Realmente existen diferencias entre desloratadina y loratadina ??? 

Data-Medicos 
Dermagic/Express No. 3-(108) 
Ocubre 2.001. October 2.001. 

EDITORIAL ESPANOL 
================= 
HOLA amigos de la red DERMAGIC, de nuevo con ustdes, en esta ocasion con el tema: REALMENTE EXISTEN GRANDES DIFERENCIAS ENTRE LA DESLORATADINA Y LORATADINA. ??? 

Antes de iniciar el tema, les comento que un dia despues de lanzada a la red el tema LA LORATADINA Y SUS 11O EFECTOS ADVERSOS, en el servidor DERMLIST de BRASIL se publico un caso de un paciente masculino de 22 años de edad quien desarrollo una HEPATITIS por droga debido al uso de LORATADINA, el testimonio esta montado en esta revision, lo cual ratifica que lo DE LA TOXICIDAD HEPATICA DE ESTA MOLECULA no es un cuento de NAVIDAD. 

Otro aspecto a señalar es la ratificacion de que desde el año 1.996 ya se conocian los efectos toxicos de esta molecula en el HIGADO, YA que el libro Mosby los publico. Ustedes pueden observar la cantidad de efectos adversos que para ese año ya se habian descrito, y tambien pueden leer LA INFORMACION DEL FABRICANTE SUMINISTRADA en las cajas de Loratadina en los Estados Unidos de America, año 2000-2001, de modo que no hay margen de error. 

El laboratorio MUY PROBABLEMENTE CONSCIENTE DE LOS EFECTOS ADVERSOS QUE HA CAUSADO LA LORATADINA desde su salida al mercado, el 11 de mayo 2.001 se OPONE a cambiar el estatus de la misma A VENTA LIBRE (OTC). En nuestro pais se VENDE LIBREMENTE. Tambien alega que el tratamiento de las alergias es complejo.

Como todos ustedes saben el 31 de Julio de este año DERMAGIC publico la primera revision de la DESLORATADINA, REVELANDO que una organizacion denominada PUBLIC CITIZEN hace una publicacion implicando al LABORATORIO fabricante de los producos ALBUTEROL, LORATADINA CON PSUDOEFEDRINA Y DESLORATADINA como productos con problemas de manufactura. 

EL laboratorio IMPLICADO REBOTO los alegatos de CITIZEN 9 DIAS DESPUES de la publicacion de DERMAGIC/EXPRESS EN todo el mundo. Pero hay que resaltar que el alegato del LABORATORIO es en FAVOR DEL PRODUCTO ALBUTEROL, con respecto a la LORATADINA CON PSEUDOEFEDRINA Y DESLORATADINA (AERIUS) NO SE PRONUNCIO. Ni se ha pronunciado HASTA el dia presente. 

... Pero el 22 DE JUNIO 2.001, ya el LABORATORIO HABIA RECONOCIDO publicamente que realmente existian problemas en sus fabricas y que se iba a abocar a resolverlos, lo mas pronto posible, ESPEREMOS QUE ESTO YA se haya cumplido. 

Con respecto a la DESLORATADINA podemos decir lo siguiente de interes: 

LA DESLORATADINA (AERIUS) ES EL MAYOR METABOLITO ACTIVO DE LA LORATADINA (descarboethoxyloratadina)UNA VEZ ES metabolizada por el HIGADO (citocromo p450 y otros), de modo que LA LORATADINA EJERCE la mayoria de sus efectos en el CUERPO HUMANO como desloratadina. Resumiendo LA DESLORATADINA ES UNA SIMPLE LORATADINA sin metabolismo de primer paso, probabalemnte con algun otro efecto. Esto es positivo pues la LIBERA DE SUS EFECTOS SOBRE EL higado, pero no la LIBERA de los OTROS efectos adversos que se le atribuyen a la molecula LORATADINA.

Interesante hecho me encuentro al revisar TODA LA BASE DE DATOS SOBRE LA DESLORATADINA donde no encuentro NINGUN ASPECTO NEGATIVO sobre esta molecula, lo mismo que OCURRIO CON LA LORATADINA y fijense la CANTIDAD DE EFECTOS ADVERSOS QUE LA FDA le ha reportado. 

La desloratadina NO HA SIDO APROBADA EN ESTADOS UNIDOS porque la patente de la LORATADINA VENCE en DICIEMBRE del 2.002, y es MENOS COSTOSA, y tambien encontre un articulo interesante donde se COMENTA que LOS BENEFICIOS DE ESTA MOLECULA SOBRE LA LORATADINA PARECEN SER MUY POCOS. Los primeros EFECTOS ADVERSOS REPORTADOS son los mismos que para la loratadina, Y ESTO ES UNA DEMOSTRACION MAS DE QUE LA LORATADINA EJERCE LA MAYORIA DE sus efectos sobre el cuerpo COMO DESLORATADINA. 

En nuestro pais venezuela SE INTRODUJO EL PRODUCTO DESLORATADINA (AERIUS) el dia 23 de AGOSTO 2.001 y a mi se me entrego una MONOGRAFIA DEL PRODUCTO y en la presentacion del mismo hay un aspecto interesante que señalar: 

Se me dijo que esta MOLECULA ES ENTRE 30 Y 50 VECES MAS POTENTE que los otros antihistaminicos LO CUAL ES FALSO Y CARECE DE BASES CIENTIFICAS, pues NO EXISTE NINGUN ESTUDIO PUBLICADO QUE AVALE estas propiedades, y DUDO que lo exista PUES la DESLORATADINA ES EL METABOLITO ACTIVO DE LA LORATADINA., COMO VA A SER 50 VECES MAS POTENTE QUE OTRO ????. 

Esta informacion TOTALMENTE LEJANA A LA REALIDAD se hizo con la finalidad COMERCIAL DE IMPLANTAR AERIUS como el mejor y nuevo antihistaminico DEL MUNDO, cuando se trata simplemente de una LORATADINA SIN metabolismo de primer paso. 

Desde la publicacion DE DERMAGIC/EXPRESS (31 DE JULIO) sobre este tema DESLORATADINA EL LABORATORIO FABRICANTE no se ha pronunciado PUBLICAMENTE AL RESPECTO. 

Los HECHOS por fecha: 
--------------------------------- 
1.) EL DIA 13 DICIEMBRE 2000 EL LABORATORIO SHERING-P envia a LA FDA peticion para aprobacion de DESLORATADINA. en 2 presentaciones. 

2.) El dia 16 DE ENERO del 2.001 DESLORATADINA ES aprobada por la union Europea para su comercializacion en Europa, EN ALERGIAS ESTACIONALES fabricada por la compañia SEPRACOR comercializada POR SHERING -P. 

3.) EL dia 25 DE ENERO 2.001 el laboratorio SCHERING-P recive una "PROBABLE" carta de aprobacion para comercializar DESLORATADINA.en estados Unidos. 9 MESES DESPUES este hecho NO SE HA HECHO REALIDAD todavia. 

4.) El dia 3 DE MARZO 2.001 PUBLIC CITIZEN DENUNCIA que el LABORATORIO SHERING-P tiene problemas con la FABRICACION DE 3 DE SUS PRODUCTOS, ALBUTEROL, LORATADINA CON PSUDOEFEDRINA Y DESLORATADINA. 

5.) EL dia 11 DE MAYO 2.001 el laboratorio FABRICANTE SE OPONE A CAMBIAR EL STATUS DE LORATADINA A PRODUCTO de venta libre (OTC) 

6.) El DIA 22 DE JUNIO 2.001 EL LABORATORIO SHERING-P anuncia que facilitara las inspecciones de la FDA, que realmente hay problemas en sus fabricas y que hara esfuerzos por corregirlos detallando el plan de accion. 

7.) EL 31 DE JULIO 2.001 DERMAGIC/EXPRESS lanza a la red LA REVISION DE DESLORATADINA develando LA VERDAD DE LOS HECHOS. 

8.) EL 9 DE AGOSTO 2.001 EL LABORATORIO SHERING -P RECUSA elegatos de PUBLIC CITIZEN con respecto a la droga ALBUTEROL, no lo hace con DESLORATADINA Y LORATADINA CON PSEUDOEFEDRINA. 

9.) EL MISMO 9 DE AGOSTO 2.001 SHERING-P VUELVE ANUNCIAR LA APROBACION DE LA UNION EUROPEA de la DESLORATADINA para uso en pacientes con URTICARIA IDIOPATICA, en ADULTOS Y NIÑOS MAYORES DE 12 AÑOS, 

10.) 23 DE AGOSTO 2.001, DESLORATADINA COMIENZA A SER comercializada en VENEZUELA, con los NOMBRES COMERCIALES DE AERIUS Y DESALEX, diciendome que el producto es 30-50 VECES MAS POTENTE QUE OTROS ANTIHISTAMINICOS. 

11.) EL DIA 5 OCTUBRE 2.001 EL LABORATORIO SHERING-P de Venezuela llama a DERMAGIC/EXPRESS por telefono y le INSINUA que LAS PUBLICACIONES SOBRE SUS MOLECULAS NIMESULIDE, LORATADINA Y DESLORATADINA TIENEN "MALA INTENCION".

- DERMAGIC/EXPRESS responde que son TOTALMENTE CIENTIFICAS Y APEGADAS A LA REALIDAD Y CON BASES BIBLIOGRAFICAS PERFECTAMENTE COMPROBABLES, Y QUE SE HICIERON PARA INFORMAR A LA COMUNIDAD NACIONAL E INTERNACIONAL ASPECTOS DE INTERES sobre estas moleculas.

- DEMAGIC/EXPRESS ha REALIZADO REVISIONES DE OTRAS MOLECULAS COMO FEXOFENADINA, TERBINAFINA ITRACONAZOLE, FINASTERIDE, ISOTRETINOINA, MINOCICLINA y OTRAS, Y NUNCA JAMAS los LABORATORIOS llamaron PARA DECIR QUE LAS REVISIONES BIBLIOGRAFICAS ERAN MAL INTENCIONADAS.

- DERMAGIC/EXPRESS RESPONDERA DE NUEVO CIENTIFICAMENTE CON OTRA REVISION SOBRE EL NIMESULIDE Y SUS EFECTOS SOBRE EL CORAZON.

- DESDE EL 21 DE AGOSTO 2.001 A LOS VISITADORES DEL LABORATORIO SHERING-P SE LES IMPIDIO LA ENTRADA A LA OFICINA DE DERMAGIC/EXPRESS.

12.) 15 OCTUBRE, 2.001 DESLORATADINA SIGUE SIN SER APROBADA POR LA FDA, en LOS ESTADOS UNIDOS DE AMERICA. 

Una vez mas alerto a TODOS LOS PAISES Y MEDICOS que PIDAN LA MONOGRAFIA DEL PRODUCTO AL LABORATORIO FABRICANTE y la lean con detenimiento y TOMEN sus debidas precauciones antes de PRESCRIBIR EL PRODUCTO. 

CONCLUSIONES: 
--------------------------
1.) PUBLIC CITIZEN TENIA RAZON. !!!

2.) DESLORATADINA FUE APROBADA POR LA UNION EUROPEA SOLO PARA EL TRATAMIENTO DE ALERGIAS ESTACIONALES (RINITIS ALERGICA) Y URTICARIA IDIOPATICA EN ADULTOS Y NIÑOS MAYORES DE 12 AÑOS. 

3.) DESLORATADINA SIGUE SIN SER APROBADA POR LA FDA. 

4.) LA TOXICIDAD HEPATICA DE LA LORATADINA ES UN HECHO COMPROBADO. 

5.) LOS EVENTOS CARDIACOS PRODUCIDOS POR LA LORATADINA SON UNA REALIDAD.

6.) SE NECESITAN MAS ESTUDIOS OBJETIVOS SOBRE LA DESLORATADINA PARA 
ENTENDER BIEN ESTA MOLECULA Y SUS VERDADEROS EFECTOS EN EL CUERPO 
HUMANO, pues si de los 110 efectos adversos QUE se le atribuyen a la LORATADINA les 
quitamos los hepaticos QUEDAN MAS DE 95 EFECTOS ADVERSOS reportados AL USO DE 
ESTA MOLECULA. La pregunta es: QUIEN LOS PRODUCE, LA LORATADINA O LA 
DESLORATADINA, el metabolito activo. ??? 

En las referencias los hechos 

Dr Jose Lapenta R. 


EDITORIAL ENGLISH
=================
HELLLO friends of the net, DERMAGIC again with you, in this occasion with the topic: BIG DIFFERENCES REALLY EXIST BETWEEN THE DESLORATADINE AND LORATADINE. ??? 

Before beginning the topic, I comment them that one day after having thrown to the net the topic THE LORATADINE AND THEIR 11O ADVERSE EFFECTS, in the server DERMLIST of BRAZIL I publishes a case of a 22 year-old masculine patient who I develop a HEPATITIS for drug due to the use of LORATADINE, the testimony is mounted one in this revision, that which ratifies that OF THE HEPATIC TOXICITY OF THIS MOLECULE is not a story of CHRISTMAS. 

Another aspect to point out is the ratification that from the year 1.996 the toxic effects of this MOLECULE were already known in the LIVER, since the Mosby Book publishes them. You can observe the quantity of adverse effects that they had been described already for that year, and you can also read THE MAKER'S INFORMATION in the boxes of LORATADINE in the United States of America, year 2000-2001, so that there is not error margin. 

The laboratory very PROBABLY AWARE OF THE ADVERSE EFFECTS THAT THE LORATADINE has CAUSED from its exit to the market, May 11 2.001 is OPPOSED to change the status the same one TO FREE SALE (OTC). in our country it is SOLD FREELY. He also alleges that the treatment of the allergies is complex.

As all you know the July 31 of this year DERMAGIC I publish the first revision of the DESLORATADINE, REVEALING that a denominated organization PUBLIC CITIZEN makes a publication implying to the manufacturing LABORATORY of the products ALBUTEROL, LORATADINE WITH PSEUDOEPHEDRINE AND DESLORATADINE like products with manufacturing troubles. 

THE IMPLIED laboratory REBUTS the allegations of CITIZEN 9 DAYS after the publication of DERMAGIC/EXPRESS in the entire world. But it is necessary to stand out that the allegation of the LABORATORY is in FAVOR OF THE PRODUCT ALBUTEROL, with regard to the LORATADINE WITH PSEUDOEPHEDRINE AND DESLORATADINA (AERIUS) he doesn't PRONOUNCE. Neither it has been pronounced UNTIL the present day. 

... But JUNE 22 2.001, the LABORATORY had already RECOGNIZED openly that problems really existed in their factorys and that it will meet to solve them, him but soon possible, let us HOPE THIS has ALREADY been completed. 

With regard to the DESLORATADINE we can say the following of interest: 

THE DESLORATADINE (AERIUS) it is THE MAJOR ACTIVE METABOLITE OF THE LORATADINE (descarboethoxyloratadin) when he is metabolized by the LIVER (cytochrome p-450 enzymes and others), so that THE LORATADINE EXERCISES most of its effects in the HUMAN BODY as DESLORATADINE. Summarizing THE DESLORATADINE is A SIMPLE LORATADINE without metabolism of first step, probably with some other effect. This is positive because it LIBERATES it OF THEIR EFFECTS ON THE liver, but it doesn't LIBERATE it of the OTHER adverse effects that are attributed to the LORATADINE molecule. 

The desloratadine has not BEEN APPROVED IN UNITED STATES because the patent of the LORATADINE EXPIRES in DECEMBER of the 2.002, and it is LESS EXPENSIVE, and I also found a I a interesting article where it is COMMENTED that THE BENEFITS OF THIS MOLECULE ON THE LORATADINE SEEM to BE VERY FEW. The first REPORTED ADVERSE EFFECTS are the same ones that for the LORATADINE, AND THIS is A DEMONSTRATION THAT THE LORATADINE EXERCISES most OF their effects on the body LIKE DESLORATADINE. 

In our country venezuela THE PRODUCT DESLORATADINE was INTRODUCED (AERIUS) the day 23 of AUGUST 2.001 and to my I am given a MONOGRAPH OF THE PRODUCT and in the presentation of the same one there is an interesting aspect that to point out: 

I was said to me, that this MOLECULE is BETWEEN 30 AND 50 TIMES BUT POTENT that the other antihistamine drugs THAT WHICH is FALSE AND it LACKS SCIENTIFIC BASES, because it doesn't EXIST ANY PUBLISHED STUDY THAT it ENDORSES these properties. and I DOUBT that it exists him THEN the DESLORATADINE it is THE ACTIVE METABOLITE OF THE LORATADINE., WHY it will BE 50 TIMES BUT POTENT THAN OTHERS ????. 

This COMPLETELY DISTANT information TO THE REALITY was made with the COMMERCIAL purpose OF IMPLANTING AERIUS like the best and new antihistame drug IN THE WORLD, when it is simply a LORATADINE WITHOUT metabolism of first step. 

From the publication DE DERMAGIC/EXPRESS (JULY 31)on this topic DESLORATADINE THE MANUFACTURING LABORATORY has not been pronounced OPENLY in this respect. 

The FACTS for date: 
------------------------------

1.) The DAY 13 DECEMBER 2000 THE LABORATORY SHERING-P sends to THE FDA petition for for approval of DESLORATADINE. in 2 presentations. 

2.) The day 16 OF JANUARY of the 2.001 DESLORATADINE it is approved by the European union for their commercialization in Europe, IN SEASONAL ALLERGIES manufactured by the company SEPRACOR marketed BY SHERING -P. 

3.) THE day 25 OF JANUARY 2.001 the laboratory SCHERING-P recive a "APPROVABLE" letter to market DESLORATADINE in United states. 9 MONTHS LATER this fact REALITY has not still BEEN MADE. 

4.) The day 3 OF MARCH PUBLIC CITIZEN it DENOUNCES that the LABORATORY SHERING-P has problems with the PRODUCTION OF 3 OF ITS PRODUCTS, ALBUTEROL, LORATADINE WITH PSUDOEPHEDRINE AND DESLORATADINE. 

5.) THE day 11 OF MAY 2.001 the MANUFACTURING laboratory is OPPOSED to CHANGE THE STATUS OF LORATADINE TO PRODUCT of free sale (OTC). 

6.) THE day 22 OF JUNE THE LABORATORY SHERING-P announces that it FACILITATED THE FDA the inspections, that there are truly problems in its factorys and that he will make efforts to correct them detailing the action plan. 

7.) The day 31 OF JULY DERMAGIC/EXPRESS throws to the net THE REVISION ABOUT DESLORATADINE REVEALING THE TRUTH OF THE FACTS. 

8.) The day AUGUST 9 THE LABORATORY SHERING -P REBUTS the allegations of PUBLIC CITIZEN with regard to the drug ALBUTEROL, he doesn't make it with DESLORATADINE AND LORATADINE WITH PSEUDOEPHEDRINE. 

9.) THE SAME one AUGUST 9 SHERING-P RETURNS to ANNOUNCE THE APPROVAL OF THE EUROPEAN UNION of the DESLORATADINE for use in patient with IDIOPATHIC URTICARIA, in ADULTS AND bigger CHILDREN of 12 YEARS. 

10.) The day AUGUST 23, DESLORATADINE BEGINS to be marketed in VENEZUELA, with the BRAND NAMES OF AERIUS AND DESALEX, saying to me that the product is 30-50 TIMES BUT POTENT THAN OTHER ANTIHISTAMINICS.

11.) THE DAY 5 OCTOBER 2.001 THE LABORATORY SHERING-P of Venezuela calls to DERMAGIC/EXPRESS and it INSINUATES him that THE PUBLICATIONS ABOUT THEIR MOLECULES NIMESULIDE, LORATADINE, AND DESLORATADINE HAVE "BAD INTENTION". 

