tested. The onset of action found to be faster with
cetirizine.
Fexofenadine
Van 688 pts Fexofenadine 120mg, 509 pts were included in the ITT analysis.
Fexofenadine and loratadine sig & mean
Cauwenberge (2 wks) loratadine lOmg, or scores for reflective (previous 24h) and
instantaneous (previous hour) total sx scores
2000 placebo daily (TSS; sneezing, rhinorrhea, itchy nose, palate, and/or
throat, itchy/watery/red eyes)
from baseline. Fexofenadine was sig better for sxs of nasal
congestion and itchy/
watery/red eyes. However, overall tx efficacy was similar
between the 3 grps, based
on MD and pt assessments. Although all 3 groups had sig ?
from baseline in quality
of life scores, fexofenadine had greatest ? compared to
loratadine and placebo.
Prenner 659 pts Fexofenadine 120mg At the end of 14 days, 389 pts were considered
responders (61% of loratadine grp,
2000 (30 days; or loratadine 1 Omg 57% of fexofenadine grp). Pts given loratadine
had a sig greater & in TSS compared
crossover after daily to fexofenadine (p=.O19). No difference was seen btx
the 2 groups based on
14 days for investigator assessment of sx severity. Among
nonresponders, 62.4% had complete,
nonresponders) marked, or moderate relief of sxs when switched to
loratadine, compared to 51.2%
when switched to fexofenadine (p=.OO5). Failure rates ? after the
switch to
fexofenadine than to loratadine (21.7% vs 10.6%, p=.Ol 1).
Howarth 842 pts Fexofenadine 120mg, All txs resulted in a & in reflective TSS from
baseline, with no sig differences seen
1999 (2 wks) fexofenadine 180mg, between the active tx groups. For individual
symptom scores and for instantaneous
cetirizine IOmg, or TSS, all 3 active txs were sig more effective than placebo.
placebo daily
4
Published studies of the efficacy of desloratadine are limited and there are no published trials
comparing it to other second generation agents. As part of the FDA approval process, the efficacy and
safety of desloratadine for SAR was evaluated in 4 multiple-dose studies. The primary endpoint of the
multiple-dose SAR studies was defined as the average prior 12-hour, "reflective" (i.e. symptom severity
was assessed over the prior 12 hours) AM/PM total symptom score. The total symptom score was the
sum of eight individual symptom scores---4 nasal (rhinorrhea, nasal stuffiness/congestion, nasal
itching, and sneezing) and 4 non-nasal (itching/burning eyes, tearing/watering eyes, redness of eyes,
itching of ears and palate). Results from the 4 multiple dose studies are provided below in Table 4.
One study (C98-225) failed to demonstrate a difference between desloratadine and placebo.
Table 4. Total Symptom Score AM/PM Prior 12-Hour Average for Days 2-15
Treatment Group Baseline Change from Baseline Placebo
Comparison
(N) (mean) (N) (mean) 1 % -value
Study C98-001 53
5.0 mg 172 I 14.2 172 -4.3 -28.0% co.01
Placebo 174 13.7 I 174 -2.5 -12.5% ---
Study C98-22358
5.0 mg 165 16.3 165 -4.6 -27.8% 0.03
Placebo 165 16.5 163 -3.5 -21.7% ---
Study C98-224"
5.0 mg 164 17.0 164 -5.1 -30.0% 0.02
Placebo 164 17.1 164 -3.8 -22.0% ---
Study C98-22558
5.0 mg 158 16.8 157 -4.2 1 -24.6% 1 0.41
Placebo 158 I 17.0 158 1 -3.8 [ -22.3% 1 ---
Individual symptom scores including nasal congestion/stuffiness, nasal discharge/
rhinorrhea, nasal itching, sneezing, itchy/burning eyes, tearing/watering eyes, redness of eyes,
and itching of ears/palate were collected as secondary endpoints in the 4 multiple-dose studies.
The results are presented in Table 5. Only one of the four studies (C98-001) demonstrated any
difference from placebo in the "nasal congestion/stuffiness" symptom score.
Table 5. Individual Nasal and Non-Nasal Symptom Scores AM/PM Prior 12-Hours for Days 2-15.
*p< 0.05 **p< 0.01 Bolded figures represent NON-statistical significance from placebo
(Mean change from baseline for 5.0mg dose. P values reflect comparison to placebo treatment.)
