Desloratadina contra Loratadina !!!

Data-Medicos 
Dermagic/Express No. 3-(102) 
31 Julio 2.001.31 July 2.001. 

EDITORIAL ESPANOL
==================
Hola amigos DERMAGICOS, de nuevo con ustedes CON el interesante TEMA DE LA DESLORATADINA, (NOMBRE CODIGO: R06A X27) producto que la compañia SCHERING-PLOUGH se prepara a lanzar a NIVEL MUNDIAL con los nombres de CLARINEX, NEOCLARITINE Y AERIUS, y AZOMIR en algunos sitios de Europa. El producto es una VERSION MEJORADA DE la POPULAR LORATADINA que el mismo laboratorio comercializa a nivel mundial, con unas ventas astronomicas, desde el año 1.993 (USA) con el nombre DE CLARITYNE. Por eso el nombre de la revision: CLARITYNE CONTRA NEOCLARITYNE. 

Hay muchas cosas interesantes que decir sobre este hecho algunas BUENAS y otras realmente SORPRENDENTES. voy a ir deshojando la flor poco a poco a traves de estos hechos: 

ACTO I 
---------- 

LA DESLORATADINA: 
--------------------------------- 

1.) El producto es 5 veces mas potente que la LORATADINA, ya que es un metabolito activo de la misma y es un inhibidor selectivo de los receptores H1 de la Histamina. 
2.) No tiene efectos Cardiovasculares ni sedantes. 
3.) Parece ser efectiva y bien tolerada en pacientes que padecen de rinitis alergica estacional. 
4.) No tiene efectos adversos cuando se usa en combinacion con medicamentos que utilizan la via del citocromo P450. como el ketoconazole, tampoco cuando es usada con azitromicina. 
5.) Carece de efectos potenciadores con el alcohol. 
6.) Mejora los signos y sintomas de la uricaria idiopatica cronica. 
7.) Tiene un tiempo de vida media de 21-24 horas por lo tanto se indica una vez al dia, y la presentacion es de 5 mgrs Tabs. 
8.) No produce alteraciones a niveles electrocardiograficos (intervalo QTc). 
9.) Ha sido probada en niños de 2 a 5 años de edad sin mayores efectos adversos. 
10.) En fin un dechado de virtudes. 

LA LORATADINA (aprobada en 1.993-USA) 
-------------------------- 
Por años se nos ha dicho que la LORATADINA ES LA PIEDRA de oro DE LOS ANTIHISTAMINICOS, que hasta DIOS la toma ARRIBA EN EL CIELO y que NO PRODUCE EFECTOS SECUNDARIOS, pero les voy a demostrar que esto no es asi: 

LOS HECHOS: (Referencia No. 35) 

Segun un reporte de la FDA la loratadina (Clarityne) ha estado involucrada en los siguientes efectos adversos.: 

Para Abril del año 2.000 se reportaron por LA FDA 4.081 eventos adversos en asociacion con productos que contenian loratadina, incluyendo 55 MUERTES. 
Los efectos adversos mas reportados fueron: 

1.) Inefectividad de la groga. 
2.) Interaccion de la droga. 
3.) Dolor de Cabeza. 
4.) Palpitaciones. 
5.) Somnolencia. (12%) 
6.) Sequedad de la boca 
7.) Arritmias ventriculares. (86 casos incluyendo 16 muertes) 
8.) Muerte Subita. 
9.) Convulsiones. (43 Casos, de los cuales se comprobo 26 fueron ocasionados por la loratadina) 
10.) hepatotoxixidad. (103 Casos donde se reporto ictericia, hepatits y necrosis hepatica, incluidos 5 casos de falla hepatica donde 4 necesitaron trasplante de higado.).

LA FDA OBLIGO AL LABORATORIO a colocar las advertencias de injuria hepatica y convulsiones en el empaque del producto. Lo cual por SUPUESTO NO SE HIZO EN NUESTRO PAIS. 