- DERMAGIC/EXPRESS responds that they are COMPLETELY SCIENTIFIC AND ATTACHED TO THE REALITY AND WITH PERFECTLY VERIFIABLE BIBLIOGRAPHICAL BASES, AND THAT they were MADE to INFORM TO THE MEDIC COMMUNITY NATIONAL AND INTERNATIONAL ASPECTS OF INTEREST ON these molecules.

-DERMAGIC/EXPRESS has CARRIED OUT REVISIONS OF OTHER MOLECULES LIKE FEXOFENADINE, TERBINAFINE, ITRACONAZOLE, FINASTERIDE, ISOTRETINOIN, MINOCYCLINE and OTHERS, AND the LABORATORIES NEVER called NEVER to SAY THAT THE BIBLIOGRAPHICAL REVISIONS were WITH "BAD INTENTION". 

-DERMAGIC/EXPRESS WILL RESPOND SCIENTIFICALLY AGAIN WITH A NEW REVISION ABOUT NIMESULIDE AND THEIR EFFECTS ON THE HEART.

- SINCE AUGUST 2.001 21 TO THE VISITORS OF THE LABORATORY SHERING-P were IMPEDED THE ENTRANCE TO THE DERMAGIC/EXPRESS'S OFFICE.

12.) 15 OCTOBER 2.001 , DESLORATADINE CONTINUES WITHOUT being APPROVED BY THE FDA, in THE UINITES STATES DE AMÉRICA. 

Once but I alert ALL THE COUNTRIES AND DOCTORS that REQUEST THE MONOGRAPH FROM THE PRODUCT TO THE MANUFACTURING LABORATORY and read it thoroughly and TAKE their due cautions before PRESCRIBING THE PRODUCT. 

CONCLUSIONS: 
-------------------------
1.) PUBLIC CITIZEN HAD REASON. !!!

2.) DESLORATADINE was APPROVED BY THE EUROPEAN UNION ALONE FOR THE TREATMENT OF SEASONAL ALLERGIES (ALLERGIC RINITIS) AND IDIOPATHIC URTICARIA IN ADULTS AND bigger CHILDREN OF 12 YEARS. 

3.) DESLORATADINE CONTINUES WITHOUT being APPROVED BY THE FDA. 

4.) THE HEPATIC TOXICITY OF THE LORATADINE is A PROVEN FACT. 

5.) THE CARDIAC EVENTS PRODUCED BY LORATADINE ARE A REALITY.

6.) MORE OBJECTIVE STUDIES are NEEDED ON THE DESLORATADINA to 
UNDERSTAND THIS MOLECULE AND THEIR TRUE EFFECTS WELL IN THE HUMAN 
BODY, because if of the 110 adverse effects THAT are attributed to the LORATADINE we 
remove them the hepatic ones they are MORE THAN 95 ADVERSE EFFECTS reported TO THE USE OF THIS MOLECULE. The question is: WHO PRODUCES THEM, THE LORATADINE 
OR THE DESLORATADINE, the active metabolite. ??? 

In the references the facts 

Dr José Lapenta R. 
=============================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
=============================================================
0.) A new case of hepatic TOXICITY from loratadine, testimony
1.) In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-oh-desloratadine for five human cytochrome p-450 enzymes.
2.) Effect of desloratadine and loratadine on rhinovirus-induced intercellular adhesion molecule 1 upregulation and promoter activation in respiratory epithelial cells.
3.) Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein.
4.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.
5.) Desloratadine.
6.)[A new antihistamine. Inhibiting inflammation in rhinorrhea and nasal congestion].
7.) Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.
8.) Desloratadine: A new, nonsedating, oral antihistamine.
9.) Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study.
10.) The pharmacologic profile of desloratadine: a review.
11.) Desloratadine: a new approach in the treatment of allergy as a systematic disease--pharmacology and clinical overview. Introduction.
12.) Desloratadine in the treatment of chronic idiopathic urticaria.
13.) Desloratadine activity in concurrent seasonal allergic rhinitis and asthma.
14.) Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis.
15.) Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.
16.) Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents.
17.( Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 2nd communication: lack of central nervous system and cardiovascular effects.
18.) Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects.
19.) Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.
20.) Desloratadine - first clinical data in rhinitis revealed
21.) SCHERING-PLOUGH SUBMITS U.S. MARKETING APPLICATIONS
FOR TWO NEW FORMULATIONS OF DESLORATADINE
22.) European Committee Recommends Approval of Desloratadine for Chronic Idiopathic Urticaria
23.) Quality of life improves in seasonal allergic rhinitis patients treated with desloratadine
24.) Efficacy and Tolerability of Once-Daily 5mg Desloratadine, an H1-Receptor Antagonist, in Patients with Seasonal Allergic Rhinitis Assessment during the Spring and Fall Allergy Seasons
25.) Schering-Plough Announces European Union Approval of Desloratadine 
26.) DESLORATADINE 
27.) SCHERING-PLOUGH REPORTS DESLORATADINE RECEIVES FDA "APPROVABLE" LETTER
28.) SCHERING-PLOUGH ANNOUNCES EUROPEAN UNION APPROVAL OF DESLORATADINE FOR TREATMENT OF CHRONIC IDIOPATHIC URTICARIA
29.) PUBLIC CITIZEN 
30.) SCHERING-PLOUGH REBUTS PUBLIC CITIZEN ALLEGATIONS
31.) LORATADINE INFORMATION FROM MOSBY YEAR BOOK. 1.996
32.) The original packing information of the product CLARITIN® brand of loratadine 2.000-2.001 
33.) SCHERING-PLOUGH DISAGREES WITH FDA ADVISORY PANEL’S RECOMMENDATION REGARDING CLARITIN (LORATADINE)
34.) SCHERING-PLOUGH PROVIDES UPDATE ON MANUFACTURING ISSUES
AND FDA INSPECTIONS OF U.S. MANUFACTURING FACILITIES
=============================================================
=============================================================
0.) A new case of hepatic TOXICITY from loratadine, testimony
=============================================================
Source: DERMLIST Brasil, Dr Mauro Siqueira.

1. DR. MAURO SIQUEIRA
Subject: Loratadina - aconteceu comigo!


Caro Dr. Jose Lapenta:

Há cerca de 3 meses um meu paciente de 22 anos de idade apresentou uma forte dermatite e euprescrevi LORATADINA por seis dias....algumas semanas depois veio com queixas de astenia e palidez, a provas hepaticas estavam
fortemente alteradas. A pesquisa de hepatite A, B e C resultou negativa e as outras possiveis causas do quadro foram afastadas pelo hepatologista. O
diagnostico foi hepatite medicamentosa e a unica causa era a loratadina!

Grato pelo alerta!

Mauro Siqueira
=============================================================
1.) In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-oh-desloratadine for five human cytochrome p-450 enzymes.
=============================================================
Drug Metab Dispos 2001 Sep;29(9):1173-5 

Barecki ME, Casciano CN, Johnson WW, Clement RP.

Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, New Jersey.

The purpose of this study was to evaluate loratadine, desloratadine, and 3-OH-desloratadine as inhibitors of certain human liver cytochrome P-450 enzymes. Pooled human liver microsomes were used to determine whether loratadine, desloratadine, and 3-OH-desloratadine were inhibitors of cytochrome P-450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4. Loratadine did not inhibit CYP1A2 or CYP3A4 at concentrations up to 3829 ng/ml, which is approximately 815-fold greater than the expected maximal human plasma concentration (4.7 +/- 2.7 ng/ml) following the recommended dose of 10 mg/day. Loratadine inhibited CYP2C19 and CYP2D6 with IC(50) values of approximately 0.76 &mgr;M [291 ng/ml; K(i) congruent with 0.61 &mgr;M (234 ng/ml)] and 8.1 &mgr;M [3100 ng/ml; K(i) congruent with 2.7 &mgr;M (1034 ng/ml)], respectively, which are approximately 62 and 660 times the expected loratadine therapeutic exposure concentration. Neither desloratadine nor 3-OH-desloratadine inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 greater than 25% at concentrations of 3108 or 3278 ng/ml, respectively. These results suggest that loratadine and the active metabolites desloratadine and 3-OH-desloratadine are unlikely to affect the pharmacokinetics of coadministered drugs which are metabolized by these five cytochrome P-450 enzymes.

=============================================================
2.) Effect of desloratadine and loratadine on rhinovirus-induced intercellular adhesion molecule 1 upregulation and promoter activation in respiratory epithelial cells.
=============================================================
J Allergy Clin Immunol 2001 Aug;108(2):221-8 

Papi A, Papadopoulos NG, Stanciu LA, Degitz K, Holgate ST, Johnston SL.

University Medicine, University of Southampton, Southampton, UK.

BACKGROUND: Rhinoviruses have been recently associated with the majority of asthma exacerbations for which current therapy is inadequate. Intercellular adhesion molecule 1 (ICAM-1) has a central role in airway inflammation in asthma, and it is the receptor for 90% of rhinoviruses. Rhinovirus infection of airway epithelium induces ICAM-1. Desloratadine and loratadine are compounds belonging to the new class of H(1)-receptor blockers. Anti-inflammatory properties of antihistamines have been recently documented, although the underlying molecular mechanisms are not completely defined. OBJECTIVE: We have investigated the effects of desloratadine and loratadine on rhinovirus-induced ICAM-1 expression, mRNA upregulation, and promoter activation. METHODS: Cultured primary bronchial or transformed (A549) respiratory epithelial cells were pretreated with desloratadine and loratadine for 16 hours and infected with rhinovirus type 16 for 8 hours. ICAM-1 surface expression was evaluated with flow cytometry, and ICAM-1 mRNA was evaluated with specific RT-PCR. In A549 cells promoter activation was evaluated with a chloramphenicol acetyltransferase assay, and binding activity of nuclear factor kappa B in nuclear extracts was evaluated with an electrophoretic mobility shift assay. RESULTS: Desloratadine and loratadine (0.1-10 micromol/L) inhibited rhinovirus-induced ICAM-1 upregulation in both primary bronchial or transformed (A549) respiratory epithelial cells. In A549 cells the 2 compounds showed a dose-dependent inhibition with similar efficacy (inhibitory concentration of 50%, 1 micromol/L). Desloratadine and loratadine also inhibited ICAM-1 mRNA induction caused by rhinovirus infection in a dose-dependent manner, and they completely inhibited rhinovirus-induced ICAM-1 promoter activation. Desloratadine also inhibited rhinovirus-induced nuclear factor kappa B activation. Desloratadine and loratadine had no direct effect on rhinovirus infectivity and replication in cultured epithelial cells. CONCLUSION: These effects are unlikely to be mediated by H(1)-receptor antagonism and suggest a novel mechanism of action that may be important for the therapeutic control of virus-induced asthma exacerbations.

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3.) Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein.
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Drug Metab Dispos 2001 Aug;29(8):1080-3 Books, LinkOut 

Wang Ej, Casciano CN, Clement RP, Johnson WW.

Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, New Jersey.

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC(50) of loratadine (~11 &mgr;M) was ~160 times the maximum observed plasma concentration (C(max)) following a dose of 10 mg. The IC(50) of desloratadine (~43 &mgr;M) was ~880 times the C(max) following a dose of 5 mg. The positive control, cyclosporin A, had an IC(50) of ~1 &mgr;M. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had a V(max) about 200% basal activity and K(m) of ~3 &mgr;M for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates.

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4.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.
Expert Opin Investig Drugs 2001 Mar;10(3):547-60 
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Agrawal DK.

Center for Allergy, Asthma and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA. [email protected]

Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine. Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine. Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation. Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance. Desloratadine has an excellent overall safety profile. It has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice. The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion. Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria. Desloratadine improves quality of life and is well-tolerated.

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5.) Desloratadine.
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Drugs 2001;61(6):789-96; discussion 797 

McClellan K, Jarvis B.

Adis International Limited, Mairangi Bay, Auckland, New Zealand. [email protected]

Desloratadine is the orally active major metabolite of the nonsedating H1-antihistamine loratadine. The drug had no adverse cardiovascular effects in various animal models or when administered at 9 times the recommended adult dosage for 10 days in volunteers. Therapeutic dosages had no effects on wakefulness or psychomotor performance in healthy volunteers. No clinically significant interactions have been reported between desloratadine and drugs that inhibit the cytochrome P450 system, nor does the drug potentiate the adverse psychomotor effects of alcohol. Oral desloratadine 5 mg once daily for up to 4 weeks in patients with seasonal allergic rhinitis (SAR) significantly reduced nasal (including congestion) and non-nasal symptoms and improved health-related quality of life compared with placebo. Similar beneficial effects were observed in patients with SAR and coexisting asthma (in whom asthma symptoms and use of beta2-agonists were reduced). Desloratadine 5 mg once daily for 6 weeks significantly improved pruritus and reduced the number of hives compared with placebo in patients with chronic idiopathic urticaria (CIU). Sleep and daytime performance also improved. Desloratadine was well tolerated in clinical trials and had an adverse event profile similar to that of placebo in patients with SAR (with or without asthma) or CIU.

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6.)[A new antihistamine. Inhibiting inflammation in rhinorrhea and nasal congestion].
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MMW Fortschr Med 2001 Apr 5;143(14):47 

[Article in German]

Publication Types: 
News 
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7.) Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.
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Clin Ther 2001 Mar;23(3):451-66 

Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V.

Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.

BACKGROUND: Significant cardiac toxicity has been associated with some older antihistamines (eg, terfenadine and astemizole) when their plasma concentrations are increased. There is thus a need for a thorough assessment of the cardiac safety of newer antihistamine compounds. OBJECTIVE: This study was undertaken to assess the effects of coadministration of desloratadine or fexofenadine with azithromycin on pharmacokinetic parameters, tolerability, and electrocardiographic (ECG) findings. METHODS: Healthy volunteers aged 19 to 46 years participated in this randomized, placebo-controlled, parallel-group, third-party-blind, multiple-dose study. Subjects received desloratadine 5 mg once daily, fexofenadine 60 mg twice daily, or placebo for 7 days. An azithromycin loading dose (500 mg) followed by azithromycin 250 mg once daily for 4 days was administered concomitantly starting on day 3. Group 1 received desloratadine and azithromycin, group 2 received desloratadine and placebo, group 3 received placebo and azithromycin, group 4 received fexofenadine and azithromycin, and group 5 received fexofenadine and placebo. RESULTS: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (Cmax) and area under the concentration-time curve (AUC) values for desloratadine with concomitant administration of azithromycin: Cmax ratio, 115% (90% CI, 92-144); AUC, ratio 105% (90% CI, 82-134). The corresponding ratios for 3-hydroxydesloratadine were 115% (90% CI, 98-136) and 104% (90% CI, 88-122), respectively. A substantial increase was observed in mean Cmax and AUC values for fexofenadine when administered with azithromycin: Cmax, ratio, 169% (90% CI, 120-237); AUC ratio, 167% (90% CI, 122-229). Compared with the group receiving desloratadine and azithromycin, subjects receiving fexofenadine and azithromycin also displayed greater variability in pharmacokinetic parameters for the antihistamine. Mean Cmax and AUC values of azithromycin were slightly higher when administered with desloratadine (Cmax ratio, 131% [90% CI, 92-187]; AUC ratio, 112% [90% CI, 83-153]) but were lower when given in combination with fexofenadine (Cmax ratio, 87% [90% CI, 61-124]; AUC ratio, 88% [90% CI, 65-1201). The most common adverse event for all regimens was headache, reported in 20 (22%) subjects. All combinations of desloratadine or fexofenadine with and without azithromycin were well tolerated, and no statistically significant changes in PR, QT, or QT, interval, QRS complex, or ventricular rate were observed. CONCLUSIONS: Small increases (<15%) in mean pharmacokinetics of desloratadine were observed with coadministration of azithromycin. By contrast, peak fexofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic. Based on the reported adverse-events profile and the absence of changes in ECG parameters, the combination of desloratadine and azithromycin was well tolerated. This study suggests that desloratadine has a more favorable drug-interaction potential than does fexofenadine.

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8.) Desloratadine: A new, nonsedating, oral antihistamine.
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J Allergy Clin Immunol 2001 Apr;107(4):751-62 Related 

Geha RS, Meltzer EO.

Boston Children's Hospital and Harvard Medical School, Enders Building, Room 809, 300 Longwood Ave., Boston, MA 02115, USA.

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.

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9.) Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study.
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Int J Dermatol 2001 Jan;40(1):72-6 

Ring J, Hein R, Gauger A, Bronsky E, Miller B.

Klinik und Poliklinik fur Dermatologie und Allergologie am Biederstein, Technische Universitat Munchen, Munchen, Germany.

BACKGROUND: Chronic idiopathic urticaria (CIU) is the most common type of chronic urticaria, and pruritus is the most prominent symptom. Antihistamines are the first-line treatment for CIU. Sedation and anticholinergic adverse effects are often experienced with the first-generation antihistamines and there is a risk of cardiovascular adverse effects and drug interactions with some second-generation agents. Hence, new treatment options are needed. Desloratadine is a new, potent, nonsedating antihistamine that has an excellent cardiovascular safety profile. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study designed to determine the efficacy and safety of desloratadine in the treatment of moderate-to-severe CIU. A total of 190 patients, aged 12-79 years, with at least a 6-week history of CIU and who were currently experiencing a flare of at least moderate severity, were randomly assigned to therapy with desloratadine 5 mg or placebo once daily for 6 weeks. Twice daily, patients rated the severity of CIU symptoms (pruritus, number of hives, and size of largest hive), as well as the impact of CIU symptoms on sleep and daily activity. Patients and investigators jointly evaluated therapeutic response and overall condition. Safety evaluations included the incidence of treatment-emergent adverse events, discontinuations due to adverse events, and changes from baseline in vital signs, laboratory parameters, and ECG intervals. RESULTS: Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose and maintained this superiority to the end of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly better with desloratadine after the first dose; these clinical benefits were also maintained throughout the 6-week study. No significant adverse events occured. CONCLUSIONS: Desloratadine 5 mg daily is a safe and effective treatment for CIU with significant benefits within 24 h and maintained through the treatment period.

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10.) The pharmacologic profile of desloratadine: a review.
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Allergy 2001;56 Suppl 65:7-13 

Henz BM.

Department of Dermatology and Allergy, Charite Humboldt University, Berlin, Germany.

Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria. The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H1-receptor binding potency and H1 selectivity. Desloratadine has a half-life of 21-24 h, permitting once-daily dosing. No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters. No clinically relevant racial or sex variations in the disposition of desloratadine have been noted. In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and Cmax of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels. Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin. Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose. Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies. Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.

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11.) Desloratadine: a new approach in the treatment of allergy as a systematic disease--pharmacology and clinical overview. Introduction.
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Allergy 2001;56 Suppl 65:5-6 

Bonini S.

University of Naples, Italy.

Publication Types: 
Review 
Review, tutorial 
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12.) Desloratadine in the treatment of chronic idiopathic urticaria.
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Allergy 2001;56 Suppl 65:28-32 

Ring J, Hein R, Gauger A.

Division of Environmental Dermatology and Allergy GSF TUM, Dermatologische Klinik, Techniche Universitat Munchen, Munich, Germany.

Chronic idiopathic urticaria (CIU) is a common dermatologic disorder that may severely impair quality of life. Patients may suffer symptoms such as pruritus and disfigurement due to wheals for years or decades. Advances have been made in the last 10 years with the identification of an autoimmune pathogenesis in a significant proportion of patients. Despite this, treatment remains symptomatic, and antihistamines are the first choice of therapy once the diagnosis of CIU has been established. The goal of treatment is rapid, long-lasting symptom relief, and currently available antihistamines fail to provide this in many cases. Desloratadine is a novel, potent H1-receptor antagonist with additional inhibitory effects on inflammatory mediators such as cytokines and adhesion molecules. Newly published data on the efficacy and safety of desloratadine in CIU is highly encouraging, suggesting that the drug may improve symptom control above that currently available.