As part of the desloratadine development program, a trial was conducted where the
individual symptom of nasal congestion in patients with SAR was specified as the primary
endpoint.58 In this trial, desloratadine failed to differentiate from placebo in the reduction of
nasal congestion.
An unpublished study of the 24-hour efficacy of desloratadine 5mg daily evaluated 282
patients with SAR over 4 weeks. Researchers found the 24-hour TSS decreased by 16.5%
after the first dose versus 6.7% with placebo (~~0.05) and 28.1% from days 1 to 29 versus
20.9% with placebo (p<O.O5)?
Unlike the results presented earlier, a number of unpublished analyses of pooled data of
patients with SAR have revealed that desloratadine results in significant nasal decongestion
compared to placebo. The nasal decongestion efficacy was maintained over the duration of the
trials.56v57 A multicenter, double-blind, placebo-controlled trial evaluated the ability of desloratadine to
relieve symptoms of nasal congestion in 326 patients with SAR and mild-to-moderate asthma
symptoms.63 Patients were randomized to desloratadine 5mg daily or placebo for 4 weeks.
Compared to placebo, desloratadine improved the average AM/PM reflective congestion score by
26.8% over baseline (p=O.O14) at 4 weeks. Desloratadine 5mg daily was compared to placebo over
4 weeks in a randomized, double-blind trial of 331 patients with SAR and asthma.65 Significant
reductions in nasal congestion were noted with desloratadine after the first dose (-18.3% vs -10.1%
with placebo; p<O.Oll). Overall total symptom scores were significantly reduced with desloratadine
compared to placebo (p=O.OOl).
In one double-blind trial, 346 patients were randomly assigned to treatment with either
desloratadine 5mg or placebo once daily for 2 weeks. Patients rated symptoms of nasal congestion
or stuffiness twice daily, on a scale of 0 (none) to 3 (severe). Other symptoms of intermittent
allergic rhinitis-including rhinorrhea, nasal itching, sneezing, itching/burning or tearing/watering
eyes, eye redness, and ear or palate itching-were also assessed by the patients.23 Reductions in
morning and evening nasal congestion scores were significantly lower with desloratadine compared
to placebo (p<O.O5), beginning on day 2 of treatment. Total symptom scores also decreased from
baseline with desloratadine, with a significantly greater reduction than seen with placebo (p<O.Ol).
An unpublished retrospective literature evaluation of double-blind, placebo-controlled trials
of cetirizine, fexofenadine, and loratadine compared the reported effects of these agents on nasal
congestion to that of desloratadine 5mg daily.e4 Only trials that specifically reported the effects on
nasal congestion and used clinically approved drug doses were included. Placebo effects of the
agents were factored out and standardization of severity scores was performed. The pooling and
standardization of the desloratadine data resulted in a reduction in congestion of 0.1-0.19 units
from baseline. In trials of fexofenadine (60mg BID - 120mg QD), congestion was reduced by
0.064-0.088 units. Cetirizine (1 Omg QD) and loratadine (1 Omg QD) reduced congestion by 0.08
and 0.03-0.1 units, respectively. Statistical analyses of these reductions were not reported.
Asthma
The role of histamine in asthma is well established. Histamine has the potential to
cause smooth muscle contraction, mucus hypersecretion, mucosal edema, and bronchial
hyperresponsiveness in sensitive individuals. The additional anti-inflammatory effects make
them potential adjuncts to traditional asthma therapy.
Cetirizine 15mg daily for 14 days in 57 patients with pollen-associated asthma resulted in a
decrease in pulmonayO y m toms with a decrease in the use of beta-agonists and corticosteroids
compared to placebo. Another randomized, double-blind trial enrolling 43 subjects with grass
pollen-induced asthma evaluated the effects of cetirizine IOmg BID and terfenadine 60mg BID.