A pesar de estos "pequeños detalles" LA FDA SIGUE CONSIDERANDO A LA LORATADINA COMO UN BUEN PRODUCTO. 

LA CETIRIZINA: (Aprobada en 1.995) 
----------------------------------
Efectos adversos observados en el 39.3% de los pacientes reportados POR LA FDA para marzo del 2.001 por el uso de cetirizina: 3094 casos, de los cuales 16 murieron. 

1.) Sedacion (306) 
2.) Dolor de cabeza (107) 
3.) Inmsonio. (98) 
4.) Sincope. (54) 
5.) Agitacion. (49) 
6.) Nerviosism. (48) 
7.) Convulsiones (44) 
8.) Confusion (41) 
9.) Ansiedad (40) 
10.) Parestesia (38) 
11.) Tremor (38) 
12.) Sueños anormales (38) 
13.) Despersonalizacion (37) 
14.) Malestar (34) 
15.) Depresion 32) 
16.) Sindorme Hiperquinetico (27) 
17.) Pensamientos anormales (26) 
18.) Perdida de conciencia (25) 
19.) Alucinaciones (16) 
20.) Convulsiones. 
21.) Daño hepatico. 
22.) Arritmias cardiacas 
23.) Trombocitopenia. (11) 

Se han reportado 16 muertes de las cuales 4 probablemente se atribuyo a desordenes primarios del sistema nervioso y eventos psiquiatricos. Un paciente se suicido luego de ingerir una tableta al presentar alucinaciones. 

Para abril del año 2.000 se reportaron 16 nuevos casos de convulsiones relacionadas al uso de la cetirizina. En otros 11 casos de convulsiones temporales hubo exsacerbaion de las convulsiones despues de iniciado el tratamiento con cetirizina. y se reportaron 11 casos de Trombocitopenia.

Para abril del año 2.000 se reportaron 27 casos de arritmias vntriculares, muerte subita y prolongacion temporal del intervalo QT asociado a la administracion de cetirizina. Hubo 5 muertes en este grupo. La FDA considera que pudiera haber una relacion causal entre la cetirizina y las arritmias cardiacas, pero los datos parecen no ser concluyentes.

A pesar de estos "pequeños detalles" LA FDA SIGUE CONSIDERANDO A LA CETIRIZINA COMO UN BUEN PRODUCTO. 

LA FEXOFENADINA (aprobada en 1.996) 
------------------------------ 
Para el 5 de Abril del 2.000 la FDA reporto un total de 1768 efectos adversos asociados al uso de fexofenadina, metabolito activo de la terfenadina, de los cuales 360 fueron serios y 18 murieron. 

1.) Arritmias ventriculares. (39 casos, de los cuales 11 murieron) 
2.) Convulsiones. (30) 
3.) Incremento del estatus convulsivo.
4.) Muerte subita. 
5.) Trastornos de la coagulacion en asociacion a uso con warfarina.(3) 
6.) Prolongacion del intervalo QT y arritmias cardiacas en asociacion a uso con macrolidos (9 casos), cisapride y antimicoticos. 

En el empaque de la fexofenadina no se hace la advertencia sobre los efectos en las convulsiones.

A pesar de estos "pequeños detalles" LA FDA SIGUE CONSIDERANDO A LA FEXOFENADINA COMO UN BUEN PRODUCTO. 

CONCLUSIONES: 

1.) EL NUMERO DE CASOS POR EFECTOS ADVERSOS, ARRTIMIAS VENTRICULARES Y MUERTES REPORTADOS POR LA FDA PARA EL AÑO 2.000 ES MAYOR PARA LA LORATADINA QUE PARA LA CETIRIZINA Y FEXOFENADINA. 

2.) NO SE REPORTAN CASOS DE INJURIA HEPATICA Y MUERTES CAUSADAS POR CTIRIZINA Y FEXOFENADINA , CON LORATADINA SI. 

3.) LA CETIRIZINA PRODUCE MAS EFECTOS ADVERSOS QUE LA LORATADINA y FEXOFENADINA, PERO HAN MUERTO MENOS PACIENTES POR SU USO. 

