The Desloratadine X files / Expedientes X de la desloratadina

COMENTARIOS ESPAÑOL:
==========================
ESTE DOCUMENTO es definitivamente APOCALÍPTICO, como ustedes recordaran todavía se discute SI LA DESLORATADINA es REALMENTE EFECTIVA O NO.

Encontré en el LADO CLARO DE LA RED este documento NADA MAS Y NADA MENOS QUE EN LA FDA, y usted podrá usted sacar una CONCLUSIÓN MAS PRECISA AL RESPECTO. Traduzco literalmente los últimos párrafos:

" La vida-media larga de la DESLORATADINA se ha citado como una facilidad en la habilidad de que el producto proporcione 24 horas llenas de efecto en comparación con la vida-media más corta de la LORATADINA; sin embargo, DATOS COMPARATIVOS EN PACIENTES CON ENFERMEDAD ALÉRGICA NO EXISTEN.

"Se ha sugerido que la DESLORATADINA puede ofrecer ventajas terapéuticas encima de otros Antihistamínicos no-sedantes para el tratamiento de la SAR (Rinitis Alérgica Estacional), debido a sus propiedades de descongestionante".

"NO HAY NINGÚN ESTUDIO PEER TO PEER (Entre Iguales), QUE PRUEBE ESTA CARACTERÍSTICA (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 CLÍNICOS de múltiples-dosis que fueron conducidos por la FDA en el proceso de aprobación, LA DESLORATADINA FALLO EN DIFERENCIARSE DEL PLACEBO en EL SÍNTOMA promedio DE "CONGESTIÓN /PESADEZ nasal" .

Una determinación FINAL DE POTENCIALES ventajas clínicas para la DESLORATADINA en TÉRMINOS DE INICIO de efectos, DURACIÓN, EFICACIA, (especialmente promedios de congestión nasal), y CALIDAD DE VIDA, comparado CON LOS VIEJOS ANTIHISTAMÍNICOS DE SEGUNDA GENERACIÓN, ESPERAN LA REALIZACIÓN DE ESTUDIOS CLÍNICOS ENTRE IGUALES (PEER TO PEER P2P), de los productos.

Basados en los datos disponibles NO HAY SIGNIFICANCIA CLÍNICA O factores de DIFERENCIACION SEGUROS (CONFIABLES), entre LA DESLORATADINA Y LOS OTROS ANTIHISTAMÍNICOS NO SEDANTES, QUE EVITARÍAN 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 antihistamínico 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 RAZÓN con respecto a esta droga que TODAVÍA NO TERMINA DE convencernos como antihistamínico 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 ASMÁTICA y alérgica a la ASPIRINA, e-mail que me llego procedente de REPUBLICA DOMINICANA.

NOTA: Para hoy día, 2025, mas de 20 años después, la DESLORATADINA consiguió su venta Over The Counter (OTC), lo que significa de venta sin Récipe Medico, siendo comercializada a NIVEL MUNDIAL, y también en combinación con la MOLÉCULA MONTELUKAST, con el nombre de DESLER.

En las referencias, los hechos

saludos

Dr. José Lapenta R.

ENGLISH COMMENTS:
=====================
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 NOTHING MORE AND NOTHING LESS THAN THE FDA, you could 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 CETIRIZINEand 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.

NOTE: By today, 2025, more than 20 years later, DESLORATADINE was sold Over The Counter (OTC), which means without a Medical Prescription, being marketed WORLDWIDE, and also in combination with the MONTELUKAST MOLECULE, under the name DESLER.

In the references, the facts

greetings

Dr José Lapenta R.

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DERMAGIC/EXPRESS 4-(2)
================================================================
REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES
================================================================
1.) THE DESLORATADINE SECRET X FILE
2.) Testimonial EFECTOS SECUNDARIOS desloratadina (Republica Dominicana)
==============================================================
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1.) THE DESLORATADINE SECRET X FILE
==================================================================
SOURCE: THE FDA

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21555 Oxnard Street
Robert Seidman
Woodland Hills, CA 91367 hief harmacy Officer
Tel (818) 234-4817
Pharmacy Department
Fax (818) 234-3011
email [email protected]

April 15 2002

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,

WELLPOINT
HEALTHNETWORKS@

Non Sedating Antihistamines Literature Review

I. 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.

II.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)

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

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

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.

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.

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.