The results of the trial showed that cetirizine was significantly better than terfenadine at improving
nasal obstruction, dyspnea, morning peak flow, consumption of beta-agonists, and the efficacy
index on asthma (p~O.05).~' Other studies were unable to demonstrate a significant protective
effect with cetirizine on allergen-induced bronchospasm.82183 Cetirizine has also been shown to
significantly improve asthma symptoms, although not g:&6flow or FE&, in patients with
concomitant SAR and asthma in a number of studies. ' ' In a small number of patients,
loratadine did not have a significant effect on symptoms or peak flow either alone or as adjunctive
therapy.87*88 However, a larger more recent study using loratadine with pseudoephedrine found
that the combination significantly improved pulmonary function as well as rhinitis and asthma
symptoms.8g
A double-blind, placebo-controlled unpublished study of desloratadine in 278 patients
with concurrent SAR and mild asthma symptoms evaluated patients over 2 weeks of
treatment!' With desloratadine 5mg daily, the total asthma symptom score improved from
baseline (~~0.05 vs placebo). In addition, the use of inhaled beta-agonists was decreased from
baseline (p=O.O02 vs placebo). Another unpublished placebo-controlled trial evaluated
desloratadine 5mg daily in 604 patients with SAR and mild-to-moderate asthma over 4 weeks.`*
Compared to placebo, desloratadine significantly reduced the total asthma symptom score
(TASS) after the first dose (~~0.05). The reduction in TASS was maintained throughout the
study (p=O.O22). In addition, desloratadine significantly reduced the use of inhaled beta-
agonists over the duration of the study (p=O.O03).
Another area of research is the potential for these agents to prevent the progression to
allergic asthma from atopic dermatitis. A double-blind, placebo-controlled trial evaluated cetirizine
O.fimg/kg/day over 18 months in 800 children at risk of developing allergic asthma. This study
showed that in those sensitized to pollen or house dust mites, cetirizine halved the number of
children developing asthma.go
Chronic Idiopathic Urticaria
Although not the focus of this review, antihistamines are widely used in the treatment of
chronic idiopathic urticaria (CIU). The primary target of therapy for urticaria is relief of pruritis,
which is the most bothersome symptom for these patients. Although the first generation agents
may offer the fastest onset of action and the greatest potency, their problematic side effects have
resulted in a preference for the second generation products for this indication. It should be noted
that often doses that are twice the usual recommended dose for these products are required for
the treatment of CIU, which may result in some degree of sedation. Loratadine, fexofenadine, and
cetirizine all possess FDA-approved indications for the treatment of urticaria. Desloratadine is not
yet approved for this indication but a number of trials have been performed to investigate its
efficacy.
A double-blind, placebo-controlled trial of 190 patients with CIU currently in flare compared
desloratadine 5mg daily to placebo for 6 weeks? Significant improvement in the mean AM/PM
reflective pruritis score was seen (-45.2 vs -14.0%; p<O.OOl) within 36 hours of the first dose. The
mean reflective total symptom score was also significantly reduced with desloratadine after the
first dose (-41.6 vs -10.6; p<O.OOl). The reduction in the reflective pruritis score was maintained
for the duration of the study (p<O.OOl vs placebo) as was the total symptom score compared to
placebo (p<O.OOl). During the final week of the trial, the improvement in sleep with desloratadine
was 75% compared to 54% with placebo (~~0.03). Similar improvements were seen in daily
performance (78% with desloratadine vs 40% with placebo; p<O.OOl). A number of unpublished
trials have also shown desloratadine to significantly decrease individual symptoms (pruritis,
number of hives, size of largest hive), total symptoms scores, interference with sleep and daily
activities.66~67*68
Antihistamine/Decongestant Combinations
Three of the second generation antihistamines-loratadine, fexofenadine, and
cetirizine-are available in combination with a decongestant, pseudoephedrine. Currently, no
studies are available comparing these various antihistamine/decongestant combinations to each
other. Table 6 provides a brief overview of trial assessing efficacy with combination therapy.
Table 6. Second Generation Antihistamine/Decongestant Combinations24-26
Reference No Regimen Outcomes
pts/duration
Sussman 651 Fexofenadine 120mg, The combo therapy was sig better than
pseudoephedrine alone (pc.001) in 4 the
1999 (14-20 days) pseudoephedrine 250mg, or reflective TSS (minus nasal congestion scores);
however, there was no sig
Fexofenadine/ pseudo- difference btx combo and fexofenadine alone (p=. 1579).
For nasal congestion
ephedrine 120/250 mg daily scores, the combo was better than fexofenadine alone
(pc.005) but not better
than pseudoephedrine alone (p=.O59).