4.) LA FEXOFENADINA PRODUCE MENOS EFECTOS ADVERSOS QUE LA LORATADINA,Y CETIRIZINA, PERO TAMBIEN PRODUCE ARRIMIAS CARDIACAS Y MUERTES, 

5.) DE LOS TRES PRODUCTOS EL DE MENOR NUMERO DE MUERTES REPORTADAS ES LA CETIRIZINA, AUNQUE ES LA QUE TIENE MAYORES EFECTOS ADVERSOS. 

6.) CON LOS TRES PRODUCTOS SE HAN REPORTADO CASOS DE ARRITMIAS CARDIACAS Y MUERTE.


ACTO II 
------------ 
Para poner el tema mas caliente, encontre varias referencias en la red que ponen en duda LA CALIDAD DE FABRICACION de algunos de los productos de SHERING-PLOUGH, a nivel de sus fabricas especificamente: ALBUTEROL, LORATADINA con PSEUDOEFEDRINA, Y DESLORATADINA. Suena como una locura, QUE UN PRODUCTO que va a ser lanzado al MERCADO COMO NUEVO tenga problemas en su fabricacion, PERO NO LO ES y voy a demostrarlo: 

LOS HECHOS: 
---------------------
1.) La compañia ha estado experimentado dificultades en sus plantas de New Jersey (Kenilworth), Manati, Puerto Rico y Las Piedras Puerto Rico. 
2.) La compañia no esta cumpliendo con las regulaciones de la FDA para la fabricacion de algunos de sus productos. (albuterol, loratadina con pseudoefedrina, y desloratadina). 
3.) Los problemas de manufacturación parecen ser bastante serios. 
4.) Estos hechos han retardado la APROBACION FINAL DE LA DESLORATADINA por la FDA. 
5.) Para el 15 de enero del 2.001 la compañia admitio los problemas en sus fabricas y estimaron una disminucion en sus ganancias anuales, tambien reconocio QUE LUEGO DE HACER LOS CORRECTIVOS propuestos por la FDA en cuanto a la fabricacion de la DESLORATADINA, seria APROBADA.
6.) La patente de CLARITINE vence en el año 2.002, y el lanzamiento de DESLORATADINA cuya patente vence en el 2.004 haria caer las ventas millonarias de este producto con las consecuentes bajas en la bolsa de valores. 

PROBLEMAS DETECTADOS EN LA MANUFACTURACION DE LA DESLORATADINA:

1.) No hay ninguna conviccion que los procesos de manufacturacion, parametros, equipos, protocolos y criterios de aceptacion conducidos y generados en multiples sitios para la produccion del Clarinex (desloratadina 5 mgrs Tabs) sean iguales y de la misma calidad.
2.) El metodo del test de transferencia de La fabrica de Schering en Kenilworth a la Fabrica de Schering en Puerto Rico no demostro resultados exactos y confiables.
3.) Hay Datos insuficientes de comparabilidad de la droga desloratadina manufacturada en Irlanda y Singapur como para asegurar una equivalencia en el suministro del producto.
4.) En conlusion esta claro que existe una extraordinaria variedad de serios problemas en la planta de manufactura de Schering-Plough en Kenilworth, Nueva Jersey que amenaza la seguridad en el envio de las drogas fuera de la planta.
5.) Se espera que la FDA investigue la posibilidad de conducta delictiva por parte de aquéllos oficiales del Schering-Plough que pueden haber enviado productos farmacéuticos defectivos a sabiendas para el uso en pacientes confiados. 


ACTO III 
-------------- 
Lo mas resaltante de esta revision LO CONSTITUYE EL HECHO DE QUE LA MOLECULA DESLORATADINA NO FUE DESARROLLADA POR EL LABORATORIO SCHERING-PLOUGH 


La compañia que desarrollo la DESLORATADINA SE DENOMINA SEPRACOR, la misma que desarrollo la FEXOFENADINA y le vendio los derechos de autor al LABORATORIO MARION ROUSSEL (AVENTIS). Ahora desarrollo la DESALORATADINA Y SCHERING-PLOUGH le pagara derechos de autor al igual que AVENTIS con FEXOFENADINA. 