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13.) Desloratadine activity in concurrent seasonal allergic rhinitis and asthma.
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Allergy 2001;56 Suppl 65:21-7 

Baena-Cagnani CE.

Division of Immunology and Respiratory Medicine, Infantile Hospital, Cordoba, Argentina.

Seasonal allergic rhinitis (SAR) and asthma, which are frequently comorbid, share some common allergic pathogenic bases. Clinical manifestations of these disorders might therefore be viewed as local manifestations of a systemic inflammatory state. Not only do the onsets of allergic-rhinitis (AR) and asthma symptoms often coincide (within 1 year), but also nasal challenges with SAR allergens can induce airways hyperreactivity (AHR). Eosinophils, which are key effector cells in both SAR and asthma, cause AHR, tissue damage, and neuronal effects through secretion of toxic granule proteins, enzymes, and other mediators. The novel, nonsedating, histamine H1-receptor antagonist, desloratadine, which exerts various favorable effects on the allergic cascade, significantly decreased SAR symptoms (e.g., nasal congestion) and diminished daily beta2-agonist use and improved asthma symptoms, while maintaining pulmonary function, in patients with SAR-asthma who were treated with once-daily desloratadine regimens.

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14.) Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis.
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Allergy 2001;56 Suppl 65:14-20 

Bachert C.

ENT Department, University Hospital Ghent, Belgium.

Recent advances in experimental immunologic approaches to seasonal allergic rhinitis (SAR) have led to a shift in the concepts of its pathogenesis. The conventional view of SAR as a local response to inhaled allergens has largely given way to a new view of this disorder as a systemic condition with local tissue manifestations. This concept, together with an increasing recognition of specific mediators' distinct roles in driving the early- and late-phase allergic responses, has opened multiple lines of therapeutic attack within the allergic cascade. Potent inhibition of inflammatory mediator release at distinct points in this cascade is conferred by desloratadine. In addition to the familiar range of SAR symptoms amenable to antihistamine therapy, desloratadine uniquely attenuates patient ratings of nasal congestion. This novel, nonsedating histamine H1-receptor antagonist is the only once-daily antiallergic product with a consistent decongestant effect that begins within hours of the first morning dose and is sustained for the entire treatment period.

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15.) Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.
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Br J Clin Pharmacol 2000 Dec;50(6):581-9 

Kosoglou T, Salfi M, Lim JM, Batra VK, Cayen MN, Affrime MB.

Departments of Clinical Pharmacology, Drug Metabolism and Pharmacokinetics and Biostatistics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. [email protected]

AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

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16.) Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents.
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J Allergy Clin Immunol 2000 Nov;106(5 Suppl):S303-9 

Marshall GD Jr.

Division of Allergy and Clinical Immunology, The University of Texas-Houston Medical School, 77030, USA.

As has been reported throughout this supplement, the pathophysiologic factors of allergic diseases involve many elements of systemic disease-effector-cell recruitment from circulation, stimulation of bone marrow progenitors, systemic effector-cell priming, anaphylactic reactions, and others. With this understanding, allergic inflammation can be thought of as a reflection of systemic immunologic responses with compartmentalized manifestations in various organ systems, including the upper respiratory tract, lungs, gastrointestinal tract, and skin. Thus, any therapeutic approach to the treatment of allergic disease should address, in addition to the localized disease manifestations, the systemic immunologic dysregulation. Second-generation antihistamines (cetirizine, fexofenadine, loratadine) have been used since the 1980s to treat localized allergy symptoms in upper airways, skin, and, in some cases, the lungs; however, the efficacy of these agents in controlling systemic immune dysregulation and chronic allergic inflammation (eg, nasal congestion) has not been proved. The potential role of newer antihistamines in the amelioration of both localized and systemic aspects of allergic disease represents an active area of interest. Desloratadine, a new selective histamine H(1)-receptor antagonist with potent antihistaminic and anti-inflammatory activity, is introduced and its potential for treating the systemic aspects of allergic disease is discussed.

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17.( Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 2nd communication: lack of central nervous system and cardiovascular effects.
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Arzneimittelforschung 2000 May;50(5):441-8 

Kreutner W, Hey JA, Chiu P, Barnett A.

Schering-Plough Research Institute, Kenilworth, New Jersey, USA.

Desloratadine (descarboethoxyloratadine, CAS 100643-71-8) is a selective histamine H1 antagonist that exhibits qualitatively similar pharmacodynamic activity to its parent, loratadine (CAS 79794-75-5), but is 2.5-4 times more potent orally. In studies of central nervous system (CNS) effects that might lead to sedation, desloratadine had no behavioral, neurological or autonomic effects in the conscious mouse and rat. At large multiples of the antihistaminic dose in the mouse, it did not inhibit convulsions caused by electroconvulsive shock and inhibited acetic acid-induced writhing only at a dose approximately 1,000 times the antihistaminic dose in the mouse. Desloratadine had no effects on blood pressure, heart rate or electrocardiographic parameters in the rat or guinea pig or on electrocardiographic parameters in the monkey. Notably, there was no effect on the corrected Q-wave to T-wave (QTc) interval. Desloratadine did not inhibit IKr channel human ether-a-go-go-related gene (HERG)-induced current in a study in which HERG was expressed in Xenopus oocytes. In the rat, desloratadine did not cause effects in urine volume, electrolytes or creatinine, or inhibit gastric emptying or intestinal transit, or cause any harmful effects on gastric mucosa. The results of these preclinical studies provide evidence that desloratadine is a safe antihistamine without CNS or cardiovascular effects.

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18.) Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects.
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Arzneimittelforschung 2000 Apr;50(4):345-52 

Kreutner W, Hey JA, Anthes J, Barnett A, Young S, Tozzi S.

Schering-Plough Research Institute, Allergy, Kenilworth, New Jersey, USA.

Desloratadine (descarboethoxyloratadine, CAS 100643-71-8) is an active metabolite of loratadine (CAS 79794-75-5) that exhibits qualitatively similar pharmacodynamic activity with a relative oral potency in animals 2.5-4 times greater than loratadine. Its antihistaminic effect lasts 24 h. Desloratadine was shown to be a selective H1 antagonist with more potent antihistaminic activity in vitro than either loratadine or terfenadine (CAS 50679-08-8), as indicated by its displacement of 3H-mepyramine from H1 receptors in rat brain, guinea pig brain, and guinea pig lung, and by its antagonism of histamine-induced contractions of guinea pig ileum. Antihistaminic activity and anitallergic effects also were observed in vivo. After oral administration, desloratadine was 2.5 to 4 times more potent than loratadine in protecting against histamine-induced lethality in the guinea pig and paw edema in the mouse; after topical administration, it was almost 10 times more potent in antagonizing histamine-induced increases in nasal microvascular permeability in the guinea pig. Histamine-induced changes in pulmonary resistance and compliance were also prevented by oral administration of desloratadine and loratadine in the monkey. An oral antiallergic effect was demonstrated by important reductions of acute bronchospasm in the allergic monkey and potent inhibition of allergic cough in the guinea pig. These preclinical studies provide evidence that desloratadine is an antihistaminic agent with a greater potency than loratadine and, together with results from numerous published studies, suggest an antiallergic effect of desloratadine.

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19.) Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.
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Eur J Pharmacol 1999 Jun 18;374(2):249-54 

Cardelus I, Anton F, Beleta J, Palacios JM.

Almirall Prodesfarma, Research Center, Pharmacology Department, Barcelona, Spain. [email protected]

Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H and muscarinic M 1 and M3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA2 = 6.67+/-0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (pA2 = 9.44+/-0.02) and NPC-14695 (pA2 = 9.18+/-0.03) also behaved as competitive antagonists, whereas tiotropium bromide (pD'2 = 9.06+/-0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (pA2 = 5.64+/-0.04) and fexofenadine (pA2 < 4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long lasting mydriasis (> 120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED50 = 30 microg/ml) and tiotropium bromide (ED50 = 10 microg/ml) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.


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20.) Desloratadine - first clinical data in rhinitis revealed
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From: Inpharma April 29, 2000: 1235 7 

Desloratadine, an active metabolite of Schering-Plough's nonsedating antihistamine loratadine [`Claritin'], is a selective inhibitor of histamine H1 receptors which appears to possess more potent antiallergic properties than loratadine itself. The first clinical data on the use of desloratadine in seasonal allergic rhinitis were finally revealed at the 56th Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) [San Diego, US; March 2000]. Highlights were studies showing that the drug has a lack of clinically significant cardiovascular toxicity, and, unlike most other antihistamines, has decongestant effects. Presentations were dominated by research from Schering-Plough Research Institute, US, who has licensed desloratadine from Sepracor, in the hope of retaining patients when their patent for loratadine expires in 2002 - the patent for desloratadine runs through until 2014. 
Dr Luis Salmun and colleagues from Schering-Plough Research Institute, US, said that desloratadine appears to be effective and well tolerated in patients with seasonal allergic rhinitis.[819171] In 2 separate studies, > 900 such patients were randomised to receive oral desloratadine 5 or 7.5mg once daily, or placebo, for 14 days.
The researchers said that all desloratadine recipients had significant improvements from baseline in total and individual nasal and non-nasal symptom severity scores(*), and joint patient/physician evaluations, compared with placebo recipients.
Headache was the most common adverse event, and was reported by similar numbers of placebo (14-22%) and desloratadine (16-24%) recipients. Somnolence occurred in 2-4% of desloratadine recipients and 2% of placebo recipients. Additionally, no cardiac, hepatic or renal toxicities were reported. 
Decongestant effects
Unlike most other antihistamines, desloratadine appears to have a decongestant effect in patients with seasonal allergic rhinitis, according Dr A Nayak from the University of Illinois Peoria, US, and colleagues from Schering-Plough Research Institute, US.[819170] Dr Nayak reported pooled data from clinical trials involving > 1300 patients with seasonal allergic rhinitis who were randomised to receive oral desloratadine 5 or 7.5 mg once daily, or placebo, for 14 days. At baseline, patients had a mean severity score of 2.4 for nasal congestion and stuffiness, an indication of moderate-to-severe congestion, according to Dr Nayak.
Patients treated with either dose of desloratadine had significantly greater improvements in 14-day symptom severity scores and nasal congestion/stuffiness scores, compared with placebo recipients, said Dr Nayak. 

Absence of cardiovascular toxicity?
-----------------------------------

Another study reported by researchers from Schering-Plough Research Institute, US, showed that high dosages of desloratadine have no clinically relevant adverse cardiovascular effects in healthy volunteers.[819167] In this study, 24 healthy volunteers received oral desloratadine 45mg (9 times the proposed clinical dose), and placebo, for 10 days each in a crossover fashion. ECG assessment was performed an average of 31 times in each volunteer on days 1 and 10 of each treatment period. The treatment periods were separated by a 14-day washout period.
The investigators said that change from baseline in QTc interval did not exceed 6.5% or 24 msec with either desloratadine or placebo administration. The maximum QTc interval was 433 msec with desloratadine, and 429 msec with placebo, administration. There were also no between-treatment differences in PR or QRS intervals. The mean ventricular rate with desloratadine administration was 9.4 beats per minute (bpm) higher than with placebo administration, but this was deemed clinically insignificant because there was a single isolated heart rate of 117 bpm during desloratadine therapy compared with 112 bpm during placebo administration.
Mild-to-moderate headache was the most frequent adverse event and occurred in 54% of patients after desloratadine administration and 46% of patients after placebo administration. 

Coadminstration with cytochrome inhibitors OK
----------------------------------------------

Desloratadine also exhibited no clinically relevant adverse cardiovascular effects when combined with the cytochrome p450 pathway inhibitor ketoconazole, according to researchers from Schering-Plough Research Institute, US.[819175] In this study, 24 healthy adults were randomised to receive oral desloratadine 7.5mg once daily in combination with oral ketoconazole 200mg twice daily and placebo, for 10 days each in a crossover fashion.
The study results showed that neither the maximal change in QTc interval nor the average maximal QTc interval differed significantly when desloratadine was administered with placebo or ketoconazole. Additionally, no clinically important pharmacokinetic changes occurred when desloratadine was combined with ketoconazole.
Headache was the most frequent adverse event and occurred in 42% of patients after desloratadine plus placebo administration and 38% of patients after desloratadine plus ketoconazole administration.
Dr P Glue from Schering-Plough Research Institute reported a similar lack of ECG effects or alterations in desloratadine pharmacokinetics, when the antihistamine was combined with erythromycin, another inhibitor of the cytochrome p450 pathway.[819177] In this study, 24 healthy volunteers were randomised to receive oral desloratadine 7.5mg once daily in combination with oral erythromycin 500mg every 8 hours and placebo, for 10 days each in a crossover fashion. 

Improvement in QOL
-------------------

Treatment with desloratadine led to improved quality of life (QOL) in patients with seasonal allergic rhinitis [evaluated by the Short-Form 36 (SF-36) Survey and the Rhinoconjunctivitis QOL Questionnaire (RQLQ)], reported Dr Eli Meltzer from the Allergy and Asthma Medical Group in San Diego, California, US.[819169] A total of 407 patients from placebo-controlled trials completed both questionnaires.
At baseline, the patients had lower scores than the general population in 4 of the 8 domains assessed by the SF-36 (role limitations, bodily pain, social functioning, and vitality). Scores on the RQLQ ranged between 2.9 and 4.3, `indicating patients carried a moderate burden of disease and were moderately to very troubled by their SAR [seasonal allergic rhinitis] symptoms.'
Following desloratadine treatment, patient scores for social functioning and vitality improved significantly on the SF-36 and on 4 of 8 domains assessed by the RQLQ (practical problems, nasal symptoms, eye symptoms and activities). Improvement in QOL correlated with symptom improvement, noted the researchers, and patients who had the greatest improvement in QOL scores also had the most marked 

improvement in SAR symptoms. 
-----------------------------

Lack of alcohol potentiation
Desloratadine does not potentiate the effects of alcohol on psychomotor performance, according to the results of a small placebo-controlled clinical study supported by Schering-Plough Research Institute.[819178] The study involved 25 healthy volunteers whose psychomotor performance was evaluated after they were randomised to receive a single 7.5mg dose of desloratadine or placebo, with or without alcohol (adjusted to an average blood level of 100 mg/dL), in a 4-way crossover fashion.
Alcohol ingestion was associated with impaired performance on 4 psychomotor tests: the Stanford Sleepiness Scale, Digit Symbol Substitution Test, Serial Add Subtract Reaction Time Test and the Psychomotor Vigilance Test. However, the degree of alcohol-related impairment did not differ significantly between desloratadine and placebo administration for any of the 4 tests.
Studies presented at the AAAAI meeting support the efficacy and acceptable tolerability profile of desloratadine. Of particular note is the possible decongestant benefit and lack of clinically significant cardiovascular adverse effects. 
*Symptoms evaluated included rhinorrhoea; itching; stuffiness; sneezing; itching, tearing and redness of eye; itching of ears or palate; and cough. 

Editorial Comment: 
------------------
Sepracor holds the patent rights to desloratadine and has exclusively licensed the drug to Schering-Plough. Schering-Plough has submitted a New Drug Application to the US FDA for marketing clearance for desloratadine as an orally administered agent for the treatment of seasonal allergic rhinitis. An analogous application has been made by Schering-Plough to the European Medicines Evaluation Agency of the European Union.

References:
1 Electrocardiographic effects of multiple high doses of desloratadine. Journal of Allergy and Clinical Immunology 105: 383, Part 2, Jan 2000 
2 Desloratadine improves quality of life in patients with seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 105: 383-384, Part 2, Jan 2000 
3 Decongestant effects of desloratadine in patients with seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 105: 384, Part 2, Jan 2000 
4 Efficacy and safety of desloratadine in seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 105: 384-385, Part 2, Jan 2000 
5 Desloratadine and ketoconazole: pharmacokinetics and electrocardiographic pharmacodynamic effects. Journal of Allergy and Clinical Immunology 105: 386, Part 2, Jan 2000 
6 Desloratadine and erythromycin: pharmacokinetics and electrocardiographic pharmacodynamic effects. Journal of Allergy and Clinical Immunology 105: 387, Part 2, Jan 2000 
7 Comparative effects of desloratadine and placebo with and without alcohol on performance measures. Journal of Allergy and Clinical Immunology 105: 394, Part 2, Jan 2000 

Citation: Innes C Desloratadine - first clinical data in rhinitis revealed. Inpharma 1235: 7-8, 29 Apr 2000

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21.) SCHERING-PLOUGH SUBMITS U.S. MARKETING APPLICATIONS
FOR TWO NEW FORMULATIONS OF DESLORATADINE
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KENILWORTH, N.J., Dec. 13, 2000 — Schering-Plough Corporation (NYSE: SGP) today announced it has submitted separate New Drug Applications (NDA) to the U.S. Food and Drug Administration (FDA) for two new formulations of its nonsedating antihistamine desloratadine.

The first NDA seeks clearance to market desloratadine syrup for the treatment of seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU), or hives of unknown cause, in patients as young as 2 years of age. The second NDA seeks approval to market desloratadine in a fixed combination with the decongestant pseudoephedrine sulfate as a twice-daily treatment of SAR in adults and children 12 years of age and older.

Desloratadine syrup and the combination of desloratadine and a decongestant are the second and third formulations of desloratadine to be submitted for marketing approval to the FDA. Separate marketing applications for desloratadine tablets are currently pending with the FDA for the treatment of SAR and CIU.

The Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products issued a positive opinion on Sept. 21, 2000, recommending approval to the European Commission of desloratadine tablets as a once-daily treatment of SAR.

Allergies affect an estimated 45 million Americans and can have a significant impact on everyday activities at work, school and leisure time. The direct cost of seasonal allergies, including medications and physician visits, has been estimated at $4.5 billion annually. Indirect costs from absenteeism include an estimated 6 million workdays and 2 million lost school days each year. In addition, there is a growing body of evidence that points to an association between allergies and even more serious conditions such as asthma.

Affecting an estimated 20 to 25 percent of Americans at least once in their lives, urticaria is a reaction to a variety of substances, including food, drugs and topical agents, and characterized by an eruption of itchy, swollen welts on the skin. An estimated 25 percent of urticaria patients develop chronic idiopathic urticaria, which is defined as a case that lasts for a period of at least six weeks and has no identifiable cause.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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22.) European Committee Recommends Approval of Desloratadine for Chronic Idiopathic Urticaria
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SOURCE: Schering-Plough Corporation 

KENILWORTH, NJ -- May 9, 2001 -- Schering-Plough Corporation today announced that the Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) has issued a positive opinion recommending approval of its nonsedating antihistamine desloratadine 5 mg tablets as a once-daily treatment of the symptoms of chronic idiopathic urticaria (CIU) such as itching or hives. Desloratadine is currently marketed in the European Union (EU) for the treatment of seasonal allergic rhinitis (SAR) under the brand names Aerius™ and Neoclarityn™.

Desloratadine is a long-acting, H1 receptor antagonist that blocks the effects of histamine release in the body. The centralized Type II variation for desloratadine in the treatment of CIU is based on results of two large, randomized, placebo-controlled studies in which desloratadine proved effective in treating the symptoms associated with CIU.

The CPMP opinion serves as the basis for a European Commission approval, which typically follows in approximately three to four months. Commission approval will result in a Marketing Authorization with unified labeling that will be valid in all 15 European Union-Member States as well as in Iceland and Norway.