Kaiser 469 pts Loratadine/pseudo- Compared to placebo, both active txs resulted in sig
& from baseline in total
1998 (2 wks) ephedrine 5mg/l20mg 2X nasal (TNSS) and non-nasal (TnNSS) symptom
scores, and in TSS. Reductions
daily, loratadine/ in TNSS were similar between the 2 active txs, while the
lo/240 mg combination
pseudoephedrine was more effective in & TnNSS and TSS compared to the
5/120mg combination.
1 Omg/240mg 1 x daily, or Mean 4 in individual sx scores for rhinorrhea and nasal
stuffiness were sig &
placebo from baseline for the 2 active txs compared to placebo at study
endpoint.
Horak 24 pts Cetirizine/pseudo-ephedrine Following allergenic challenge, a single dose of
cetirizine/pseudoephedrine was
1998 (1 wk; 5mg/l20mg or sig ? than placebo in relieving sxs (nasal obstruction,
running/itching nose,
crossover placebo 2x daily sneezing), improving overall sx scores, and in overall
subjective sxs. Overall,
after 2 wks) objective parameters (nasal airflow, nasal secretions, nasal
patency) also
improved. After multiple dosing, similar results found w/active tx
resulting in sig
improvements in subjective and objective measures.
v. ADVERSE EFFECTS
Overall, the second generation antihistamines are well tolerated.`93V27 Their primary
advantage is their relative lack of sedation compared to first generation agents. However, it is
useful to review the problems associated with the measurement of sedation.36 Terms such as
sedation, drowsiness, or sleepiness are often thought of interchangeably, but are actually quite
different. Sedation means impairment of cognitive and psychomotor functioning and can be
measured objectively. Drowsiness is the increased likelihood of falling asleep and is a
subjective or objective measure depending on the means of measurement (subjective survey
versus EEG). An interesting phenomenon is that patients may be unaware of changes in levels
of cognitive and motor impairment. Therefore, significant disagreement may be seen in
objective and subjective measures of impairment. To further complicate matters, it is known
that allergic rhinitis itself leads to performance and learning impairment.37 As a result, studies
of sedation employing normal volunteers may not accurately represent actual use situations.
In addition to low sedation potential, these agents possess a relative lack of anticholinergic
effects as compared to the first generation products. Although cetirizine is considered a second
generation agent, it possesses a different sedation potential than other agents in the class.
Cetirizine, the active metabolite of the first generation antihistamine hydroxyzine, has been
described as a low-sedating, rather than non-sedating. The incidence of reported sedation or
somnolence with cetirizine has varied, ranging from 13.7% to 25% and may be dose-related.
Additionally, cetirizine has been reported to impair driving abilities in patients receiving the drug,
while these effects were not reported with loratadine. Overall, both objective and subjective
measures of sedation are conflicting for cetirizine and the lack of a standard approach to study
designs makes meta-analysis difficult.36 The sedative effects of cetirizine may be potentiated by
alcohol, producing more sedation than either the drug or alcohol alone.`13127 Sedative effects
appear
to be minimal with fexofenadine, even when the drug was combined with alcohol.
The most commonly reported adverse effects with the second generation agents are
headache, pharyngitis, dry mouth, and somnolence; however, the incidence of these effects
generally does not differ from placebo except for somnolence with cetirizine, which is double
the incidence seen in placebo groups.3 For desloratadine, the incidence of adverse effects
(including somnolence) with a 5mg dose was similar to that seen with placebo.4
Mann and colleagues conducted a post-marketing surveillance study to determine the
incidence of sedation with the non-sedating antihistamines.28 Data were collected on 4
antihistamines - cetirizine, fexofenadine, loratadine, and acrivastine. Of the 3 antihistamines
marketed in the US, cetirizine had the highest incidence of drowsiness or sedation (OR 3.53,
95% Cl 2.07 to 5.42) followed by loratadine (OR 1, as comparator), and fexofenadine (OR 0.63,
95% Cl 0.36 to 1 .I 1). No significant difference was seen in the risk of sedation or drowsiness
between loratadine and fexofenadine (p=O.l). The authors found no difference in the
occurrence of accidents or injury between the 4 agents.