LA PERLA: 
"Schering le pagará derechos de autor a Sepracor por las ventas de desloratadina que comenzaran con el lanzamiento del producto en países donde se han emitido patentes. Los derechos de autor realizarán una escalada con el tiempo y en el logro de ciertas ventas y otras metas. "  

DE MODO QUE LA COMPAÑIA SEPRACOR es quien esta DETRAS DE TODA ESTA DANZA MILLONARIA CON LA FEXOFENADINA (ALLEGRA) Y AHORA DESLORATADINA (AERIUS),  

ACTO FINAL: 
------------------
Luego de demostrado con evidentes referencias bibliograficas que LA LORATADINA si tiene efectos adversos y produce arritmias cardiacas, muerte y daño hepatico, lo menos que podemos preguntarnos es: QUE PASARA CON LA DESLORATADINA, la cual se dice es 5 -50 veces mas potente que otros antihistaminicos ? solo el tiempo lo dira.

Esperemos que el producto sea bueno de verdad.

Esperemos TAMBIEN QUE LOS LABORATORIOS SEAN ETICOS y nos DIGAN tanto lo bueno como lo malo de sus productos 

En Venezuela el producto Aerius (desloratadina YA FUE LANZADO ESTA SEMANA. 
Dos visitadores Medicos del Laboratorio Schering-Plough me visitaron esta semana. 
Uno de ellos PUSO EN DUDA mi revision sobre los FECTOS ADVERSOS DEL NIMESULIDE y reconocio que SI ERA CIERTO tenian problemas con el PRODUCTO EN EUROPA.
EL OTRO RECONOCIO QUE SI ERA VERDAD LOS PROBLEMAS QUE TIENE EL LABORATORIO A NIVEL DE SU FABRICA. !!!!! 

En base a estos hechos recientes (las ultimas 3 revisiones bibbliograficas) yo personalmente en nombre de DERMAGIC/EXPRESS he tomado las siguientes decisiones: 


1.) NO prescribir mas el producto LAMISIL (TERBINAFINA) - NOVARTIS. por las advertencias que la FDA dio sobre sus efectos toxicos al higado. 
2.) NO prescribir mas el producto SPORANOX (ITRACONAZOLE) JANSSEN-CILAG, por las advertencias que la FDA dio sobre sus efectos toxicos al higado y corazon. 
3.) NO prescribir PRODUCTOS QUE CONTENGAN loratadina con psudoefedrina, SCHERING-PLOUGH, en la ultima inspeccion de la FDA en la fabrica de Kenilwort, se encontraron deficiencias en la produccion de Claritin D.  
4.) NO prescribir el PRODUCTO DESLORATADINA (AERIUS, DESALEX)  SCHERING-PLOUGH, HASTA que la FDA le de su aprobacion final. y porque es una molecula NUEVA, esperare mejores y mas objetivos estudios. 
5.) NO prescribir mas el PRODUCTO NIMESULIDE-SCHERING-PLOUGH y OTROS LABORATORIOS,  y ALERTAR a los colegas de Europa donde es comercializado para que tengan CUIDADO con este producto, por los efectos adversos reportados tales como toxicidad hepatica y renal. 

En las referencias y en las 2 siguientes revisiones los hechos.

Dr. Jose Lapenta R. 


EDITORIAL ENGLISH
==================
Hello DERMAGIC'S friends , again with you WITH the interesting TOPIC OF THE DESLORATADINE, (NAME CODE: R06A X27) product that the company SCHERING-PLOUGH gets ready to rush at WORLD LEVEL with the names of CLARINEX, NEOCLARTYN AND AERIUS, and AZOMIR in some places of Europe. The product is a IMPROVED VERSION OF the POPULAR LORATADINE that the same laboratory markets in all world, with some astronomical sales, from the year 1.993 (USA) with the name OF CLARITIN. For that reason the name of the revision: CLARITIN AGAINST NEOCLARITYN.