Affecting an estimated 20 to 25 percent of people at least once in their lives, urticaria is a reaction to a variety of substances, including food, drugs and topical agents, and characterized by an eruption of itchy, swollen lesions on the skin. An estimated 25 percent of urticaria patients develop CIU, which is defined as a case that lasts for a period of at least six weeks and has no identifiable cause.

In the United States, Clarinex™ (desloratadine) 5 mg Tablets has received an "approvable" letter from the U.S. Food and Drug Administration (FDA) for the treatment of SAR. Separate marketing applications for Clarinex Tablets are pending with the FDA for the treatment of CIU and allergic rhinitis, which encompasses SAR and perennial allergic rhinitis.

Marketing applications are also pending with the FDA for Clarinex™ RediTabs®, a rapidly disintegrating tablet formulation; Clarinex™ Syrup, for use in patients as young as two years of age; and Clarinex-D™ 12-Hour, a fixed combination of Clarinex and a decongestant. The most common treatment-related side effects with desloratadine are headache, dry mouth and fatigue. These occurred with an incidence rate similar to placebo.

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23.) Quality of life improves in seasonal allergic rhinitis patients treated with desloratadine
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CE Baena-Cagnani1, THE Desloratadine Study Group2
1 Infantile Hospital Cordoba, Cordoba, AR

2 Schering Plough Research Institute, Kenilworth, New Jersey, US

Seasonal allergic rhinitis (SAR) is a highly prevalent condition affecting 10-30% of adults in the US. SAR results in significant impairments in activities required for daily functioning at home, school and work, and can impair quality of life (QoL). Desloratadine (DL) is a nonsedating, selective H1-receptor antagonist effective in reducing the symptoms of SAR. A randomized, placebo-controlled trial (n = 496) of DL 5 and 7.5 mg QD for 14 days assessed QoL at baseline and end of therapy using disease-specific (Rhinoconjunctivitis Health-related QoL Questionnaire [RQLQ]) and generic (SF-36) instruments. RQLQ domains (sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, activities, emotions, overall) were rated from 0 (not troubled) to 6 (extremely troubled). Baseline scores (ranging from 2.9-4.3) indicated that SAR symptoms were moderately to quite bothersome. Compared to the general US population, 4 of 8 SF-36 domains were negatively affected at baseline, indicting subjects with SAR experience mild yet consistent QoL decrements associated with burden of disease. At the end of DL therapy, 5 RQLQ domains improved (practical problems, nasal symptoms, eye symptoms, activities, overall). A significant improvement was also seen in 2 SF-36 domains that showed decrements at baseline (social functioning, vitality). Improvements in both QoL measures were positively correlated with therapeutic response. DL improves QoL by improving the bothersome symptoms of SAR.

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24.) Efficacy and Tolerability of Once-Daily 5mg Desloratadine, an H1-Receptor Antagonist, in Patients with Seasonal Allergic Rhinitis Assessment during the Spring and Fall Allergy Seasons
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[Clin Drug Invest 21(1):25-32, 2001

Eli O. Meltzer, Allergy and Asthma Medical Group and Research Center, San Diego, California, USA; Bruce M. Prenner, Allergy Associates Medical Group, San Diego, California, USA; Anjuli Nayak, Peoria School of Medicine, University of Illinois, Peoria, Illinois USA and the Desloratadine Study Group 

Abstract

Objective: To evaluate the efficacy and tolerability of desloratadine 5mg once daily, a new, selective, H1-receptor antagonist, for the treatment of patients with seasonal allergic rhinitis (SAR) during the two major pollen seasons in the USA.
Design: Two multicentre, randomised, double-blind, placebo-controlled, parallel-group investigations in patients with SAR are reported, one conducted during the spring (172 and 174 patients in the desloratadine and placebo groups, respectively) and the other during the fall (164 patients each in the desloratadine and placebo groups) allergy season.
Study Participants: Patients 12 years of age or older with clinically symptomatic SAR and a minimum 2-year history of SAR.
Interventions: Desloratadine 5mg or placebo once daily for 14 days following a 1-week screening period.
Main Outcome Measures: The primary efficacy assessment was the mean change from baseline in the average reflective am/pm total symptom score (TSS) averaged over the 2-week study period.
Results: In both seasons, desloratadine 5mg once daily resulted in a significant improvement in TSS for patients with SAR (p < 0.01 and p = 0.02, respectively) over the 2-week study. Adverse events reported were mild to moderate in severity and similar to placebo. Assessment of sedation and ECG data revealed no clinically significant changes from baseline with desloratadine- or placebo-treated patients.
Conclusion: Desloratadine 5mg once daily was effective and well tolerated in the treatment of symptoms associated with SAR following the first dose of therapy and continuing for the 2-week duration of the study during both the spring and fall allergy seasons. [Clin Drug Invest 21(1):25-32, 2001. © 2001 Adis International Limited] 

Introduction

Allergic rhinitis is estimated to afflict 10 to 30% of adults and up to 40% of children in the United States.[1] Prevalence studies of allergic rhinitis in other parts of the world indicate that allergic disease is a worldwide problem and that it is on the rise.[2,3] Symptoms of seasonal allergic rhinitis (SAR) pose a substantial disease burden to affected patients. 
Allergic rhinitis is the local manifestation of a systemic atopic condition. The signs and symptoms are largely the result of the release of histamine from mast cells and basophils, though other mediators, cytokines, chemokines and eosinophils also play significant roles.[4] H1-receptor antagonists are an important first-line management for the symptomatic relief of SAR. However, the use of some agents in this class has been limited by treatment failure, poor tolerability, adverse effects, drug interactions, and the need for frequent drug administration; therefore, current agents have not been ideal for all patients. 

Desloratadine is a new oral, potent, selective peripheral H1-receptor antagonist. Binding studies have demonstrated that desloratadine is 14 to 17 times more potent than loratadine in inhibiting radio labelled mepyramine binding to H1-receptors in membrane preparations from guinea pig brain and lung tissue.[5] In animal studies, desloratadine is four times more potent than loratadine in blocking the activity of histamine-induced mouse paw oedema, and 10-fold more potent than loratadine in reducing guinea pig nasal response to histamine challenge.[5] Desloratadine demonstrates H1-receptor specificity including 15- to 50-fold lower affinity for muscarinic receptors (M1,M2,M4,M5) compared with H1-receptors.[5] 

In human pharmacokinetic and pharmacodynamic studies, desloratadine has a relatively long elimination half-life (27 hours),[6] [Schering-Plough, data on file] supporting once-daily administration. The pharmacokinetic profile of desloratadine is not altered by coadministration with food.[7] Clinical pharmacokinetic studies have documented no significant interaction with drugs that inhibit the cytochrome P450 enzyme system, including ketoconazole and erythromycin.[8,9] Also in human studies, desloratadine has no clinically significant effect on electrocardiographic parameters, even when administered in up to nine times the recommended clinical dose (5mg) for 10 days.[10] 

Desloratadine has been evaluated for the treatment of patients with SAR. In a dose-ranging study the 5mg dose was determined to be the optimal clinical dose for patients 12 years and older. The following summarises the tolerability and efficacy of the 5mg dose of desloratadine given once daily for 14 days to patients with documented SAR from two placebo-controlled trials, one conducted during the spring allergy season and the second during the fall allergy season. 

Patients and Methods
General Study Designs
Both studies were multicentre, randomised, double-blind, placebo-controlled, parallel-group investigations designed to ensure that 150 patients were to be evaluable for each study group for the primary endpoint. Patients enrolled were >/=12 years of age, of either gender and of any race, and had at least a 2-year documented history of SAR and a positive (prick or intradermal) skin test response to the appropriate seasonal allergens within 12 months prior to enrolment. All patients were clinically symptomatic at both the screening and baseline visits with at least moderate nasal rhinorrhoea (i.e. score >/=2), a total nasal (nasal itching, nasal stuffiness/congestion, rhinorrhoea and sneezing) symptom score >/=6, and a total non-nasal (itching or burning eyes, itching of ears or palate, eye redness and eye tearing) symptom score >/=5 (table I). Patients were in general good health as confirmed by routine laboratory and clinical testing. Clinical laboratory tests (CBC, blood chemistries, urinalysis) were within normal limits or clinically acceptable to the investigator. Patients were free of any clinically significant disease (e.g. haematopoietic, cardiovascular, hepatic, renal, neurological, psychiatric, autoimmune disease) that would interfere with the study evaluation. All patients provided written, informed consent and the study was performed in accordance with the Declaration of Helsinki.
Exclusion criteria included patients with: rhinitis medicamentosa; clinically significant sinusitis or chronic purulent postnasal drip; investigational drug use within 30 days prior to screening; or women who were pregnant or nursing. Any patient with an upper respiratory infection (URI) or sinus infection requiring antibiotics within 14 days of screening or a viral URI within 7 days of screening and patients with nasal structural abnormalities that interfered with nasal airflow were also excluded. Additionally, patients receiving immunotherapy were excluded unless they were on a regular maintenance schedule for 6 months or more that would be continued throughout the study. Excluded medications were asthma medications, nasal, oral or ocular decongestants, nasal topical antihistamines, nasal corticosteroids, and systemic antibiotics. Eligible patients were randomised to receive either 5mg desloratadine or placebo using a computer-generated schedule.

Patients completed a 1-week screening period during which the severity of symptoms was recorded twice a day for at least 3 complete days before the baseline visit. Symptoms were scored based on a reflection of how patients felt over the previous 12 hours (reflective) and how they felt at the time of the assessment, and were recorded in a diary twice daily [morning (am) and afternoon (pm)]. During the 2-week treatment period, the primary assessment of efficacy was the change from baseline in the average reflective 12-hour am/pm total symptom score (TSS). The TSS was determined by a summation of the individual nasal and non-nasal symptom scores. The primary end-point was the mean change from baseline in the TSS averaged over the 2-week study period (i.e. days 2 to 15). Other parameters evaluated included a change from baseline in morning instantaneous (end of dosage interval) total symptom scores. Other efficacy assessments included total nasal and non-nasal symptom scores. Tolerability evaluations included monitoring of adverse events, physical examination changes, laboratory values, and ECGs obtained at baseline and at the end of the treatment period.

Statistical Analysis

A two-way analysis of variance (ANOVA) was used to analyse the primary efficacy variable in order to identify sources of variation due to treatment and centre. All patients receiving at least one dose of study drug were included in the efficacy analysis (intent-to-treat), and confirmatory analyses were based on evaluable patients who had no protocol violations.

Results

Spring Allergy Season
In this study, 172 patients were randomised to desloratadine 5mg and 174 to placebo during the spring allergy season (i.e. April to June). Baseline demographics were similar between patients in the desloratadine 5mg group and the placebo group (table II). Patients were predominantly white and between the ages of 18 and 65 years, and the mean duration of SAR was 17 years. Baseline 12-hour reflective am/pm TSS were similar in the desloratadine and placebo groups (14.2 and 13.7, respectively), as were nasal and non-nasal symptom scores (table II).
Desloratadine therapy reduced the 12-hour reflective am/pm TSS by 4.3 (a 28% reduction), averaged over the 2-week study period. This reduction was significant compared with placebo, where the TSS was reduced by 2.5 (a 12.5% reduction), averaged over the 2 weeks (p < 0.01) [fig. 1]. Reductions in the 12-hour reflective am/pm TSS ranged from 3.7 to 4.8 (a 25 to 30% reduction) for patients receiving desloratadine compared with a decrease in TSS of 1.6 to 3.2 (4 to 18% reduction) in the placebo group. Analysis of response by gender found no differences between men and women. A significant reduction in the 12-hour reflective am/pm TSS with desloratadine vs placebo was observed beginning as early as day 2 and this persisted throughout the 2-week treatment period (p < 0.01 vs placebo for all time-points) [fig. 2].

Patients also evaluated their 'instantaneous' symptoms at the end of each drug administration interval, which provided information relative to the 24-hour duration of effect for desloratadine. At the earliest evaluation following the first dose, patients receiving desloratadine had a significant reduction in TSS of 2.9 from baseline compared with those receiving placebo, which decreased by 1.5 (p <0.01).

At the efficacy evaluation on day 2, total nasal symptoms (12-hour reflective am/pm) were significantly reduced from baseline in patients receiving desloratadine 5mg compared with placebo (1.9 vs 0.9 reduction, respectively; p < 0.01). A significant effect in the desloratadine group was maintained at all evaluated time-points throughout the 2-week study (p = 0.01) [fig. 3a]. Likewise, the reduction in total non-nasal symptom score from baseline (12-hour reflective am/pm) was 1.7 in the desloratadine treatment group compared with 0.7 in the placebo treatment group (p < 0.01) at the first evaluation (day 2) [fig. 3b]. Moreover, a significant reduction from baseline vs placebo was observed at all additional time-points (p < 0.01).

Fall Allergy Season

During the fall allergy season (August to November), 164 patients were randomised to desloratadine 5mg once daily and 164 to placebo for 14 days. The demographic characteristics of both treatment groups were similar, and the mean duration of allergy symptoms was 20 years (table II). Baseline 12-hour reflective am/pm TSS were similar in the desloratadine and placebo groups (17.0 and 17.1, respectively), as were nasal and non-nasal symptom scores (table II). The average baseline TSS of patients in the fall study was higher compared with that in the spring study.
Based on the primary efficacy variable (12-hour reflective am/pm TSS averaged over days 2 to 15), desloratadine was significantly more effective than placebo at reducing allergy symptoms during the fall allergy season. In the desloratadine 5mg treatment group, a 5.1 decrease (30% reduction) over baseline in TSS was observed versus a 3.8 decrease (22% reduction) in the placebo group (p = 0.02) [fig. 4]. These significant reductions in TSS were also observed for assessments at the first and second week time-points of the study, for the overall 2-week duration of the study, and when symptom scores were assessed for either nasal or non-nasal symptoms (table III). Patients receiving desloratadine 5mg once daily experienced a decrease of 2.4 to 2.9 (26 to 32% reduction) in total nasal symptoms compared with 1.9 to 2.1(21 to 23%, p < 0.05) for placebo. Similarly, there was a decrease of 2.3 to 2.8 (30 to 37%reduction) in total non-nasal symptoms versus 1.7 to 2.1 (21 to 25% reduction, p </= = 0.04) in the placebo group (table III). Analysis of response by gender found no differences between men and women.

Tolerability Evaluation

Data from both studies demonstrated a placebo-like tolerability profile for desloratadine 5mg given once daily for 14 days. The pattern and incidence of total and treatment-related adverse events were similar for desloratadine 5mg and placebo (table IV). Total adverse events reported in both studies were 40 to 49% for patients treated with desloratadine 5mg and 37 to 52% for patients treated with placebo. Adverse events reported were mild to moderate in severity, and no serious adverse events were attributed to desloratadine therapy. The most frequent adverse event was headache, occurring in 16 to 24% of patients treated with desloratadine 5mg once daily; however, patients treated with placebo had a similar frequency of headache (14 to 27%) [table IV]. The incidence of somnolence was also similar for desloratadine and placebo in both studies (table IV).
No unusual or unexpected adverse events were reported in either study. Results of routine physical examinations and laboratory tests (including evaluations of renal and hepatic function) were unremarkable and no significant changes from baseline were observed with desloratadine therapy. In the spring study, five patients in the desloratadine group discontinued treatment because of an adverse event compared with 10 in the placebo group. Five patients discontinued treatment in the fall study, and only one adverse event was considered treatment related. A similar number of patients discontinued in the placebo group.

Assessment of ECG data revealed no clinically significant changes from baseline between desloratadine- and placebo-treated patients. In the spring study, patients receiving desloratadine had a 2% reduction from baseline for the QTc interval compared with a 3% reduction in patients receiving placebo. In the fall study, patients receiving either desloratadine or placebo had </=0.3% reduction in QTc interval from baseline.

Discussion

SAR is a highly prevalent condition causing significant morbidity for chronic sufferers. People with SAR generally have predictable onset of allergic symptoms that can last through the allergy season if untreated. Tree sensitivities are often presenting early spring,followed by grasses and weeds in late summer through the fall.[11] Most studies[12-16] reported in the literature with the newer H1-receptor antagonists were conducted during the fall allergy season so there is less information on the efficacy of these agents during the spring allergy season.
Desloratadine 5mg once daily effectively reduced the symptoms of SAR during both the spring and fall allergy seasons as demonstrated in these two double-blind, placebo-controlled studies. Desloratadine administration resulted in a significant reduction of the total symptom scores, which included the nasal and non-nasal symptoms associated with SAR in both studies for the full 2-week study period. Furthermore, improvement in symptoms was observed after only one dose of desloratadine. Symptomatic improvement was maintained for the full 24-hour drug administration interval and throughout the duration of the studies. In addition, a reduction in both total nasal (nasal itching, nasal stuffiness/congestion, rhinorrhoea, sneezing) and total non-nasal (itching or burning eyes, itching of ears or palate, eye redness or tearing) symptoms was seen, indicative of the breadth of desloratadine efficacy against the spectrum of SAR symptoms.

In both of these placebo-controlled trials, the 5mg dose was well tolerated. Importantly, no effect on ECG parameters was observed with desloratadine.

Conclusion

Desloratadine 5mg once daily is effective for the treatment of symptoms of both spring and fall seasonal allergic rhinitis, resulting in relief of nasal and non-nasal symptoms that is maintained with continued administration. Once-daily administration provides full 24-hour improvement in symptoms. The tolerability profile of desloratadine is similar to placebo, with no somnolence or other significant CNS or cardiovascular adverse effects.

Acknowledgements
Funding was provided by Schering-Plough Research Institute, Kenilworth, New Jersey, USA.

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25.) Schering-Plough Announces European Union Approval of Desloratadine 
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Dateline: January 16, 2001
Schering-Plough Press Release 
KENILWORTH, N.J. - Schering-Plough Corporation announced that the European Commission of the European Union (EU) has granted marketing authorization for desloratadine 5 mg tablets as a once-daily, nonsedating treatment of seasonal allergic rhinitis (SAR) in adults and children 12 years of age and older. Desloratadine will be marketed in the EU under the brand names Aerius and Neoclarityn. 

Commission approval of the centralized application for Aerius/Neoclarityn results in a single Marketing Authorization with unified labeling that is immediately valid in all 15 EU-Member States. The Commission’s decision follows the product’s recommendation for approval in September 2000 by the EU’s Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA). 

Aerius/Neoclarityn will be introduced upon receiving pricing and/or reimbursement approvals, where necessary, from individual EU countries. 

In the United States, marketing applications for desloratadine tablets are currently pending with the U.S. Food and Drug Administration (FDA) for the treatment of SAR and chronic idiopathic urticaria (CIU), or hives of unknown cause, and for desloratadine in a rapidly disintegrating tablet formulation as a treatment of SAR and CIU. The company has also submitted separate applications to the FDA for desloratadine syrup as a treatment of SAR and CIU in patients as young as 2 years of age, and for desloratadine tablets in a fixed combination with a decongestant as a twice-daily treatment of SAR for adults and children 12 years of age and older. 

"The approval of desloratadine in Europe represents a significant step in establishing desloratadine as an important new therapy for the treatment of seasonal allergies on a global basis," said Roch F. Doliveux, president, Schering-Plough International. "With this approval, Schering-Plough expects to move swiftly to market Aerius and Neoclarityn in the European Union." 

Seasonal allergies affect an estimated 36 million people in the five major European countries of France, Germany, Italy, Spain and the United Kingdom. Seasonal allergy symptoms, which classically include sneezing, itching, nasal discharge, nasal congestion, ocular itching, tearing and redness, and itching of the palate, can have a significant impact on everyday activities at work, school and leisure time. In addition, there is a growing body of evidence that points to an association between allergies and even more serious conditions such as asthma. 