Salmun and colleagues conducted a prospective, randomized, double-blind trial to
determine somnolence and motivation during the workday in patients taking antihistamines.*'
Sixty patients with allergic rhinitis were given either loratadine or cetirizine IOmg at 8AM daily for 7
days. Adverse effects, including somnolence and motivation, were graded 3 times daily using a
visual analog scale (1 =wide awake or fully motivated to 1 O=extremely somnolent or not motivated
at all) and recorded in an electronic diary. Somnolence scores were similar between the 2
treatment groups at baseline and at 8AM; however, at IOAM, noon, and 3PM, somnolence scores
were higher with cetirizine compared to loratadine (p=.OO8, p=.OOl, and p<.OOl , respectively).
Similar results were seen for motivation scores.
In 2 randomized, cross-over studies of a total of 44 healthy volunteers, desloratadine
7.5mg did not significantly effect wakefulness or psychomotor performance compared to
placebo? In the same studies, diphenhydramine 50mg decreased wakefulness and impaired
psychomotor performance significantly more than placebo or desloratadine (p<O.Ol). A
randomized, placebo controlled crossover study of 18 healthy volunteers evaluated driving
performance 2 and 3 hours after administration of desloratadine 5mg, diphenhydramine 50mg,
and pIacebo.45 Diphenhydramine significantly impaired brake reaction time (p=O.OOl vs
desloratadine) and the ability to maintain a steady lateral position (p<O.OOOl vs desloratadine and
placebo). Desloratadine did not differ from placebo on either of these measures.
Prolongation of the QT interval was reported with both astemizole and terfenadine and
ultimately led to the withdrawal of these products from the US market. QT prolongation has
subsequently been shown not to be a class effect of these agents and fexofenadine, loratadine,
and cetirizine appear to have a very low potential for cardiotoxicity.3" In 2 unpublished trials,
desloratadine at a dose of 45mgIday for 10 days showed no significant effect on the QT interval
in healthy voIunteers.42'43
VI. DRUG INTERACTIONS
As a class, antihistamines may interact with other drugs which cause CNS depression,
such as alcohol, benzodiazepines, analgesics, and antidepressants, potentiating the sedative
effects of antihistamines.3 However, such effects are less likely to be seen with the second
generation antihistamines, due to their lesser sedative effects. According to one placebo-
controlled randomized 4-way cross-over study in 25 healthy volunteers, desloratadine 7.5mg
did not potentiate the effects of alcohoL5'
The biggest concern regarding drug interactions with the second generation
antihistamines is related to the cytochrome P450 (CYP450) enzyme system. Two second
generation antihistamines-astemizole and terfenadine-were removed from the market due to
serious, life-threatening QT prolongation resulting from drug interactions involving the
cytochrome P450 enzyme system. To date, no significant cardiac effects have been reported
with the available second generation antihistamines. A recent study evaluated the
cardiovascular effects of fexofenadine in doses up to 240mg daily given in combination with
9
erythromycin or ketoconazole.30 No increased incidence of adverse effects or QT prolongation
were noted when fexofenadine was given in combination with these agents, although clinically
and statistically significant increases in the fexofenadine Cmax and AUC were seen (135% and
164%, respectively for ketoconazole; and, 82% and 109%, respectively for erythromycin).8 The
mechanism for this interaction appears to be either enhanced GI absorption or decreased
biliary excretion or GI secretion. Fexofenadine should also not be administered within 15
minutes of a magnesium and aluminum containing antacid, as the Cmax and AUC of
fexofenadine decrease by 43% and 41%, respectively.' Additionally, in healthy volunteer
studies assessing the drug and food interaction potential of fexofenadine and desloratadine, a
significant increase in serum concentrations of fexofenadine was seen with azithromycin and a
significant decrease was seen with grapefruit juice.4g15o No difference in the pharmacokinetics
of desloratadine was seen with co-administration of either agent. Serum concentrations of
loratadine are increased when administered concurrently with drugs that inhibit the CYP450
isoenzymes; erythromycin, ketoconazole, cimetidine.4'36 Although no adverse cardiac effects
have been reported, there is potential for a higher risk of sedation. Cetirizine is primarily
eliminated as unchanged drug in the urine and is unlikely to interact with CYP450 inhibitors or
inducers.g In fact, administration of cetirizine with erythromycin, azithromycin, or ketoconazole
has been shown to produce no discernable change in electrocardiographic findings.33q34*35
No
relevant interactions between desloratadine and erythromycin, fluoxetine, cimetidine, or
ketoconazole have been documented.7*47*48
VII. INDICATIONS/DOSING
The indications and recommended doses of the second generation antihistamines are
given in Tables 7.