There are many interesting things that to say on this fact some GOOD ones and other really SURPRISING ones. I will go defoliating the flower little by little through these facts: 

ACT I: 
-------- 

THE DESLORATADINE: 
--------------------------------- 

1.) The product is 5 times but potent than the LORATADINE, since is an metabolite active of the same one and it is a selective inhibitor of the receptors H1 of the Histamine. 
2.) He doesn't have Cardiovascular neither sedative effects. 
3.) it seems to be effective and very well tolerated in patients that suffer of seasonal allergic rhinitis. 
4.) He doesn't have adverse effects when it is used in combination with medications that use the cytochrome p450 pathway, as the ketoconazole, neither when it is used with azithromycin. 
5.) it lacks Lack of alcohol potentiation. 
6.) it improves the signs and symptoms of the chronic idiopatic urticaria. 
7.) He has a time of half life of 21-24 hours therefore it is indicated once a day, and the presentation is of 5 mgrs Tabs. 
8.) it doesn't produce electrocardiographics alterations QTc interval). 
9.) it has been proven in children from 2 to 5 years of age without adverse effects. 
10.) in short a paragon of virtues. 

THE LORATADINE (approved in 1.993-USA) 
-------------------------- 
Per years we have been said that the LORATADINE is THE STONE of gold OF THE ANTIHISTAMINICS that until GOD taking UP IN THE SKY and that it doesn't PRODUCE SECONDARY EFFECTS, but I will demonstrate to all that this is not really the truth: 

THE FACTS: (reference No. 35) 

According to a report of the FDA the loratadine (Claritin) it has been involved in the following adverse effects.: 

For April of the year 2.000 they were reported by THE FDA 4.081 adverse events in association with products that contained loratadine, including 55 DEATHS. 
The adverse but reported effects were: 

1.) Drug ineffectiveness. 
2.) Drug interaction. 
3.) Headache. 
4.) Palpitations. 
5.) Sedation.(12%) 
6.) Dryness of the mouth, 
7.) ventricular arrhythmias. (86 cases including 16 deaths) 
8.) Sudden death. 
9.) seizures. (43 cases, of which he was proven 26 were caused by the loratadine) 
10.) Hepatotoxicity. (103 cases where reports jaundice, hepatits and hepatic necrosis, included 5 cases of hepatic failure where 4 needed liver transplant). 


THE FDA FORCES TO THE LABORATORY to place the warnings of hepatic risk and seizures in the packing of the product. That which of course was not MADE IN OUR COUNTRY. 

In spite of these "small" details THE FDA CONTINUES CONSIDERING TO THE LORATADINE LIKE A GOOD PRODUCT. 

THE CETIRIZINE: (Approved in 1.995) 
---------------------------------- 
Adverse effects observed in 39.3% of the patients reported BY THE FDA for March of the 2.001 for the cetirizine use: 3094 cases, of which 16 died. 

1.) Sedation (306) 
2.) Headache (107) 
3.) Inmsonia. (98) 
4.) syncope. (54) 
5.) Agitation. (49) 
6.) Nervousness. (48) 
7.) Convulsions (44) 
8.) Confusion (41) 
9.) Anxiety (40) 
10.) Paresthesia (38) 
11.) Tremor (38) 
12.) Abnormal dreams (38) 
13.) Depersonalization (37) 
14.) Malaise (34) 
15.) Depression 32) 
16.) Hyperkinetic syndrome (27) 
17.) abnormal thinking (26) 
18.) Loss of consciousness (25) 
19.) hallucinations (16) 
20.) I damage hepatic. 
21.) Heart arrhythmias. 
22.) thrombocytopenia.(11) 

16 deaths have been reported of which 4 probably attribute to primary disorder of the nervous system and psychiatric events. One patient committed suicide when he became confused, depressed and had hallucinations after taking cetirizine. 