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40. Norman P, Dihlmann A, Rabasseda X. Desloratadine: a preclinical and clinical overview. Drugs Today 2001;37:215-27.

41. Horak F, Stubner P, Zieglmayer R, et al. Onset and duration of effects of multiple high doses of desloratadine [abstract 1 OOO]. Allergy 2000;55 (suppl 63):279.

42. Banfield C, Padhi D, Glue P, et al. Electrocardiographic effects of multiple high doses of desloratadine [abstract 11191. J Allergy Clin lmmunol2000;105 (1 pt 2):383.

43. Marino M, Glue P, Herron JM, et al. Lack of electrocardiographic effects of multiple high doses of desloratadine [abstract 9991. Allergy 2000;55 (suppl63):279.

44. Schatf MD, Kay G, Rikken G, et al. Desloratadine has no effect on wakefulness or psychomotor performance [abstract IOOI]. Allergy 2000; 55 (suppl 63):280.

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47. Brannan M, Affrime M, Cayen M. Effects of various cytochrome P450 inhibitors on the clearance of loratadine (L)/descarboethocyloratadine (DCL) and lack of effects of increased L and DCL plasma concentrations on QTc intervals [abstract]. Allergy 1997;52 (suppl 37):207.

48. Banfield C, Gupta S, Kantesaria B, et al. No drug interaction between fiuoxetine and desloratadine, a new nonsedating once-daily antihistamine [abstract 5291. J Allergy Clin lmmunol2001;107 (2 pt 2).

49. Gupta S, Banfield C, Lim J, et al. Unlike fexofenadine, the pharmacokinetics of desloratadine are minimally altered by co-administration with azithromycin [abstract 5241. J Allergy Clin lmmunol 2001;107 (2 pt 2).

50. Banfield C, Gupta S, Cayen M, et al. Grapefruit juice has no effect on the bioavailability of desloratadine, but reduces the Cmax and AUC of fexofenadine by 30% [abstract 601. Ann Allergy Asthma lmmunol2001; 86.

51. Rikken G, Scharf MB, Danzig MR, et al. Desloratadine and alcohol coadministration: no increase in impairment of performance over that induced by alcohol alone [abstract 9931. Allergy 2000;55 (suppl63):277.

52. Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin lmmunol 1997;99:S798-S806.

53. Meltzer EO, Prenner BM, Nayak A. Efficacy and tolerability of once-daily 5mg desloratadine, an Hl- receptor antagonist, in patients with seasonal allergic rhinitis. Clin Drug Invest 2001;21:25-32.

54. Debuske LM. Desloratadine. Plenary lecture. European Asthma Congress; Sept 9-12 2001; Moscow, Russia.

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57. Nathan R. Desloratadine relieved nasal congestion in patients with seasonal allergic rhinitis and concurrent asthma [abstract 511. Ann Allergy Asthma lmmunol2001; 86.

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60. Ring J, Hein R, Gauger A, et al. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J Dermatol 2001;40: 1-5.

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2.) Testimonial EFECTOS SECUNDARIOS DESLORATADINA (Republica Dominicana)
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DESLORATADINA:/ ENVIADO A DERMAGIC/EXPRESS día 4/JUNIO / 2002

Estimados señores:

Deseo saber si hay contraindicación de este medicamento (DESLORATADINA) 5mg para una paciente- asmática y alérgica a la aspirina. Deseo saber específicamente si este medicamento tiene reacción cruzada con la aspirina ya que la paciente al tomarla, se siente además de SOÑOLIENTA, DESESPERADA, incómoda y el pasado domingo tuvo que acudir a un centro medico de EMERGENCIA debido a que se sentía DESVANECER con la PRESION MUY BAJA, y estaba casi inconsciente. También reporta haber perdido el control y memoria. Favor recomendar si debe suspender dicho tratamiento, ya que es una persona de escasos 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 agradecería, antes le había sugerido Claritine, pero le daba sueño, pero en todo caso no le presento ningún otro síntoma adverso. Ella aparentemente se aprieta o le dan ataques de asma al tener alergia respiratoria, y le causa cosquilla en la tráquea o pecho.

Muchas gracias por toda su ayuda.

Marie Anne Granata

Republica Dominicana

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DATA-MÉDICOS/DERMAGIC-EXPRESS No 4-(2) X file) 15/06/2.002 DR. JOSÉ LAPENTA R.
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The Desloratadine Secret X File !!!!

El Expediente Secreto X de la Desloratdina !!!