Aerius/Neoclarityn is a highly potent H-1 receptor antagonist that effectively controls SAR symptoms with nonsedating relief for 24 hours. In clinical trials the most common side effects were headache, dry mouth and fatigue, with an incidence rate similar to placebo. 

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide. 

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26.) DESLORATADINE 
============================================================
Source: Prescribing Points July 2001

Desloratadine, a newly licensed antihistamine, has recently been turned down by the Oxford Radcliffe Medicines Advisory Committee for inclusion in the hospital formulary. The following paper outlines the data that was presented to the Committee. It is hoped that before next years hayfever season we will be able produce a complete review of hayfever treatment with Mr Grant Bates at the RI and the help of one or two GPs. 

Pharmacological action

Desloratadine is a potent, selective, non-sedating histamine H1-receptor antagonist with antiallergic and anti-inflammatory properties. It is the major metabolite of loratadine. Following oral administration, loratadine is metabolised to desloratadine and a number of less active metabolites that compete for the H1 receptor. 

Indication

Desloratadine is indicated for the relief of symptoms associated with seasonal allergic rhinitis (SAR) in adults and children over 12 years. Unlike the other six non-sedating antihistamines, desloratadine is not currently licensed for the treatment of urticaria. 


Efficacy

A review of the treatment of seasonal allergic rhinitis by the National Prescribing Centre concluded that oral antihistamines relieve ocular symptoms, rhinorrhoea, sneezing and nasal irritation but have little or no effect on nasal congestion. The review stated that there is no difference in efficacy between any of the antihistamines in terms of efficacy, however response to a particular agent may vary between individuals. The choice of non-sedating agent should be based on relative safety, individual response and patient preference1. This review did not include desloratadine or fexofenadine. 

In addition to its anti-histamine actions, desloratadine is reported to exhibit anti-inflammatory properties. In vitro desloratadine inhibits a wide range of mediators including IL-4, IL-6, IL-8, IL-13 and P-selectin at therapeutic concentrations2. The anti-inflammatory activity of desloratadine against IL-6 and IL-8 has been shown to be of the same order of magnitude as dexamethasone3. 

In trials involving patients with moderate to severe SAR, desloratadine conferred rapid and sustained relief of nasal congestion. Pooled results from four randomised, parallel group, double blind placebo controlled studies (1982 patients) showed a significant improvement (25%) in nasal congestion scores at both 2 days and 15 days (p<0.05)5. Fexofenadine has also been shown to reduce nasal congestion in some studies. There is no evidence to show that this improvement in nasal congestion will reduce the need for topical nasal steroids. 

Tolerability

In studies the incidence of side effects is comparable to placebo. No clinically relevant effects, including cardiovascular effects have been reported5 (see table 2). In a placebo controlled study to assess the effects of desloratadine on driving performance, there was no significant difference from placebo4. 

Table 2: Adverse drug reactions reported for desloratadine reported by >2% patients 

Adverse event Placebo
(n=661) Desloratadine 5mg
(n=659) Desloratadine 7.5mg
(n=662) 
All events 83 (12.6) 111 (16.8) 102 (15.4) 
Headache 26 (3.9) 38 (5.8) 36 (5.4) 
Fatigue 10 (1.5) 17 (2.6) 17 (2.6) 
Somnolence 15 (2.3) 14 (2.1) 18 (2.7) 
Dry mouth 12 (1.8) 21 (3.2) 14 (2.1) 

Summary

The choice of non-sedating antihistamine should be based on relative safety, individual response and patient preference. The most commonly prescribed agents in Oxfordshire are loratadine and cetirizine and these should be considered first line non-sedating antihistamines. 

Desloratidine was not accepted onto the formulary by the Medicines Advisory Committee mainly due the fact that loratidine will to come off patent in the near future and thus is likely to be considerably cheaper. It was also felt that the benefits of desloratidine are likely to be small. Patients with nasal congestion may require a steriod nasal spray to control symptoms in addition to oral antihistamines Prescribing Points June 1999 Vol 8.4). 

Antihistamine Expenditure Chart

References 

1. National Prescribing Centre. Treatment of seasonal allergic rhinitis (hay fever). MeReC Bulletin 1998; 9(3): 9-12. 

2. Molet S et al. Inhibitory activity of loratadine and desloratadine on histamine-induced activation of endothelial cells. Clin Exp Allergy 1997; 27: 1167-1174. 

3. Lippert U et al. Pharmacological modulation of IL-6 and IL-8 secretion by the H1antagonist desloratadine and dexamethasone by human mast and basophilic cell lines. Exper Dermatol 1995; 4: 272-276. 

4. Vuurman EFMP et al. Desloratadine does not impair actual driving performance: a three-way crossover comparison with diphenhydramine and placebo. Unpublished data on file 2000. 

5. Nayak A et al. Decongestant effects of desloratadine in patients with seasonal allergic rhinitis. J Allergy Clin Immunology 2000; 105(1): 

Ali Harris
Clinical Effectiveness Pharmacist, RI 
=============================================================
27.) SCHERING-PLOUGH REPORTS DESLORATADINE RECEIVES FDA "APPROVABLE" LETTER
=============================================================
KENILWORTH, N.J., Jan. 25, 2001 – In response to inquiries and a media report, Schering-Plough Corporation (NYSE: SGP) confirmed today that it received an "approvable" letter for its nonsedating antihistamine desloratadine on Jan. 19, 2001, from the U.S. Food and Drug Administration (FDA). The product is subject to final approval by the FDA.

Schering-Plough Corporation is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

DISCLOSURE NOTICE: The information in this press release includes certain forward-looking information relating to the potential approval of a new product. Due to market factors, governmental regulations and legislation, the regulatory review process, manufacturing issues, patent positions and litigation, trade buying patterns, among other things, the potential approval of desloratadine and its market potential are subject to risks and uncertainties. For further details and a discussion of these and other risks and uncertainties, see the company’s Securities and Exchange Commission filings, including the company’s 1999 annual report on Form 10-K.

=============================================================
28.) SCHERING-PLOUGH ANNOUNCES EUROPEAN UNION APPROVAL OF DESLORATADINE FOR TREATMENT OF CHRONIC IDIOPATHIC URTICARIA
=============================================================
KENILWORTH, N.J., Aug. 9, 2001 ¾ Schering-Plough Corporation (NYSE: SGP) today announced that the European Commission of the European Union (EU) has granted marketing authorization for desloratadine 5 mg tablets as a once-daily, nonsedating treatment for the symptoms of chronic idiopathic urticaria (CIU) such as itching or hives in adults and children 12 years of age and older. Desloratadine received EU approval for the treatment of seasonal allergic rhinitis (SAR) in January 2001 and is marketed in the EU under the brand names AERIUS and NEOCLARITYN.

Commission approval of the centralized application for desloratadine in CIU results in a single Marketing Authorization with unified labeling that is immediately valid in all 15 EU-Member States as well as in Iceland and Norway. The Commission’s decision follows the product’s recommendation for approval in April 2001 by the EU’s Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA).

"Since its EU approval in January, desloratadine has gained rapid acceptance in several major European markets as a significant new therapy for the treatment of seasonal allergies," said Roch F. Doliveux, president, Schering-Plough International. "The approval of desloratadine in the treatment of CIU represents another important step in our efforts to expand and enhance its clinical profile."

Affecting an estimated 15 to 25 percent of people at least once in their lives, urticaria is a reaction to a variety of substances, including food, drugs and topical agents, and characterized by an eruption of itchy, swollen lesions on the skin. An estimated 25 percent of urticaria patients develop CIU, which is defined as a case that lasts for a period of at least six weeks and has no identifiable cause. Up to 20 percent of prescription antihistamine use in the EU can be attributed to CIU therapy.

Desloratadine is a highly potent H-1 receptor antagonist that effectively controls the symptoms of SAR and CIU with nonsedating relief for a full 24 hours. In clinical trials the most common side effects were headache, dry mouth and fatigue, with an incidence rate similar to placebo.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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29.) PUBLIC CITIZEN 
=============================================================
source PUBCLIC CITIZEN

March 1, 2001

Tommy Thompson, Secretary, 
Department of Health and Human Services
200 Independence Avenue, SW
Washington, D.C. 20201

Dear Secretary Thompson:

During the past 15 months, 59 million asthma inhalers manufactured by Schering-Plough for treating acute attacks of asthma had to be recalled because of dangerously sloppy manufacturing procedures which resulted in many units failing to contain the active ingredient, albuterol (brand name Proventil(1)). We have obtained a confidential external audit by the AAC Consulting Group of Rockville, Maryland, contracted for by Schering-Plough, conducted at Schering-Plough's manufacturing facility at Kenilworth NJ, where these life-sustaining products were manufactured. This audit took place from February 28, 2000 to April 14, 2000(2). The auditors were extremely critical of the general attitude of management personnel who described to them--- "an imbalance between quality and production, leaning considerably toward production". They also found serious specific problems with the quality control of the production of the asthma inhalers such as the fact that "An in-process assay for the active ingredient in Proventil is not performed." Managers told the auditors that "aerosol products are a major money maker for the company". But, the auditors concluded, "significant manufacturing problems have been experienced with this product class, which is indicative of insufficient technical expertise and managerial oversight...." 

In addition, we have obtained the summary of a very recent 31-day FDA inspection of the same plant completed January 19th of this year in which FDA inspectors found a persistence of many of the same kinds of problems with the quality of manufacturing uncovered one year ago during the private audit of Schering. The FDA investigators concluded that "The process validation for many products fails to support claims that manufacturing processes were capable of consistently producing products with the same quality, purity and safety."(3) 

We urge you to launch an investigation into criminal charges against Schering-Plough based on the possibility that the company knowingly shipped millions of the 59 million units of albuterol-containing asthma drug eventually recalled between the time the company became aware of the seriously flawed manufacturing processes and the time the recall was finally accomplished. We also urge that you investigate the company for continuing to ship other prescription drug products while fully aware of the serious violations of FDA good manufacturing practice (GMP) regulations during their production.

The current quality control problems found in that manufacturing plant during the recent FDA inspection are so serious that there has been a "temporary interruption of some production lines"(4) and it will not be allowed by the FDA to gain approval or start shipping its new allergy drug, Clarinex, a metabolite of the active ingredient in its top-selling Claritin, which it had previously planned to ship very soon. During that inspection, FDA investigators found that "There was no assurance that the manufacturing process, parameters, equipment or protocols...conducted at multiple sites for the production of Clarinex (Desloratidine tablets, 5 mg) are equivalent or capable of producing product of the same quality." No other new Schering-Plough products will be approved until these serious manufacturing problems are resolved.

SCHERING'S PRIORITY OF PRODUCTION OVER QUALITY: A FORM OF CONTEMPT FOR THE SAFETY OF PATIENTS 

Added to the findings of Schering-Plough's own consultants and the results of the FDA's most recent inspection of the Kenilworth NJ facility, is the fact that the FDA has issued at least five Warning Letters to the company since June, 1998 detailing serious GMP problems in its manufacturing facilities in New Jersey, Puerto Rico, and Ireland. 

Table 1 below summarizes the five Warning Letters directed at various Schering-Plough plants since June 29, 1998 for serious deviations from GMP guidelines. 

Table 1 ­ Warning Letters Issued to Schering-Plough by the Food and Drug Administration for Good Manufacturing Practice Guideline Deficiencies for the Production of Human Drugs Since June 1998 
Date Facility Drug(s) Involved Examples of Problems Noted in Warning Letters 
6/29/98 (5) Las Piedras, Puerto Rico Theo-Dur, 
Claritin 10 mg Extension of expiration period for Theo-Dur, an asthma drug.
Failure to investigate variability in Claritin 10 mg tablets, an antihistamine. 
10/23/98 (6) Kenilworth and Union, New Jersey Proventil Inhaler, Claritin D, 
Diprolene Oint., Nasonex Nasal Spray Proventil Inhaler, an important asthma drug, failing pressure results. 
Claritin D, a combination antihistamine-decongestant, dissolution rate problems. 
Diprolene Ointment, a topical steroid, out of specification assay results. 
Nasonex Nasal Spray, used for allergy, failed to conform to all specifications. 
11/23/98 (7) Innishannon, County Cork, Ireland Intron A Intron A is an injectable used to treat a variety of disorders including some cancers and chronic hepatitis C. Failure to establish appropriate procedures to insure that Intron A is sterile. 
7/21/99 (8) Kenilworth and Union, New Jersey Vanceril DS Inhaler, Proventil Inhaler Vanceril Inhaler, used to treat chronic asthma, failure to follow test procedures and failure to meet specifications. 
Proventil Inhaler, also for asthma, there was failure to properly test the content of canisters. 
5/8/00 (9) Manati, Puerto Rico Garamycin Ophthalmic Solution, 
Vancenase AQ, Nasonex Nasal Garamycin is an antibiotic used to treat eye infections. There was failure to perform adequate investigation into the cause of out of specifications results for stability testing for some batches of the drug. 
Vancenase AQ and Nasonex Nasal suspension are used for allergy treatment. There were deviations from protocol for the Uniformity of Spray Content Assays for these products. 

Six months before the FDA began their most recent inspection of the Kenilworth NJ facility on November 1, 2000, Schering-Plough's consultants, AAC Consulting Group, noted in their audit of this plant on April 27, 2000: 

Upper management needs to demonstrate its long term commitment to product quality, such as through increased staffing/budget resource allocations and investments in new equipment, in order to supplant the traditional emphasis on production and firmly establish a company culture in which quality is, in fact, the number one priority.(10) 

AAC Consulting found that "Most units fail to have documentation demonstrating that operators are qualified in all required critical tasks. Some areas also lack approved training procedures." The consultants noted that although Schering-Plough's upper management had recently placed some emphasis on quality " there is staff concern that this commitment to quality may not be long term."(11) 

The consultants asked supervisors, managers, and operators if they perceived a real change in the company's commitment to improving product quality since the aerosol recalls and problems with the FDA in late 1999. The consultants observed: 

Most managers/supervisors have adopted a wait and see attitude, to determine if upper management will "walk the talk" with respect to long term commitment to product quality. They state that for many years they have been under significant pressure to get production out and don't feel they have had enough time or people to do a quality job. They indicated that there has been in the past a continual push for increased production and decreased down time sometimes at the expense of quality work and GMP compliance. They believe there has been an imbalance between quality and production, leaning considerably toward the side of production.(12) 

After five Warning Letters for serious GMP violations in a period of only two years and an audit conducted by outside consultants of the Kenilworth NJ facility, a plant that had previously had been issued two Warning Letters, serious GMP violations were found seven months later by the FDA. The first point in the FDA's report referred to the quality of products produced at this facility. The FDA inspectors observed: 

The Quality Control Unit failed to assure that drug products were manufactured in compliance with cGMPs and therefore have the safety, quality, and purity that they purport, or are represented to possess.(13) 

CHRONOLOGY AND REPEATED MANUFACTURING DEFECTS WITH IMPORTANT DRUGS 

Appendix 1, at the end of this document, is the chronological sequence of important events in the Schering-Plough affair. 

ALBUTEROL (PROVENTIL) ASTHMA INHALERS 
------------------------------------

Two of the Warning Letters, 10/23/98 and 7/21/99, involve manufacturing problems with albuterol (PROVENTIL) aerosol inhalers. Albuterol is a drug of vital importance for asthmatics. It is frequently used to stop acute asthma attacks. 

The 7/21/99 Warning Letter also reveals meetings and communications between Schering-Plough and the FDA's Center for Drug Evaluation and Research (CDER). On 6/25/99, CDER informed Schering-Plough's Vice President for Worldwide Regulatory Affairs of a four phase prior approval program for the release of albuterol inhalers by the company. 

Defective manufacturing of albuterol led to almost 60 million canisters of this drug being recalled because some canisters did not contain the active ingredient. The first recall took place on 9/9/99 and involved 190,679 units of the drug. The second, on 3/29/00, recalled 58,936,179 canisters of albuterol. 

Schering-Plough knew of problems with the production of albuterol inhalers during the July 30, 1998 inspection of the Kenilworth NJ facility that resulted in the October 23, 1998 Warning Letter. By late June of 1999, the company had to agree to prior approval by the FDA before any albuterol inhalers could be distributed by the company.

The AAC Consulting Group began their audit at Kenilworth NJ on February 28, 2000 and submitted its final report to Schering-Plough on April 27, 2000. After two Warning Letters and two recalls involving albuterol inhalers, the consultants made the following observations regarding the manufacturing of albuterol inhalers: 

Evaluation of this manufacturing area disclosed significant changes in both procedures and record keeping practices. Overall, these were found to be positive, but some observations did reflect potential problem areas and perhaps even some degree of over-reaction to the recent aerosol product recalls.(14) 
It is our understanding, based on interviews with supervisors and managers, that aerosol products are a major money make for the company. In addition, significant manufacturing problems have been experienced with this product class, which is indicative of insufficient technical expertise and managerial oversight. This production area does not have the visibility and importance from an organizational standpoint that it needs in order to quickly and effectively recover from past problems, maintain satisfactory regulatory compliance, attract and retain necessary expertise, and grow in the future.(15) 
Some components, such as aerosol valves from 3M Neotechnic, are received for testing already pre-sampled by the vendor. There is no assurance that the samples provided to Schering were collected by the vendor according to accepted sampling procedures and are representative of the entire lot.(16) 
Updating aerosol test procedures should be given the highest priority in light of past problems with this product class and the intense scrutiny Schering operations in this area is currently undergoing by FDA.(17) 
An in-process assay for the active ingredient in Proventil is not performed. Reportedly, R&D has been trying for several years without success to shorten the Proventil final release assay procedure, so that it is suitable for in-process testing.(18) 
An in-process assay method for Proventil should be developed and validated as soon as possible so that the active ingredient is quantified in-process as is done for all other Schering aerosol products.(19) 
The AAC audit was completed six months before the FDA's most recent inspection of Kenilworth NJ. Still the FDA observed deficiencies in the manufacture of albuterol inhalers: 

Aerosol Manufacturing Line 76 with the online stress testing heating blocks was validated in that the two validation attempts have failed to meet the validation protocol acceptance criteria.(20) 
Validation Summary Report #Val-9-184, (validation for the use of the heating blocks for on-line stress testing for Proventil/Albuterol) was inadequate in that 1 out of 3 original Validation Batches, #9-BBS-640, was rejected for excessive downtime and rejected canisters (purged cans). An additional Validation Batch, #9-BBS-643, was also rejected due to out-of-specification leak test results.(21) 
A second validation attempt of the heating blocks for on-line stress testing was executed under Validation Summary Report #VAL-00-48. This validation was inadequate in that Validation Batch #'s 0-BBS-572m 0-BBS-573 & 0-BBS-574 failed to meet the process validation acceptance criteria for total content of Albuterol. Additionally, the rinse method utilized by the laboratory to retest the total content of Albuterol per canister was never validated.(22) 
The Product Quality Review (PQR) methods for the Delivery of Albuterol through the Actuator and Particle Size for Proventil Aerosol Inhaler were inadequate in that the methods exhibit various unidentified extraneous peaks. PQR Methods for Total Content of Albuterol per Can Assay and Estimation of Degradation Products were also inadequate in that there was a lack of resolution between typical unknown peaks from neighboring active or placebo peaks. These methods were used to test and release product batches, as well as stability samples, from 10/11/99-12/7/00.(23) 

LORATADINE WITH PSEUDOEPHEDRINE (CLARITIN D) 
---------------------------------------------

Problems with the production of the antihistamine loratadine in combination with pseudoephedrine (CLARITIN D) were identified in the July 30, 1998 inspection of the Kenilworth NJ plant that resulted in the October 23, 1998 Warning Letter. 