As of April 2000, there were 16 reports of new onset seizures temporally related to cetirizine administration. In 11 other cases, there was exacerbation of seizures after initiating treatment with cetirizine. and 11 cases of thrombocytopenia. 

As of April 2000, there were 27 cases of ventricular arrhythmias, sudden cardiac death and QT prolongation temporally associated with cetirizine administration. There were 5 fatalities in this group. Based on a careful review of these cases by FDA it appears that a causal relationship may be present between cetirizine and cardiac arrhythmias, however, the data are by no means conclusive. 

In spite of these "small" details THE FDA CONTINUES CONSIDERING TO THE CETIRIZINE LIKE A GOOD PRODUCT. 


THE FEXOFENADINE (approved in 1.996) 
------------------------------ 
For April 5 of the year 2.000 the FDA reports a total of 1768 adverse effects associated to the fexofenadine use, (active metabolite of the terfenadine), of which 360 were serious and 18 died. 

1.) ventricular arrhythmias. (39 cases, of which 11 died) 
2.) Seizures. (30) 
3.) Increase in seizure frequency 
4.) sudden death. 
5.) Coagulation abnormalities have been reported following co-administration of fexofenadine and warfarin. (3)
6.) Prolongation of the interval QT and heart arrhythmias in association to use with macrolide antibiotics (9 cases), cisapride and antifungal (azoles). 

Seizure as an adverse event of fexofendine use is not listed in the current approved package insert. 

In spite of these "small" details THE FDA CONTINUES CONSIDERING TO THE FEXOFENADINA LIKE A GOOD PRODUCT. 

CONCLUSIONS: 

1.) THE I NUMBER OF CASES FOR ADVERSE EFFECTS, VENTRICULAR ARRHYTMIAS AND REPORTED DEATHS FOR THE FDA FOR THE YEAR 2.000 it is bigger FOR THE LORATADINE THAN FOR THE CETIRIZINE AND FEXOFENADINE. 

2.) CASES are not REPORTED OF DAMAGE AND LIVER DEATHS FOR CETIRIZINE NEITHER FEXOFENADINE, BUT WITH LORATADINE A REAL TRUTH. 

3.) THE CETIRIZINE PRODUCES MORE ADVERSE EFFECTS THAN THE LORATADINE and FEXOFENADINE, BUT they have DIED LESS PATIENT FOR ITS USE. 

4.) THE FEXOFENADINE PRODUCES LESS ADVERSE EFFECTS THAN THE LORATADINE, AND THE CETIRIZINE, BUT it ALSO PRODUCES HEART ARRHYTMIAS AND DEATHS, 

5.) OF THE THREE PRODUCTS THE ONE OF smaller NUMBERS OF REPORTED DEATHS it is THE CETIRIZINE, ALTHOUGH it is THE ONE THAT HAS bigger ADVERSE EFFECTS. 

6.)THE THREE PRODUCTS PRODUCES HEART ARRHYTMIAS AND DEATHS. 

ACT II:
------------ 
To put the topic but it HOT, I found several references in the net that they question THE QUALITY OF PRODUCTION of some of the products of SHERING-PLOUGH, at level of their manufacture specifically: ALBUTEROL, LORATADINe with PSEUDOEPHEDRINE, AND DESLORATADINE. It sounds like a madness THAT A PRODUCT that will be thrown to the MARKET AS NEW has problems in its production, BUT it IS NOT IT and I will demonstrate it: 

THE FACTS: 
-------------------
1.) that the Company was experiencing manufacturing difficulties at its plants in Union, NJ, Kenilworth, NJ, Manati, Puerto Rico and Las Piedras, Puerto Rico, such that it was distracted from producing products at the levels budgeted for the respective plants; 

2.) that the Company's manufacturing policies and procedures at its plants in Union, NJ, Kenilworth, NJ, Manati, Puerto Rico and Las Piedras, Puerto Rico, did not comply with applicable FDA regulations regarding the manufacture of pharmaceutical products; 

3.)that the Company's manufacturing problems were more widespread and severe than the previously-announced problems at the aerosol plant; 

4.) Given the Company's manufacturing difficulties, the risk that the FDA would force the Company to curtail its operations and delay FDA approval of desloratadine so that the Company could correct the problems was much greater than defendants had disclosed; and 

5.) That based on past practices and policies of the FDA and the nature and extent of the identified deficiencies, it was certain that the FDA would conduct a follow-up inspection of the New Jersey facilities. 