Table 7. Indications and Dosing of Second Generation Antihistamines3B4931
Agent Indication Dosage form Usual dose
Loratadine Relief of nasal/non-nasal sxs of SAR and Claritin tablets, Adults and children (>6
y): IOmg once daily; Hepatic/
for idiopathic ut-ticaria in pts >6 YO. syrup renal function impaired: 1 Omg every
other day.
Loratadine For relief of symptoms of seasonal Claritin-D Adults and adolescents
(~12~): 1 tablet ever 12 h; Renal
w/pseudoephedrine allergic rhinitis. 12 hour function impaired: 1 tablet daily;
Contraindicated in pts
with hepatic dysfunction.
Claritin-D Adults and adolescents (>12y): 1 tablet daily;
Renal
24 hour function impaired: 1 tablet every other day;
contraindicated in pts with hepatic dysfunction.
Desloratadine For relief of nasal and non-nasal sxs of Clarinex Adults and adolescents
(>12 y): 5mg once daily;
SAR and PAR in ps 12 years and >. For tablets 5mg every other day should be
used in pts with hepatic
treatment of chronic idiopathic urticaria. dysfunction.
Fexofenadine For relief of sxs of SAR (sneezing, Allegra Adults and adolescents (>12
y): 60mg 2x daily or 180mg
rhinorrhea, itchy nose, palate and throat, capsules daily; 6Omg/day should be used
in pts with impaired renal
and itchy watery, and red eyes). For tx function. Children 6-l 1 years: 30mg
2x daily; 30mg/day
of uncomplicated skin manifestations of should be used in pts with
impaired renal function.
chronic idiopathic urticaria.
Fexofenadine For relief of symptoms of SAR. Allegra-D Adults & adolescent (>12y):
1 tablet 2x daily; 1 tablet/day
w/pseudoephedrine capsules should be used in pts w/impaired renal
function.
Cetirizine Relief of symptoms associated with Zyrtec tablets Adults and children (>6 y): 5
to 10mg once daily; Children
seasonal/perennial allergic rhinitis and and syrup 2-5 years: 2.5mg daily to max of
5mg daily or 2.5mg every
chronic idiopathic urticaria. 12 hrs. Hepaticirenal function impaired:
5mg lx daily for
adults & children >6 y. For children ~6 y with
hepatic/
renal impairment, use of cetirizine is not
recommended.
Cetirizine For relief of symptoms of seasonal or Zyrtec-D Adults and children (>12 y):
1 tablet every 12 hours.
w/pseudoephedrine perennial allergic rhinitis. Hepatic/renal function impaired: 1
tablet daily.
10
VIII. PHARMACOECONOMICS
A recent retrospective analysis of the costs associated with the use of second
generation antihistamines for allergic rhinitis included an evaluation of loratadine, fexofenadine,
cetirizine and nasal steroids.g' A total of 202,426 patients diagnosed with allergic rhinitis who
had at least one prescription claim for an allergic rhinitis therapy were identified. Seventy-one
percent of those patients had a claim for a second generation antihistamine. The most
common regimen was monotherapy with loratadine in 28% of patients. The next most common
regimen was combination therapy with loratadine and a nasal steroid in 20% of patients. Those
patients with the highest severity index, as determined by the number of co-morbid conditions,
were the most likely to receive combination therapy. The annual treatment charges for allergic
rhinitis included inpatient, outpatient, ancillary, emergency, and drug costs. The mean annual
treatment charge across all patients was $465.21. The greatest departmental cost was
pharmacy-related costs at an average of $236.02 per year. There were differences found in the
total costs among the regimens studied, with fexofenadine monotherapy or combination therapy
with nasal steroids being significantly less costly than loratadine or cetirizine based regimens;
however, the cost of the drug was the primary determinant of the total treatment costs.
IX. CONCLUSIONS
Overall, all of the second generation antihistamines appear to be effective in relieving
symptoms of allergic rhinitis, with little differences seen in efficacy. To date, none of the
currently available second generation agents have been reported to cause or be associated
with serious adverse events. Unlike earlier second generation agents, QTc prolongation does
not appear to be a concern with the currently available products.