Eighteen months later AAC Consulting continued to find problems with the production of Claritin-D: 

Previously filed validation reports for Claritin-D (Once-a-Day), with the same product ID (GJKS), were performed in 1993. The protocols and final reports were reviewed and approved by production and quality in 1995. One of the batches manufactured failed final blend specifications, but this validation was approved by management nearly two years later. There was no statement as to the batch's disposition.(24) 
The annual product review for Claritin-D 24 reflected 45 of 752 finished tablet batches were rejected. Of those there were 35 rejected for high moisture, 5 for variable loratadine content. This would seem to reflect that the process is not validated. There also were 44 batches that had low granulation yield based on product hang-up in the equipment. This same issue has been seen with other products and it is not apparent that there has been a for cause investigation done to determine why product is hanging up in the equipment. There also were 307 batches that had low yield. This has caused variance and MRB reports. It appears that the specs may not be appropriate and/or the process is not validated. Addressing this issue could cut down on a lot of unnecessary investigation time.(25) 
The FDA also continued to find deficiencies in the production of Claritin-D in their most recent inspection of the Kenilworth NJ plant: 

Validation of the Claritin D-24hr. ER Tablet process, using a drug substance from a new source (Schering, Singapore) was not adequate in that only one batch was manufactured. Change Authorization #CA-99-248 allows for the use of this alternate source. The new drug substance was used to manufacture batch #'s 0-DCS-257 through 0-DCS-340, approximately 95 batches.(26) 
The current revalidation Protocol, #VAL-0-61, for Claritin D-24 hr. ER Tablet Cores contained incorrect acceptance criteria, but was signed and approved by Validation, QC, and Manufacturing Departments. Specifications for two finished product tablet tests were erroneously included as the acceptance criteria for the tablet cores.(27) 

DESLORATADINE (CLARINEX) 
------------------------

Desloratadine (CLARINEX) is Schering-Plough's replacement for its overpriced antihistamine loratadine (CLARITIN). Desloratadine is the major metabolic breakdown product of loratadine. It appears from the FDA's recent Kenilworth NJ inspection that there are serious problems with the production of desloratadine that will prevent final approval of the drug. The FDA observed the following in their recent inspection: 

There was no assurance that the manufacturing process, parameters, equipment, or protocols and acceptance criteria, conducted and generated at multiple sites for the production of Clarinex (Desloratadine Tablets, 5 mg) are equivalent, or capable of producing product of the same quality. 
The test method transfer from Schering, Kenilworth to Schering, Puerto Rico failed to demonstrate that accurate and reliable results could be obtained from the QC laboratory. 
There was insufficient comparability data for the drug substance, Desloratadine, manufactured at the firm's Ireland and Singapore sites to assure equivalence of the drug substance supply.(28) 
In conclusion, it is clear that there are an extraordinary variety of serious problems at the Schering-Plough manufacturing plant in Kenilworth, New Jersey which threaten the safety of drugs already shipped out of the facility and bespeak the need for extreme caution in allowing any further products to be shipped from that plant. In addition, we hope you insist that the FDA investigate the possibility of criminal behavior on the part of those Schering-Plough officials who may have knowingly shipped defective pharmaceutical products for use in unsuspecting patients. We expect a prompt response to this urgent request. 

Sincerely, 

Larry Sasich, Pharm.D., MPH 
Research Associate 

Sidney M. Wolfe, M.D., Director 
Public Citizen's Health Research Group

Appendix 1 ­ Chronological Sequence of Events 
Date Action Drugs Mentioned Documentation 
5/7/98 Inspection - Las Piedras, PR From the 6/29/98 Warning Letter 
6/29/98 Warning Letter - Las Piedras, PR Theo-Dur Claritin 10 mg www.fda.gov/foi/warning_letters/d1423b.pdf accessed 2/19/01 
7/30/98 Inspection - Kenilworth and Union, NJ From 10/23/98 Warning Letter 
10/23/98 Warning Letter - Kenilworth and Union, NJ
"Current regulations specify that drug products failing to meet standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed, provided certain criteria are met according to written procedures. The practice of partial releases, no matter how stringent the re-sampling, raises doubt as to the safety and efficacy of the product being released. It is not acceptable to substitute testing over adequate control of a process." Claritin-D, Diprolene Oint, Proventil Inhaler, Nasonex Nasal Spray www.fda.gov/foi/warning_letters/m2366n.pdf accessed 2/19/01 
11/23/98 Warning Letter - County Cork, Ireland Intron A www.fda.gov/foi/warning_letters/m2327n.pdf accessed 2/19/01 
5/28/99 Inspection Union and Kenilworth, NJ From 7/21/99 Warning Letter 
6/7/99 Teleconference in NJ between S-P and CDER concerning Proventil and Vanceril inhalers. From 7/21/99 Warning Letter 
6/17/99 Meeting at FDA between S-P and CDER to discuss conditions under which S-P may resume shipment of Proventil Inhalers. From 7/21/99 Warning Letter 
6/25/99 CDER letter to Dr. Alexander Giaquinto, Sr. VP, Worldwide Regulatory Affairs detailing a four-phase proposal for the release of Proventil Aerosol. S-P must strictly adhere to the proposal to continue distributing Proventil Inhalers. This amounts to "prior approval" by the FDA. From 7/21/99 Warning Letter 
7/21/99 Warning Letter - Union and Kenilworth, NJ 
The 6/15/99 response to the 10/23/98 Warning Letter was not satisfactory. Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Retesting later is not an acceptable practice. Vanceril 
Proventil www.fda.gov/foi/warning_letters/m2818n.pdf accessed 12/19/01 
9/9/99 Class I Recall ­ Warrick Pharmaceuticals Albuterol Aerosol. 190, 679. AL, CT, FL, GA, KY, MD, MA, NJ, NY, NC, OH, PA, RI, TN, VA, WV. Some units fail to contain active ingredient. 
The recall affects a lot that was distributed between late April and early May 1999. Schering-Plough Press Release 9/9/99 
12/2/99 Class II Recall - Vanceril Double Strength Aerosol. 82,029 units nationwide. Some units may not contain active drug. Drug was distributed in November 1999. 
"The cause of the problem has been identified as inadequate batch start-up practices that occurred for a short period during filling of the subject lots. The company has taken corrective actions to prevent a recurrence." Schering-Plough Press Release 12/2/99 
3/28/00 Inspection - Manati, PR 5/8/00 ­ Warning Letter 
3/29/00 Class II Recall ­ Proventil/Albuterol inhalers, 58,936,179; Vanceril 84 mcg, 831,594 units; Vanceril 42 mcg, 5,274,819 units; Vancenase, 2,706,424 units nationwide, PR, and Canada. Some canisters may not have active ingredient. 
This recall relates to an aerosol manufacturing problem that had been previously identified in October 1999. 
Does not involve any inhaler manufactured after September 30, 1999. These inhalers would have an expiration date of Oct 2001 or later. Schering-Plough Press Release 3/29/00 
4/27/00 AAC Consulting Group audit of Kenilworth, NJ. Audit began 2/28/00 
AAC found that an in-process assay for the active ingredient in Proventil is not performed. AAC Audit Report 
5/8/00 Warning Letter - Manati, PR Garamycin Ophthalmic Solution, Vancenase, Nasonex Diprolene Gel
Celestone Injection www.fda.gov/foi/warning_letters/m3847n.pdf accessed 2/19/01 
1/19/01 FDA 483 Observations of Kenilworth, NJ 
The Product Quality Review (PQR) methods for the Delivery of Albuterol through the Actuator and Particle Size for Proventil Aerosol Inhaler were inadequate in that the methods exhibit various unidentified extraneous peaks. PQR Methods for the Total Content of Albuterol pr Can Assay and Estimation of Degradation Products were also inadequate in theat there was a lack of resolution between typical unknown peaks from neighboring active or placebo peaks. These methods were used to test and release product batches, as well as stability samples, from 10/11/99-12/07/00. (page 12) FDA 483 Inspection Report 

--------------------------------------------------------------------------------

1. The first recall, 9/9/99, involved 190,000 units and the second, 3/29/00, involved 58.9 million units. Some units manufactured by Schering in the same New Jersey facility were sold under the name of their subsidiary, Warrick, as generic albuterol. In a Q & A accompanying the second recall, Schering-Plough explained that the purpose of the recall was to "address the remote possibility that an aerosol container may not contain active drug" and said, in an extraordinary and reckless understatement of what could be a life-threatening situation, "Proventil and Warrick brand albuterol patients using a canister without active drug will not obtain their usual relief from asthma symptoms." 

2. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000. Final report is dated April 27, 2000. 

3. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1. 

4. Schering-Plough press release, February 15, 2001. 

5. Warning Letter addressed to Mr. Francisco R. Rodriquez, General Manager, Schering-Plough Products Inc., Las Piedras, Puerto Rico from Samuel Jones, District Director, Puerto Rico District, Food and Drug Administration dated June 29, 1998. 

6. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District Director, New Jersey District dated October 23, 1998. 

7. Warning Letter addressed to Colman Casey, Ph.D., Managing Director, Schering-Plough (Brinny) Co., Innishannon, Couny Cork, Ireland from Jerome A. Donlan, M.D., Ph.D., Acting Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, Food and Drug Administration dated November 23, 1998. 

8. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District Director, New Jersey District dated July 21, 1999. 

9. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Mildred R. Barber, District Director, Food and Drug Administration dated May 2, 2000. 

10. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 6. 

11. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 5. 

12. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 76. 

13. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1. 

14. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 36. 

15. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 65. 

16. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 91. 

17. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106. 

18. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106. 

19. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106. 

20. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3. 

21. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3. 

22. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3. 

23. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 12. 

24. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 9. 

25. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 85. 

26. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 2. 

27. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3. 

28. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 15. 

=============================================================
30.) SCHERING-PLOUGH REBUTS PUBLIC CITIZEN ALLEGATIONS
=============================================================
KENILWORTH, N.J., Aug. 9, 2001 –Schering-Plough Corporation (NYSE: SGP) today issued the following response to allegations made by the Public Citizen activist group regarding recalls conducted in 1999 and 2000 of the company’s albuterol inhaler products for asthma.

Schering-Plough is confident that all of its products on the market are safe and effective. The health and safety of patients who use our products remain our No. 1 priority. 

The company is extremely disturbed that the letter by Public Citizen misrepresented data and drew unfounded conclusions, which could unnecessarily alarm asthma patients. Schering-Plough emphasized that asthma patients should continue to take their medications as prescribed. 

Contrary to Public Citizen’s allegations, in all adverse event reports involving deaths where an albuterol canister was tested by the company, the canister was shown to contain active ingredient. Further, every inhaler involved in a patient’s claim of injury that has been tested by the company has been shown to date to contain active ingredient. 

Schering-Plough knows of no death or injury to a patient shown to have been caused by an inhaler lacking active ingredient. While there are some lawsuits claiming otherwise, the company is contesting them vigorously. 

Schering-Plough is committed to manufacturing products of the highest quality and took extraordinary measures in 1999 and 2000 to ensure that all of its inhalers in the marketplace were safe and effective. In all instances, the company acted promptly and responsibly with respect to the above product recalls, and in consultation with the U.S. Food and Drug Administration (FDA). 

Asthma is a very serious disease and causes more than 5,400 deaths in the United States annually. Under FDA regulations, adverse event reports are routinely reported to the FDA. Public Citizen’s allegations are based on a flawed analysis of a small number of events, which does not address event rates that occur with similar asthma rescue inhaler products. 

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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31.) LORATADINE INFORMATION FROM MOSBY YEAR BOOK. 1.996
=============================================================
CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY
------------------------------------------------------
CATEGORIES: Allergies; Antihistamines; FDA Approved 1993 Apr; FDA Class 1S ("Standard Review"); Lacrimation; Non-Sedating Antihistamines; Patent Expiration 1998 Aug; Pregnancy Category B; Respiratory & Allergy Medications; Rhinitis; Rhinorrhea; Sales > $500 Million; Sneezing; Top 100 Drugs; Urticaria
BRAND NAMES: Claritin; Clarityne*; Fristamin*; Lisino*
* Foreign brand name outside U.S.
FORMULARIES: BC/BS; Medi-Cal
COST OF THERAPY: $58.06 (Rhinitis; Tablet; 10 mg; 1/day; 30 days)
PRIMARY ICD9: 477.9 (Allergic Rhinitis, Cause Unspecified)

DESCRIPTION
-----------
Claritin Tablets contain 10 mg micronized loratadine, an antihistamine, to be administered orally. They also contain the following inactive ingredients: corn starch, lactose, and magnesium stearate.
Loratadine is a white to off-white powder not soluble in water, but very soluble in acetone, alcohol, and chloroform. It has a molecular weight of 382.89, and empirical formula of C22H23CIN2O2; its chemical name is ethyl 4-(8-chloro-5,6-dihydro-11H-benzo(5,6)cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate.

CLINICAL PHARMACOLOGY
---------------------
Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity.
Human histamine skin wheal studies following single and repeated 10 mg oral doses of Claritin Tablets have shown that the drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with Claritin Tablets.
Pharmacokinetic studies following single and multiple oral doses of loratadine in 115 volunteers showed that loratadine is rapidly absorbed and extensively metabolized to an active metabolite (descarboethoxyloratadine). Approximately 80% of the total dose administered can be found equally distributed between urine and feces in the form of metabolic products after 10 days. The mean elimination half-lives found in studies in normal adult subjects (n=54) were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite (descarboethoxyloratadine). In nearly all patients, exposure (AUC) to the metabolite is greater than exposure to parent loratadine. Loratadine and descarboethoxyloratadine reached steady-state in most patients by approximately the fifth dosing day. The pharmacokinetics of loratadine and descarboethoxyloratadine are dose independent over the dose range of 10 to 40 mg and are not significantly altered by the duration of treatment.
In vitro studies with human liver microsomes indicate that loratadine is metabolized to descarboethoxyloratadine predominantly by P450 CYP3A4 and, to a lesser extent, by P450 CYP2D6. In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with significantly increased plasma concentrations of loratadine (see DRUG INTERACTIONS section).
In a study involving twelve healthy geriatric subjects (66 to 78 years old), the AUC and peak plasma levels (Cmax) of both loratadine and descarboethoxyloratadine were significantly higher (approximately 50% increased) than in studies of younger subjects. The mean elimination half-lives for the elderly subjects were 18.2 hours (range = 6.7 to 37 hours) for loratadine and 17.5 hours (range = 11 to 38 hours) for the active metabolite.
In the clinical efficacy studies, Claritin Tablets were administered before meals. In a single-dose study, food increased the AUC of loratadine by approximately 40% and of descarboethoxyloratadine by approximately 15%. The time to peak plasma concentration (Tmax) of loratadine and descarboethoxyloratadine was delayed by 1 hour with a meal.
In patients with chronic renal impairment (creatinine clearance ú 30 ml/min) both the AUC and peak plasma levels (Cmax) increased on average by approximately 73% for loratadine; and approximately by 120% for descarboethoxyloratadine, compared to individuals with normal renal function. The mean elimination half-lives of loratadine (7.6 hours) and descarboethoxyloratadine (23.9 hours) were not significantly different from that observed in normal subjects. Hemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite (descarboethoxyloratadine) in subjects with chronic renal impairment.
In patients with chronic alcoholic liver disease the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite (descarboethoxyloratadine) was not significantly changed from that in normals. The elimination half-lives for loratadine descarboethoxyloratadine were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.
There was considerable variability in the pharmacokinetic data in all studies of Claritin Tablets, probably due to the extensive first-pass metabolism. Individual histograms of area under the curve, clearance, and volume of distribution showed a log normal distribution with a 25-fold range in distribution of healthy subjects.
Loratadine is about 97% bound to plasma proteins at the expected concentrations (2.5 to 100 ng/ml) after a therapeutic dose. Loratadine does not affect the plasma protein binding of warfarin and digoxin. The metabolite descarboethoxyloratadine is 73% to 77% bound to plasma protein (at 0.5 to 100 ng/ml).
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue distribution studies in mice and rats, and in vivo radioligand studies in mice have shown that neither loratadine nor its metabolites readily cross the blood-brain barrier. Radioligand binding studies with guinea pig pulmonary and brain H1-receptors indicate that there was preferential binding to peripheral versus central nervous system H1-receptors.
Clinical trials of Claritin Tablets involved over 10,700 patients who received either Claritin Tablets or another antihistamine and/or placebo in double-bind randomized controlled studies. In placebo-controlled trials, 10 mg once daily of Claritin Tablets was superior to placebo and similar to clemastine (1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic rhinitis. In these studies, somnolence occurred less frequently with Claritin Tablets than with clemastine and at about the same frequency as terfenadine or placebo. In studies with Claritin Tablets at doses 2 to 4 times higher than the recommended dose of 10 mg, a dose-related increase in the incidence of somnolence was observed. Therefore, some patients, particularly those with hepatic or renal impairment and the elderly, may experience somnolence.
Among those patients involved in double-blind, randomized controlled studies of Claritin Tablets, approximately 1000 patients were enrolled in studies of idiopathic chronic urticaria. In placebo-controlled clinical trials, Claritin Tablets 10 mg once daily were superior to placebo in the management of idiopathic chronic urticaria, as demonstrated by reduction of associated itching, erythema, and hives. In these studies, the incidence of somnolence seen with Claritin Tablets was similar to that seen with placebo.
In a study in which Claritin Tablets were administered at 4 times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs.

INDICATIONS
------------
Claritin Tablets are indicated for the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the management of idiopathic chronic urticaria.

CONTRAINDICATION
------------------

Claritin Tablets are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients.

PRECAUTIONS
-----------

General: Patients with liver impairment or renal insufficiency (GFR < 30 ml/min) should be given a lower initial dose (10 mg every other day) because they have reduced clearance of Claritin Tablets.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In an 18-month oncogenicity study in mice and a 2-year study in rats, loratadine was administered in the diet at doses up to 40 mg/kg (mice) and 25 mg/kg (rats). In the carcinogenicity studies, pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUC data demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (active metabolite) times higher than a human given 10 mg/day. Exposure of rats given 25 mg/kg of loratadine was 28 (loratadine) and 67 (active metabolite) times higher than a human given 10 mg/day. Male mice given 40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls. In rats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg and males and females given 25 mg/kg. The clinical significance of these findings during long-term use of Claritin Tablets is not known.
In mutagenicity studies, there was no evidence of mutagenic potential in reverse (Ames) or forward point mutation (CHO-HGPRT) assays, or in the assay for DNA damage (Rat Primary Hepatocyte Unscheduled DNA Assay) or in two assays for chromosomal aberrations (Human Peripheral Blood Lymphocyte Clastogenesis Assay and the Mouse Bone Marrow Erythrocyte Micronucleus Assay). In the Mouse Lymphoma Assay, a positive finding occurred in the nonactivated but not the activated phase of the study.
Loratadine administration produced hepatic microsomal enzyme induction in the mouse at 40 mg/kg and rat at 25 mg/kg, but not at lower doses.
Decreased fertility in male rats, shown by lower female conception rates, occurred at approximately 64 mg/kg and was reversible with cessation of dosing. Loratadine had no effect on male or female fertility or reproduction in the rat at doses of approximately 24 mg/kg.
Pregnancy Category B: There was no evidence of animal teratogenicity in studies performed in rats and rabbits at oral doses up to 96 mg/kg (75 times and 150 times, respectively, the recommended daily human dose on a mg/m2 basis). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Claritin Tablets should be used during pregnancy only if clearly needed.
Nursing Mothers: Loratadine and its metabolite, descarboethoxyloratadine, pass easily into breast milk and achieve concentrations that are equivalent to plasma levels with an AUCmilk/AUCplasma ratio of 1.17 and 0.85 for the parent and active metabolite, respectively. Following a single oral dose of 40 mg, a small amount of loratadine and metabolite was excreted into the breast milk (approximately 0.03% of 40 mg over 48 hours). A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when Claritin Tablets are administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below the age of 12 years have not been established.