6.) The Complaint further alleges that defendants' failure to disclose the extent of its exposure to its manufacturing problems, falsely implied that there were no known impediments to receiving approval for its most-important new drug, desloratadine, which was in the final stage of the FDA's review process. Desloratadine, which is to be marketed as Claritin, is scheduled to be the successor drug to Claritin, once the patent for Claritin expires in December 2002. 

After the market had closed on February 15, 2001, Schering-Plough finally disclosed the extent of the problems it was experiencing with its manufacturing practices and announced that it would be reducing sales and earnings expectations for the first quarter of 2001 and for the full-year 2001. The Company also warned that the FDA was requiring that all of its manufacturing deficiencies be resolved before the FDA would grant final approval of desloratadine. 

DETECTED PROBLEMS IN THE PRODUCTION OF THE DESLORATADINE:

1.) 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. 
2.) 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. 
3.) 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) 
4.) 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. 
5.) 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. 



ACT III 
---------- 
Him but interesting of this revision CONSTITUTES IT THE FACT THAT THE PRODUCT DESLORATADINE was not DEVELOPED BY THE LABORATORY SCHERING-PLOUGH 

The company that I develop the DESLORATADINE is DENOMINATED SEPRACOR, the same one that I develop the FEXOFENADINE and he sold him the royalties to the LABORATORY MARION ROUSSEL (AVENTIS). Now development the DESALORATADINE AND SCHERING-PLOUGH paid him royalties the same as AVENTIS with FEXOFENADINA. 

THE PEARL:

"Schering will pay royalties to Sepracor on sales of desloratadine beginning at product launch in countries where patents have been issued. Royalties will escalate over time and upon achievement of certain sales and other milestones." 

SO THAT THE COMPANY SEPRACOR is who it is BEHIND OF THIS whole MILLIONAIRE DANCE WITH THE FEXOFENADINE (ALLEGRA) AND NOW DESLORATADINE (AERIUS),  

FINAL ACT 
---------------- 
After having demonstrated with evident bibliographical references that THE LORATADINE has adverse effects and it produces heart arrhythmias, death and hepatic damage, WHAT it will HAPPEN WITH THE DESLORATADINE which is said is it 5 -50 times but potent than other antihistaminics ? alone the time will say it.

let us hope the product is good really,

Let us ALSO hope THE LABORATORIES are ETHICAL and they TELL us as much the good thing as the bad of their products 

In Venezuela the product Aerius (desloratadina was ALREADY THROWN THIS WEEK. 
Two Medical visitors of the Laboratory Schering-Plough visited me this week. 
One of them QUESTIONED my BIBLIOGRAPHICAL revision ABOUT THE ADVERSE EFFECTS OF THE NIMESULIDE And he RECOGNIZED THAT it was TRUE THAT they HAD PROBLEMS WITH THE PRODUCT IN EUROPE
THE OTHER one RECOGNIZED THAT: it was TRUE THE PROBLEMS THAT he HAD THE LABORATORY AT LEVEL OF THEIR it MANUFACTURES. !!!!! 