Although there appears to be little difference in efficacy between agents, one large
study between fexofenadine and loratadine found fexofenadine to have a greater effect on
quality of life and on some allergy symptoms, such as itchy/watery/red eyes and nasal
congestion. Loratadine has an indication for pediatrics and is available in a liquid formulation.
It is also available as a rapidly disintegrating tablet. Fexofenadine is available for use in
pediatrics, but only as a tablet. A liquid formulation is in development but an availability date is
not known. Desloratadine is only available in a tablet formulation for children and adults 12
years of age and older. Development of a rapidly disintegrating tablet, a liquid, and a
combination with pseudoephedrine is underway.
Unlike the other available second generation antihistamines, loratadine does undergo
hepatic metabolism via the CYP450 enzyme system and is subject to drug interactions involving
3A4 inhibitors and inducers. Fexofenadine interacts with ketoconazole and erythromycin
resulting in increased concentrations of fexofenadine. As per the precautions section of the
package insert, there were no differences in adverse events or QTc intervals following
coadministration of erythromycin or ketoconazole. It also interacts with magnesium and
aluminum containing antacids and grapefruit juice resulting in a decrease in fexofenadine
concentrations. Cetirizine and desloratadine do not appear to have any significant drug
interactions.
As would be expected, addition of a nasal decongestant (pseudoephedrine) to any of
the second generation antihistamines improved symptoms of nasal stuffiness; however, no
difference was seen in other symptoms of allergic rhinitis in studies addressing combination
therapy.
11
The long half-life of desloratadine has been cited as facilitating the products
ability to provide a full 24 hours of effect as compared to loratadine's shorter
half-life; however, comparative data in patients with allergic disease does not exist.
It has been suggested that desloratadine may offer therapeutic advantages over
other non-sedating antihistamines for treatment of SAR due to its decongestant
properties. There are no head-to-head studies to substantiate this claim.
Furthermore, although there are unpublished trials demonstrating
significant effects on nasal congestion with desloratadine versus placebo, in 3 out of
the 4 multiple-dose clinical trials that were conducted for the FDA approval process,
desloratadine failed to differentiate from placebo in the "nasal congestion/stuffiness"
symptom score. Final determination of potential clinical advantages for desloratadine
in terms of onset of effect, duration of effect, efficacy (especially nasal congestion
scores), and quality of life compared to older second generation antihistamines awaits
the performance of head-to-head trials of the products.
Based on the available data, there are no significant clinical or safety
differentiating factors between desloratadine and the other non-sedating
anti-histamines that would preclude OTC status for desloratadine. Since the FDA
has already approved the status of loratadine as an OTC antihistamine, we
recommend that desloratadine be converted to OTC status as soon as the FDA
acquires adequate naturalistic studies for its use.
12
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2.) Testimonial EFECTOS SECUNDARIOS desloratadina (Republica Dominicana)
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DESLORATADINA:/ ENVIADO A DERMAGIC/EXPRESS dia 4/JUNIO / 2002
Estimados señores:
Deseo saber si hay contraindicación de este medicamento al 5mg para una
paciente- asmática y alergica a la aspirina. Deseo saber especificamente
si este medicamento tiene reacción cruzada con la aspirina ya que la
paciente al tomarla, se siente ademas de soñolienta, desesperada,
incómoda y el pasado domingo tuvo que acudir a un centro medico de
emergencia debido a que se sentia desvanecer con la presión muy baja, y
estaba casi inconsciente. Tambien reporta haber perdido el control y
memoria. Favor recomendar si debe suspender dicho tratamiento, ya que es
una persona de escazos recursos, y ya presenta un historial de 2-3
emergencias de cuidado intensivo - que recuperó su vida por asistencia
adecuada a tiempo.
Si me puede sugerir otro medicamento mejor que este se lo agradeceria,
antes le habia sugerido Claritine, pero le daba sueño, pero en todo caso
no le presento ningun otro sintoma adverso. Ella aparentemente se
aprieta o le dan ataques de asma al tener alergia respiratoria, y le
causa cosquilla en la trachea o pecho.
Muchas gracias por toda su ayuda.
Marie Anne Granata
Republica Dominicana
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DATA-MEDICOS/DERMAGIC-EXPRESS No 4-(2) X file) 15/06/2.002 DR. JOSE
LAPENTA R.
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