Physicians GenRx
Drug names
LORATADINE
DRUG INTERACTION
Loratadine (10 mg once daily) has been safely coadministered with therapeutic doses of erythromycin, cimetidine, and ketoconazole in controlled clinical pharmacology studies. Although increased plasma concentrations (AUC 0-24 hrs) of loratadine and/or descarboethoxyloratadine were observed following coadministration of loratadine with each of these drugs in normal volunteers (n = 24 in each study), there were no clinically relevant changes in the safety profile of loratadine, as assessed by electrocardiographic parameters, clinical laboratory tests, vital signs, and adverse events. There were no significant effects on QTc intervals, and no reports of sedation or syncope. No effects on plasma concentrations of cimetidine or ketoconazole were observed. Plasma concentrations (AUC 0-24 hrs) of erythromycin decreased 15% with coadministration of loratadine relative to that observed with erythromycin alone. The clinical relevance of this difference is unknown. These above findings are summarized in the following table (TABLE 1).

TABLE 1 - Loratadine, Drug Interactions

Effects on Plasma Concentrations (AUC 0-24 hrs) of Loratadine and
Descarboethoxyloratadine After 10 Days of Coadministration (Loratadine
10 mg) in Normal Volunteers

Loratadine Descarboethoxyloratadine

Erythromycin + 40% + 46%
(500 mg Q8h)

Cimetidine + 103% + 6%
(300 mg QID)

Ketoconazole + 307% + 73%
(200 mg Q12h)

There does not appear to be an increase in adverse events in subjects who received oral contraceptives and loratadine.
ADVERSE REACTIONS
-----------------
Approximately 90,000 patients received Claritin Tablets 10 mg once daily in controlled and uncontrolled studies. Placebo-controlled clinical trials at the recommended dose of 10 mg once a day varied from 2 weeks' to 6 months' duration. The rate of premature withdrawal from these trials was approximately 2% in both the treated and placebo groups (TABLE 2).

TABLE 2 - Loratadine, Adverse Reactions

REPORTED ADVERSE EVENTS WITH AN INCIDENCE OF MORE THAN 2% IN
PLACEBO-CONTROLLED ALLERGIC RHINITIS CLINICAL TRIALS

PERCENT OF PATIENTS REPORTING
-----------------------------------------------------------------------
LORATADINE PLACEBO CLEMASTINE TERFENADINE
10 mg QD 1 mg BID 60 ng BID
n=1926 n=2545 n=536 n=684
-----------------------------------------------------------------------
Headache 12 11 8 8
Somnolence 8 6 22 9
Fatigue 4 3 10 2
Dry Mouth 3 2 4 3
-----------------------------------------------------------------------

Adverse events reported in placebo-controlled idiopathic chronic urticaria trials were similar to those reported in allergic rhinitis studies.
Adverse event rates did not appear to differ significantly based on age, sex, or race, although the number of non-white subjects was relatively small.
In addition to those adverse events reported above, the following adverse events have been reported in 2% or fewer patients.

Autonomic Nervous System:
------------------------
Altered lacrimation, altered salivation, flushing, hypoesthesia, impotence, increased sweating, thirst.

Body As A Whole: 
--------------
Angioneurotic edema, asthenia, back pain, blurred vision, chest pain, conjunctivitis, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus, upper respiratory infection, weight gain.

Cardiovascular System: 
---------------------
Hypertension, hypotension, palpitations, syncope, tachycardia.

Central and Peripheral Nervous System: 
--------------------------------------
Blepharospasm, dizziness, dysphonia, hyperkinesia, migraine, paresthesia, tremor, vertigo.

Gastrointestinal System: 
-----------------------
Abdominal distress, altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, increased appetite, nausea, stomatitis, toothache, vomiting.

Musculoskeletal System:
----------------------
Arthralgia, myalgia.

Psychiatric: 
------------
Agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, nervousness, paroniria.

Reproductive System: 
-------------------
Breast pain, dysmenorrhea, menorrhagia, vaginitis.

Respiratory System:
------------------
Bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis, nasal congestion, nasal dryness, pharyngitis, sinusitis, sneezing.

Skin and Appendages:
-------------------
Dermatitis, dry hair, dry skin, photosensitivity reaction, pruritus, 
purpura, rash, urticaria.

Urinary System: 
----------------
Altered micturition, urinary discoloration.

In addition, the following spontaneous adverse events have been reported 
-------------
rarely during the marketing of loratadine: 
abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis; alopecia; anaphylaxis; breast enlargement; erythema multiforme; peripheral edema; seizures; and supraventricular tachyarrhythmias.

DRUG ABUSE AND DEPENDENCE
-------------------------
There is no information to indicate that abuse or dependency occurs with 
Claritin Tablets.

OVERDOSAGE
------------

Somnolence, tachycardia, and headache have been reported with overdoses greater than 10 mg (40 to 180 mg). In the event of overdosage, general symptomatic and supportive measures should be instituted promptly and maintained for as long as necessary.
Treatment of overdosage would reasonably consist of emesis (ipecac syrup), except in patients with impaired consciousness, followed by the administration of activated charcoal to absorb any remaining drug. If vomiting is unsuccessful, or contraindicated, gastric lavage should be performed with normal saline. Saline cathartics may also be of value for rapid dilution of bowel contents. Loratadine is not eliminated by hemodialysis. It is not known if loratadine is eliminated by peritoneal dialysis.
Oral LD50 values for loratadine were greater than 5000 mg/kg in rats and mice. Doses as high as 10 times the recommended clinical doses showed no effects in rats, mice, and monkeys.

DOSAGE AND ADMINISTRATION
-------------------------

Adults and children 12 years of age and over: One 10 mg tablet daily.
In patients with liver failure or renal insufficiency (GFR < 30 ml/min), 10 mg every other day should be the starting dose.

Physicians GenRx
HOW SUPPLIED
-------------

Claritin Tablets, 10 mg, white to off-white compressed tablets; impressed with the product identification number "458" on one side; and "Claritin 10" on the other; high density polyethylene plastic bottles of 100 (NDC 0085-0458-03) and 500 (NDC 0085-0458-06). Also available, Claritin Unit-of-Use packages of 14 tablets (7 tablets per blister card) (NDC 0085-0458-01) and 30 tablets (10 tablets per blister card) (NDC 0085-0458-05); and 10 x 10 tablet Unit Dose-Hospital Pack (NDC 0085-0458-04).
Protect Unit-of-Use packaging and Unit Dose-Hospital Pack from excessive moisture. Store between 2o and 30oC (36o and 86oF).
(Schering Corporation, 9/95, B-14386769) (95/09)

HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE:
-----------------------------------------
Tablet, Uncoated - Oral - 10 mg
14's $36.04 CLARITIN, Schering 00085-0458-01
30's $58.06 CLARITIN, Schering 00085-0458-05
100's $193.54 CLARITIN, Schering 00085-0458-03
100's $193.54 CLARITIN, U.D., Schering 00085-0458-04
500's $967.67 CLARITIN, Schering 00085-0458-06

=============================================================
32.) F-19649873 1711 PRODUCT /The original packing information of the product
INFORMATION CLARITIN® brand of loratadine 2.000-2.001 
=============================================================
TABLETS, SYRUP, and RAPIDLY-DISINTEGRATING TABLETS
DESCRIPTION Loratadine is a white to off-white powder not soluble in water, but very soluble in acetone, alcohol, and
chloroform. It has a molecular weight of 382.89, and empirical formula of C22H23CIN2O2; its chemical name is ethyl
4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate and has the
following structural formula:
CLARITIN Tablets contain 10 mg micronized loratadine, an antihistamine, to be administered orally. It also contains
the following inactive ingredients: corn starch, lactose, and magnesium stearate.
CLARITIN Syrup contains 1 mg/mL micronized loratadine, an antihistamine, to be administered orally. It also contains
the following inactive ingredients: citric acid, edetate disodium, artificial flavor, glycerin, propylene glycol, sodium benzoate,
sugar, and water. The pH is between 2.5 and 3.1.
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) contain 10 mg micronized loratadine, an antihistamine,
to be administered orally. It disintegrates in the mouth within seconds after placement on the tongue, allowing its contents
to be subsequently swallowed with or without water. CLARITIN REDITABS (loratadine rapidly-disintegrating
tablets) also contain the following inactive ingredients: citric acid, gelatin, mannitol, and mint flavor.
CLINICAL PHARMACOLOGY Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine
H1-receptor antagonistic activity.
Human histamine skin wheal studies following single and repeated 10 mg oral doses of CLARITIN have shown that the
drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours, and lasting in
excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with CLARITIN.
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue distribution studies in mice and rats,
and in vivo radioligand studies in mice have shown that neither loratadine nor its metabolites readily cross the bloodbrain
barrier. Radioligand binding studies with guinea pig pulmonary and brain H1-receptors indicate that there was
preferential binding to peripheral versus central nervous system H1-receptors.
Repeated application of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) to the hamster cheek pouch
did not cause local irritation.
Pharmacokinetics: Absorption: Loratadine was rapidly absorbed following oral administration of 10 mg tablets, once
daily for 10 days to healthy adult volunteers with times to maximum concentration (Tmax) of 1.3 hours for loratadine and
2.5 hours for its major active metabolite, descarboethoxyloratadine. Based on a cross-study comparison of single doses
of loratadine syrup and tablets given to healthy adult volunteers, the plasma concentration profile of descarboethoxyloratadine
for the two formulations is comparable. The pharmacokinetics of loratadine and descarboethoxyloratadine are
independent of dose over the dose range of 10 mg to 40 mg and are not altered by the duration of treatment. In a singledose
study, food increased the systemic bioavailability (AUC) of loratadine and descarboethoxyloratadine by approximately
40% and 15%, respectively. The time to peak plasma concentration (Tmax) of loratadine and
descarboethoxyloratadine was delayed by 1 hour. Peak plasma concentrations (Cmax) were not affected by food.
Pharmacokinetic studies showed that CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) provide plasma
concentrations of loratadine and descarboethoxyloratadine similar to those achieved with CLARITIN Tablets. Following
administration of 10 mg loratadine once daily for 10 days with each dosage form in a randomized crossover comparison
in 24 normal adult subjects, similar mean exposures (AUC) and peak plasma concentrations (Cmax) of loratadine
were observed. CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) mean AUC and Cmax were 11% and 6%
greater than that of the CLARITIN Tablet values, respectively. Descarboethoxyloratadine bioequivalence was demonstrated
between the two formulations. After 10 days of dosing, mean peak plasma concentrations were attained at
1.3 hours and 2.3 hours (Tmax) for parent and metabolite, respectively.
In a single-dose study with CLARITIN REDITABS (loratadine rapidly-disintegrating tablets), food increased the AUC of
loratadine by approximately 48% and did not appreciably affect the AUC of descarboethoxyloratadine. The times to peak
plasma concentration (Tmax) of loratadine and descarboethoxyloratadine were delayed by approximately 2.4 and 3.7
hours, respectively, when food was consumed prior to CLARITIN REDITABS (loratadine rapidly-disintegrating tablets)
administration. Parent and metabolite peak concentrations (Cmax) were not affected by food.
In a single-dose study with CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in 24 subjects, the AUC of
loratadine was increased by 26% when administered without water compared to administration with water, while Cmax
was not substantially affected. The bioavailability of descarboethoxyloratadine was not different when administered without water.
Metabolism: In vitro studies with human liver microsomes indicate that loratadine is metabolized to descarboethoxyloratadine
predominantly by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6
(CYP2D6). In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine
predominantly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4
inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with substantially
increased plasma concentrations of loratadine (see Drug Interactions section).
Elimination: Approximately 80% of the total loratadine dose administered can be found equally distributed between
urine and feces in the form of metabolic products within 10 days. In nearly all patients, exposure (AUC) to the metabolite
is greater than to the parent loratadine. The mean elimination half-lives in normal adult subjects (n = 54) were 8.4
hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for descarboethoxyloratadine.
Loratadine and descarboethoxyloratadine reached steady-state in most patients by approximately the fifth dosing day.
There was considerable variability in the pharmacokinetic data in all studies of CLARITIN Tablets and Syrup, probably
due to the extensive first-pass metabolism.
Special Populations: Pediatric: The pharmacokinetic profile of loratadine in children in the 6- to 12-year age group
is similar to that of adults. In a single-dose pharmacokinetic study of 13 pediatric volunteers (aged 8 to 12 years) given
10 mL of CLARITIN Syrup containing 10 mg loratadine, the ranges of individual subject values of pharmacokinetic parameters
(AUC and Cmax) were comparable to those following administration of a 10 mg tablet or syrup to adult volunteers.
The pharmacokinetic profile of loratadine in children in the 2 to 5-year age group (n = 18) is similar to that of adults. In
a single-dose pharmacokinetic study of pediatric subjects (age 2 to 5 years) given 5 mL of CLARITIN Syrup containing
5 mg loratadine, the range of individual subject values of pharmacokinetic parameters (AUC and Cmax) were comparable
to those following administration of a 10 mg tablet or syrup to adult volunteers or children eight years of age and older.
Geriatric: In a study involving 12 healthy geriatric subjects (66 to 78 years old), the AUC and peak plasma levels
(Cmax) of both loratadine and descarboethoxyloratadine were approximately 50% greater than those observed in studies
of younger subjects. The mean elimination half-lives for the geriatric subjects were 18.2 hours (range = 6.7 to 37 hours)
for loratadine and 17.5 hours (range = 11 to 38 hours) for descarboethoxyloratadine.
Renal Impairment: In a study involving 12 subjects with chronic renal impairment (creatinine clearance d 30 mL/min)
both AUC and Cmax increased by approximately 73% for loratadine and by 120% for descarboethoxyloratadine, as compared
to six subjects with normal renal function (creatinine clearance e 80 mL/min). The mean elimination half-lives of loratadine
(7.6 hours) and descarboethoxyloratadine (23.9 hours) were not substantially different from that observed in normal subjects.
Hemodialysis does not have an effect on the pharmacokinetics of loratadine or descarboethoxyloratadine in subjects
with chronic renal impairment.
Hepatic Impairment: In seven patients with chronic alcoholic liver disease, the AUC and Cmax of loratadine were double
while the pharmacokinetic profile of descarboethoxyloratadine was not substantially different from that observed in
other trials enrolling normal subjects. The elimination half-lives for loratadine and descarboethoxyloratadine were 24
hours and 37 hours, respectively, and increased with increasing severity of liver disease.
Clinical Trials: Clinical trials of CLARITIN Tablets involved over 10,700 patients, 12 years of age and older, who
received either CLARITIN Tablets or another antihistamine and/or placebo in double-blind randomized controlled studies.
In placebo-controlled trials, 10 mg once daily of CLARITIN Tablets was superior to placebo and similar to clemastine
(1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic rhinitis. In these studies,
somnolence occurred less frequently with CLARITIN Tablets than with clemastine and at about the same frequency as
terfenadine or placebo. In studies with CLARITIN Tablets at doses two to four times higher than the recommended dose
of 10 mg, a dose-related increase in the incidence of somnolence was observed. Therefore, some patients, particularly
those with hepatic or renal impairment and the elderly, or those on medications that impair clearance of loratadine and
its metabolites, may experience somnolence. In addition, three placebo-controlled, double-blind, 2-week trials in 188
pediatric patients with seasonal allergic rhinitis aged 6 to 12 years, were conducted at doses of CLARITIN Syrup up to
10 mg once daily. In a double-blind, placebo-controlled study, the safety of 5 mg loratadine, administered in
5 mL of CLARITIN Syrup, was evaluated in 60 pediatric patients between 2 and 5 years of age. No unexpected adverse
events were observed.
Clinical trials of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) involved over 1300 patients who
received either CLARITIN REDITABS (loratadine rapidly-disintegrating tablets), CLARITIN Tablets, or placebo. In placebocontrolled
trials, one CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) once daily was superior to placebo
and similar to CLARITIN Tablets in effects on nasal and non-nasal symptoms of seasonal allergic rhinitis.
Among those patients involved in double-blind, randomized, controlled studies of CLARITIN Tablets, approximately
1000 patients (age 12 and older), were enrolled in studies of chronic idiopathic urticaria. In placebo-controlled clinical
trials, CLARITIN Tablets 10 mg once daily were superior to placebo in the management of chronic idiopathic urticaria, as
demonstrated by reduction of associated itching, erythema, and hives. In these studies, the incidence of somnolence
seen with CLARITIN Tablets was similar to that seen with placebo.
In a study in which CLARITIN Tablets were administered to adults at four times the clinical dose for 90 days, no clinically
significant increase in the QTc was seen on ECGs.
In a single-rising dose study in which doses up to 160 mg (16 times the clinical dose) were studied, loratadine did not
cause any clinically significant changes on the QTc interval in the ECGs.
INDICATIONS AND USAGE CLARITIN is indicated for the relief of nasal and non-nasal symptoms of seasonal allergic
rhinitis and for the treatment of chronic idiopathic urticaria in patients 2 years of age or older.
CONTRAINDICATIONS CLARITIN is contraindicated in patients who are hypersensitive to this medication or to any of its
ingredients.
PRECAUTIONS General: Patients with liver impairment or renal insufficiency (GFR < 30 mL/min) should be given a
lower initial dose (10 mg every other day). (See CLINICAL PHARMACOLOGY: Special Populations.)
Drug Interactions: Loratadine (10 mg once daily) has been coadministered with therapeutic doses of erythromycin,
cimetidine, and ketoconazole in controlled clinical pharmacology studies in adult volunteers. Although increased plasma
concentrations (AUC 0-24 hrs) of loratadine and/or descarboethoxyloratadine were observed following coadministration
of loratadine with each of these drugs in normal volunteers (n = 24 in each study), there were no clinically relevant
changes in the safety profile of loratadine, as assessed by electrocardiographic parameters, clinical laboratory tests, vital
signs, and adverse events. There were no significant effects on QTc intervals, and no reports of sedation or syncope. No
effects on plasma concentrations of cimetidine or ketoconazole were observed. Plasma concentrations (AUC 0-24 hrs) of
erythromycin decreased 15% with coadministration of loratadine relative to that observed with erythromycin alone. The
clinical relevance of this difference is unknown. These above findings are summarized in the following table:
Effects on Plasma Concentrations (AUC 0-24 hrs) of Loratadine and Descarboethoxyloratadine
After 10 Days of Coadministration (Loratadine 10 mg) in Normal Volunteers
Loratadine Descarboethoxyloratadine
Erythromycin (500 mg Q8h) + 40% +46%
Cimetidine (300 mg QID) +103% + 6%
Ketoconazole (200 mg Q12h) +307% +73%
There does not appear to be an increase in adverse events in subjects who received oral contraceptives and loratadine.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In an 18-month carcinogenicity study in mice and a
2-year study in rats, loratadine was administered in the diet at doses up to 40 mg/kg (mice) and 25 mg/kg (rats). In the
carcinogenicity studies, pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUC
data demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (descarboethoxyloratadine)
times the exposure in adults and 5 (loratadine) and 20 (descarboethoxyloratadine) times the exposure in
children given the maximum recommended daily oral dose. Exposure of rats given 25 mg/kg of loratadine was
28 (loratadine) and 67 (descarboethoxyloratadine) times the exposure in adults and 40 (loratadine) and 80 (descarboethoxyloratadine)
times the exposure in children given the maximum recommended daily oral dose. Male mice given
40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than
concurrent controls. In rats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas)
was observed in males given 10 mg/kg, and males and females given 25 mg/kg. Exposure of rats given 10 mg/kg
of loratadine was 10 (loratadine) and 15 (descarboethoxyloratadine) times the exposure in adults and 15 (loratadine) and
20 (descarboethoxyloratadine) times the exposure in children given the maximum recommended daily oral dose. The
clinical significance of these findings during long-term use of CLARITIN is not known.
In mutagenicity studies, there was no evidence of mutagenic potential in reverse (Ames) or forward point mutation
(CHO-HGPRT) assays, or in the assay for DNA damage (rat primary hepatocyte unscheduled DNA assay) or in two
assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenesis assay and the mouse bone marrow
erythrocyte micronucleus assay). In the mouse lymphoma assay, a positive finding occurred in the nonactivated but
not the activated phase of the study.
Decreased fertility in male rats, shown by lower female conception rates, occurred at an oral dose of 64 mg/kg
(approximately 50 times the maximum recommended human daily oral dose on a mg/m2 basis) and was reversible with
cessation of dosing. Loratadine had no effect on male or female fertility or reproduction in the rat at an oral dose of
approximately 24 mg/kg (approximately 20 times the maximum recommended human daily oral dose on a mg/m2 basis).
S 2 6 5 4 3
O OC2H5
Cl
N
N
C
FPO
Pregnancy Category B: There was no evidence of animal teratogenicity in studies performed in rats and rabbits at oral
doses up to 96 mg/kg (approximately 75 times and 150 times, respectively, the maximum recommended human daily
oral dose on a mg/m2 basis). There are, however, no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, CLARITIN should be used during pregnancy
only if clearly needed.
Nursing Mothers: Loratadine and its metabolite, descarboethoxyloratadine, pass easily into breast milk and achieve
concentrations that are equivalent to plasma levels with an AUCmilk/AUCplasma ratio of 1.17 and 0.85 for loratadine and
descarboethoxyloratadine, respectively. Following a single oral dose of 40 mg, a small amount of loratadine and descarboethoxyloratadine
was excreted into the breast milk (approximately 0.03% of 40 mg over 48 hours). A decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the
mother. Caution should be exercised when CLARITIN is administered to a nursing woman.
Pediatric Use: The safety of CLARITIN Syrup at a daily dose of 10 mg has been demonstrated in 188 pediatric patients
6 to 12 years of age in placebo-controlled 2-week trials. The safety and tolerability of CLARITIN Syrup at a daily dose of
5 mg has been demonstrated in 60 pediatric patients 2 to 5 years of age in a double-blind, placebocontrolled,
2-week study. The effectiveness of CLARITIN for the treatment of seasonal allergic rhinitis and chronic
idiopathic urticaria in children aged 2 to 12 years is based on an extrapolation of the demonstrated efficacy of CLARITIN in
adults in these conditions and the likelihood that the disease course, pathophysiology, and the drug's effect are substantially
similar to that of the adults. The recommended dose for the pediatric population is based on cross-study comparison
of the pharmacokinetics of CLARITIN in adults and pediatric subjects and on the safety profile of loratadine in both adults
and pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness of CLARITIN
in children under 2 years of age have not been established.
ADVERSE REACTIONS CLARITIN Tablets: Approximately 90,000 patients, aged 12 and older, received CLARITIN
Tablets 10 mg once daily in controlled and uncontrolled studies. Placebo-controlled clinical trials at the recommended
dose of 10 mg once a day varied from 2 weeks' to 6 months' duration. The rate of premature withdrawal from these trials
was approximately 2% in both the treated and placebo groups.
REPORTED ADVERSE EVENTS WITH AN INCIDENCE OF MORE THAN 2% IN PLACEBO-CONTROLLED
ALLERGIC RHINITIS CLINICAL TRIALS IN PATIENTS 12 YEARS OF AGE AND OLDER
PERCENT OF PATIENTS REPORTING
LORATADINE PLACEBO CLEMASTINE TERFENADINE
10 mg QD 1 mg BID 60 mg BID
n = 1926 n = 2545 n = 536 n = 684
Headache 12 11 8 8
Somnolence 8 6 22 9
Fatigue 4 3 10 2
Dry Mouth 3 2 4 3
Adverse events reported in placebo-controlled chronic idiopathic urticaria trials were similar to those reported in allergic
rhinitis studies.
Adverse event rates did not appear to differ significantly based on age, sex, or race, although the number of nonwhite
subjects was relatively small.
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): Approximately 500 patients received
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in controlled clinical trials of 2 weeks' duration. In these
studies, adverse events were similar in type and frequency to those seen with CLARITIN Tablets and placebo.
Administration of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) did not result in an increased reporting
frequency of mouth or tongue irritation.
CLARITIN Syrup: Approximately 300 pediatric patients 6 to 12 years of age received 10 mg loratadine once daily in
controlled clinical trials for a period of 8 to 15 days. Among these, 188 children were treated with 10 mg loratadine syrup
once daily in placebo-controlled trials. Adverse events in these pediatric patients were observed to occur with type and
frequency similar to those seen in the adult population. The rate of premature discontinuance due to adverse events
among pediatric patients receiving loratadine 10 mg daily was less than 1%.

ADVERSE EVENTS OCCURRING WITH A FREQUENCY OF e 2% IN LORATADINE SYRUP-TREATED PATIENTS (6 TO 12
YEARS OLD) IN PLACEBO-CONTROLLED TRIALS, AND MORE FREQUENTLY THAN IN THE PLACEBO GROUP
PERCENT OF PATIENTS REPORTING
LORATADINE PLACEBO CHLORPHENIRAMINE
10 mg QD 2-4 mg BID/TID
n = 188 n = 262 n = 170
------------------------
Nervousness 4 2 2
Wheezing 4 2 5
Fatigue 3 2 5
Hyperkinesia 3 1 1
Abdominal Pain 2 0 0
Conjunctivitis 2 <1 1
Dysphonia 2 <1 0
Malaise 2 0 1
Upper Respiratory
Tract Infection 2 <1 0
-----------------------
Sixty pediatric patients 2 to 5 years of age received 5 mg 
-----------------------------------------------------------
loratadine once daily in a double-blind, placebo-controlled
clinical trial for a period of 14 days. No unexpected adverse events were seen given the known safety profile of loratadine
and likely adverse reactions for this patient population. The following adverse events occurred with a frequency of 2 to 3
percent in the loratadine syrup-treated patients (2 to 5 years old) during the placebo-controlled trial, and more frequently than in the placebo group:
----------------------------------
diarrhea, epistaxis, pharyngitis, influenza-like symptoms, 
fatigue, stomatitis, tooth disorder,
earache, viral infection, and rash.

In addition to those adverse events reported above (e 2%), the following adverse events have been reported in at least
one patient in CLARITIN clinical trials in adult and pediatric patients:

Autonomic Nervous System:
------------------------
altered lacrimation, altered salivation, flushing, hypoesthesia, impotence, increased
sweating, thirst.

Body as a Whole:
----------------
angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache, eye pain, fever, leg
cramps, malaise, rigors, tinnitus, weight gain.

Cardiovascular System: 
-----------------------
hypertension, hypotension, palpitations, supraventricular tachyarrhythmias, syncope, tachycardia.
Central and Peripheral Nervous System: 
-------------------------------------
blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia,tremor, vertigo.

Gastrointestinal System: 
------------------------
altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, hiccup,
increased appetite, loose stools, nausea, vomiting.

Musculoskeletal System:
----------------------
arthralgia, myalgia.

Psychiatric:
-------------
agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia,
irritability, paroniria.

Reproductive System: 
--------------------
breast pain, dysmenorrhea, menorrhagia, vaginitis.

Respiratory System: 
--------------------
bronchitis, bronchospasm, coughing, dyspnea, hemoptysis, laryngitis, nasal dryness, sinusitis, sneezing.

Skin and Appendages: 
---------------------
dermatitis, dry hair, dry skin, photosensitivity reaction, pruritus, purpura, urticaria.

Urinary System:
---------------
altered micturition, urinary discoloration, urinary incontinence, urinary retention.

In addition, the following spontaneous adverse events have 
---------------------------------------------------------
been reported rarely during the marketing of 
loratadine:

abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis; alopecia; anaphylaxis; breast enlargement;
erythema multiforme; peripheral edema; thrombocytopenia; and seizures.
------------------------------------
DRUG ABUSE AND DEPENDENCE There is no information to indicate that abuse or dependency occurs with CLARITIN.
OVERDOSAGE In adults, somnolence, tachycardia, and headache have been reported with overdoses greater than
10 mg with the Tablet formulation (40 mg-180 mg). Extrapyramidal signs and palpitations have been reported in children
with overdoses of greater than 10 mg of CLARITIN Syrup. In the event of overdosage, general symptomatic and supportive
measures should be instituted promptly and maintained for as long as necessary.
Treatment of overdosage would reasonably consist of emesis (ipecac syrup), except in patients with impaired
consciousness, followed by the administration of activated charcoal to absorb any remaining drug. If vomiting is unsuccessful,
or contraindicated, gastric lavage should be performed with normal saline. Saline cathartics may also be of value
for rapid dilution of bowel contents. Loratadine is not eliminated by hemodialysis. It is not known if loratadine is eliminated
by peritoneal dialysis.
No deaths occurred at oral doses up to 5000 mg/kg in mice (approximately 1200 and 1400 times, respectively, the
maximum recommended daily oral dose in adults and children on a mg/m2 basis). No deaths occurred at oral doses up
to 5000 mg/kg in matured rats (approximately 2400 and 2900 times, respectively, the maximum recommended daily oral
dose in adults and children on a mg/m2 basis). However, lethality occurred in juvenile rats at an oral dose of 125 mg/kg
(approximately 100 and 70 times, respectively, the maximum recommended daily oral dose in adults and children on a
mg/m2 basis). No deaths occurred at oral doses up to 1280 mg/kg in monkeys (approximately 2100 and 1500 times,
respectively, the maximum recommended daily oral dose in adults and children on a mg/m2 basis).
DOSAGE AND ADMINISTRATION Adults and children 6 years of age and over: The recommended dose of CLARITIN is
one 10 mg tablet or reditab, or 2 teaspoonfuls (10 mg) of syrup once daily.
Children 2 to 5 years of age: The recommended dose of CLARITIN Syrup is 5 mg (1 teaspoonful) once daily.
In adults and children 6 years of age and over with liver failure or renal insufficiency (GFR < 30 mL/min), the starting
dose should be 10 mg (one tablet or two teaspoonfuls) every other day. In children 2 to 5 years of age with liver failure
or renal insufficiency, the starting dose should be 5 mg (one teaspoonful) every other day.
Administration of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): Place CLARITIN REDITABS
(loratadine rapidly-disintegrating tablets) on the tongue. Tablet disintegration occurs rapidly. Administer with or without
water.
HOW SUPPLIED CLARITIN Tablets: 10 mg, white to off-white compressed tablets; impressed with the product identification
number "458" on one side and "CLARITIN 10" on the other; high-density polyethylene plastic bottles of 100 (NDC 0085-0458-03)
and 500 (NDC 0085-0458-06). Also available, CLARITIN Unit-of-Use packages of 30 tablets (10 tablets per blister card)
(NDC 0085-0458-05); and 10 x 10 tablet Unit Dose-Hospital Pack (NDC 0085-0458-04).
Protect Unit-of-Use packaging and Unit Dose-Hospital Pack from excessive moisture.
Store between 2° and 30°C (36° and 86°F).
CLARITIN Syrup: Clear, colorless to light-yellow liquid, containing 1 mg loratadine per mL; amber glass bottles of
16 fluid ounces (NDC 0085-1223-01).
Store between 2° and 25°C (36° and 77°F).
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): CLARITIN REDITABS (loratadine rapidly-disintegrating
tablets), 10 mg, white to off-white blister-formed tablet; impressed with the letter "C" on one side; Unit-of-Use
polyvinyl chloride blister packages of 30 tablets (three laminated foil pouches, each containing one blister card of
10 tablets) supplied with Patient's Instructions for Use (NDC 0085-1128-02).
Keep CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in a dry place.
Store between 2° and 25°C (36° and 77°F). Use within 6 months of opening laminated foil pouch, and immediately
upon opening individual tablet blister.
Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 9/00 B-19649873
19628477T
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) are manufactured for Schering Corporation by
Scherer DDS, England.
U.S. Patent Nos. 4,282,233 and 4,371,516.
Copyright © 1997, 1998, 1999, 2000, Schering Corporation. All rights reserved.
CLARITIN®
brand of loratadine
TABLETS, SYRUP, and
RAPIDLY-DISINTEGRATING TABLETS

=============================================================
33.) SCHERING-PLOUGH DISAGREES WITH FDA ADVISORY PANEL’S RECOMMENDATION REGARDING CLARITIN (LORATADINE)
=============================================================
KENILWORTH, N.J., May 11, 2001 – Schering-Plough Corporation (NYSE: SGP) today said it strongly believes that CLARITIN (loratadine), the company’s nonsedating antihistamine, should remain a prescription product following a non-binding recommendation by the joint meeting of the U.S. Food and Drug Administration’s (FDA) Nonprescription Drugs Advisory Committee and the Pulmonary–Allergy Drugs Advisory Committee, which examined questions relating to the possible use of CLARITIN in an over-the-counter (OTC) setting.

The panel voted 19 to 4 to recommend that loratadine has a safety profile acceptable for OTC marketing. The panel also had serious concerns regarding appropriate OTC labeling. Additional issues on the lack of use studies as well as patient access were noted.

In making its recommendation, the panel rejected testimony from the leading medical and consumer associations, including the American Academy of Asthma, Allergy and Immunology (AAAAI) and the American Academy of Otolaryngic Allergy (AAOA) and the patient-advocacy group Allergy and Asthma Network/Mothers of Asthmatics, groups that spoke in support of maintaining the prescription status of second-generation antihistamines, including loratadine.

In his presentation today before the joint advisory committees, Robert J. Spiegel, M.D., chief medical officer of Schering-Plough and senior vice president, medical affairs, said "We believe that prescription status of these medications is necessary to protect and optimize public health."

Today’s hearing was prompted by a petition to switch CLARITIN from prescription to OTC status, which was brought by the health insurance company WellPoint/Blue Cross of California. Schering-Plough maintains that such a switch would force patients to self-diagnose, self-treat and pay the entire cost of their allergy medications, thus raising serious questions about quality of care and costs for patients.

In opposing the switch, Schering-Plough has also said it believes there are significant legal and public policy issues that would be raised if the FDA were to require a switch without drug-sponsor support. An Rx-to-OTC switch over a sponsor’s objections would constitute an unprecedented departure from past agency policy and implicate the sponsor’s statutory and constitutional rights.

The company emphasized that the advisory panel’s action today constitutes a recommendation that is not binding on the FDA, which may accept or reject the recommendation, modify it, request additional information, or take no action.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

============================================================
34.) SCHERING-PLOUGH PROVIDES UPDATE ON MANUFACTURING ISSUES
AND FDA INSPECTIONS OF U.S. MANUFACTURING FACILITIES
============================================================
KENILWORTH, N.J., June 22, 2001 ¾ Schering-Plough Corporation (NYSE: SGP) today reported that the U.S. Food and Drug Administration (FDA) has completed inspections conducted during May and June at the company’s manufacturing facilities in Kenilworth and Union, New Jersey, and Las Piedras and Manati, Puerto Rico, and has issued new inspection reports (Form FDA-483), which cited some continuing and some additional deficiencies concerning compliance with current Good Manufacturing Practices (cGMP). Depending on when the Form FDA-483 was received, Schering-Plough has either responded to or is in the process of responding to these observations and is continuing to discuss these matters with FDA. The company cannot predict the outcome of these issues or the timing of any resolution.

These most recent FDA inspections follow general cGMP inspections conducted at the company’s New Jersey and Puerto Rico facilities in late 2000 and early 2001. As reported by Schering-Plough on February 15, 2001, FDA had conducted inspections of these facilities and had issued Form FDA-483s citing cGMP deficiencies, primarily relating to production processes, controls and procedures. In late 2000 and early 2001, the company submitted written responses to FDA’s inspection reports.

In the months since FDA’s initial inspections of the New Jersey and Puerto Rico facilities, Schering-Plough believes it has moved aggressively and deliberately in an effort to resolve these manufacturing issues. The company also believes that progress has been made, but recognizes that additional work remains to be done.

On May 1, 2001, Schering-Plough submitted to FDA a comprehensive cGMP Work Plan designed to take a broad, systemic approach to all aspects of manufacturing and serve as a blueprint for quality and compliance initiatives.

Also on May 1 and continuing into June, FDA conducted reinspections of the company’s New Jersey and Puerto Rico manufacturing facilities, and subsequently issued new inspection reports. Schering-Plough has either responded to or is in the process of responding to these observations.

In its response letter to FDA on one site’s observations, the company emphasized that it takes each of the observations very seriously. Schering-Plough noted in its letter that the Form FDA-483 observations are not meant to reflect (because that is not their purpose):
- The major changes that have been made in the entire Schering-Plough corporate structure;
- The substantial resources devoted to keeping the company’s cGMP commitments to FDA;
- The large amount of cGMP work being undertaken; and
- The deep resolve of the company to continue this progress until its commitments are fully met.

Schering-Plough believes that the manufacturing issues identified by FDA will be addressed in the cGMP Work Plan now being implemented. The plan encompasses all FDA-regulated manufacturing sites, consolidates all ongoing cGMP actions and addresses six key areas: quality assurance, facilities and equipment, materials management, production, laboratories, and packaging and labeling. The plan covers all product lines and takes a uniform approach to quality, production and maintenance at all FDA-regulated manufacturing sites.

Under this plan, Schering-Plough has undertaken major structural and organizational changes. A new Worldwide Quality Operations unit has been formed and given the authority and independence to address quality issues throughout the company. This unit is responsible for all quality-related issues, including technology transfer, validation, investigation, change authorization policies and other quality-related procedures, protocols and documentation. The Quality function at all FDA-regulated sites reports directly to this new unit.

In order to address its manufacturing issues, the company is making extensive improvements to its operations, including:
-- In quality control and production, some 500 people will be added to strengthen these areas. The company is about half-way to this goal, and has recruited a number of senior level executives from outside the company;
-- In the area of equipment requalification and revalidation, the company has recruited highly qualified executives, scientists and consultants to improve revalidation studies and set up a validation review board to oversee the requalification of manufacturing equipment and the revalidation of processes and support systems;
-- In certain production areas where appropriate, equipment and manufacturing lines are being upgraded, notably in aerosol production and tablet manufacturing;
-- In global quality control, improved electronic document management and laboratory information systems are being installed; and
-- A GMP Review Board has been formed, which includes three prominent former FDA officials. This Board is overseeing progress on the company’s cGMP compliance efforts and providing periodic reports to FDA.

DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking" statements relating to the company’s plans and activities designed to resolve cGMP deficiencies identified by FDA in its inspections of the company’s New Jersey and Puerto Rico manufacturing facilities. The resolution of the issues with FDA is subject to substantial risks and uncertainties. Many factors could cause actual results to differ materially from the company’s forward-looking statements, including that the timing, scope and duration of a resolution of the manufacturing and cGMP issues will depend on the ability of the company to assure FDA of the quality and reliability of its manufacturing systems and controls, and the extent of remedial and prospective obligations undertaken by the company. Other risk factors include that any failure to meet cGMP can result in delays in the release of products, seizure or recall of products, suspension or revocation of the authority necessary for the production and sale of products, fines and other civil or criminal sanctions. For further details and a discussion of these and other risks and uncertainties, see the company’s Securities and Exchange Commission filings, including the company’s 2000 annual report on Form 10-K and subsequent quarterly report on Form 10-Q.

Schering-Plough Corporation is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(108)  /2.001 DR. JOSE LAPENTA R. 
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