Based on these recent facts ( 3 last BIBLIOGRAPHICAL REVISIONS), me personally on behalf of DERMAGIC/EXPRESS I have made the following decisions: 

1.) TO not prescribe the product LAMISIL (TERBINAFINE) - NOVARTIS. for the warnings that the FDA gave on its toxic effects to the liver. 
2.) TO not prescribe  the product SPORANOX (ITRACONAZOLE) JANSSEN-CILAG, for the warnings that the FDA gave on its toxic effects to the liver and heart. 
3.) TO not prescribe PRODUCTS THAT CONTAIN loratadine with PSEUDOEPHEDRINE (CLARITIN) SCHERINGH-PLOUGH, The FDA also continued to find deficiencies in the production of Claritin-D in their most recent inspection of the Kenilworth NJ plant.  
4.) TO not prescribe the PRODUCT DESLORATADINE (AERIUS, NEOCLARITYN SCHERINGH-PLOUGH, until the FDA authorize their final approval. and because it is a NEW molecule, I will wait better and but objective studies. 
5.) TO not prescribe the PRODUCT NIMESULIDE -SCHERINGH-PLOUGH and other LABORATORIES, and to ALERT the colleagues from Europe where it is marketed so that he is careful with this product, for the such reported adverse effects as hepatic and renal toxicity. 

In the references and in the two nexts revisions, the facts.

Dr. Jose Lapenta R. 
=============================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
=============================================================
1.) Desloratadine - first clinical data in rhinitis revealed
2.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.
3.) Desloratadine.
4.) Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.
5.) Desloratadine: A new, nonsedating, oral antihistamine.
6.) Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study.
7.) The pharmacologic profile of desloratadine: a review.
8.) Desloratadine: a new approach in the treatment of allergy as a systematic disease--pharmacology and clinical overview. Introduction.
9.) Desloratadine in the treatment of chronic idiopathic urticaria.
10.) Desloratadine activity in concurrent seasonal allergic rhinitis and asthma.
11.) Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis.
12.) Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.
13.) Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents.
14.) The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years.
15.) Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 2nd communication: lack of central nervous system and cardiovascular effects.
16.) Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects.
17.) Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.
18.) Second-generation antihistamines: the risk of ventricular arrhythmias.
19.) SCHERING-PLOUGH SUBMITS U.S. MARKETING APPLICATIONS
FOR TWO NEW FORMULATIONS OF DESLORATADINE
20.) European Committee Recommends Approval of Desloratadine for Chronic Idiopathic Urticaria
21.) Quality of life improves in seasonal allergic rhinitis patients treated with desloratadine
22.) 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
23.) Schering-Plough Announces European Union Approval of Desloratadine 
24.) Product Information of the desloratadine./ Europe.
25.) The real truth of the origin of the DESLORATADINE:
Biomed Report /After roller coaster ride, Sepracor has a new prescription.
26.) The real truth of the origin of the FEXOFENADINE AND DESLORATADINE, they have a single name: SEPRACOR.
27.) Cohen, Milstein, Hausfeld & Toll, P.L.L.C. Files Class Action Suit Against Schering-Plough Corporation 
28.)  INSPECTION REPORT March 1, 2001 about Schering-Plough Corporation
29.) Fexofenadine-induced QT prolongation: a myth or fact?
30.) lengthening and life-threatening arrhythmias associated with fexofenadine.
31.) Fexofenadine and prolonged QT intervals.
32.) Prolonged QTc time and ventricular arrhythmia with fexofenadine.
33.) QT lengthening and life-threatening arrhythmias associated with fexofenadine.
34.) QT lengthening and arrhythmias associated with fexofenadine.
35.) LORATADINE, FEXOFENADINE AN CETIRIZINE ADVERSE EFFECTS FDA REPORT
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1.) 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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2.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.
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Expert Opin Investig Drugs 2001 Mar;10(3):547-60 

Agrawal DK.

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

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3.) 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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4.) 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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5.) Desloratadine: A new, nonsedating, oral antihistamine.
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J Allergy Clin Immunol 2001 Apr;107(4):751-62 

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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6.) 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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7.) The pharmacologic profile of desloratadine: a review.
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Allergy 2001;56 Suppl 65:7-13 Related Articles, Books 

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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8.) 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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9.) 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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10.) 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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11.) 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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12.) 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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13.) 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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14.) The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years.
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Clin Ther 2000 May;22(5):613-21 

Salmun LM, Herron JM, Banfield C, Padhi D, Lorber R, Affrime MB.

Allergy/Respiratory Diseases Clinical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA. [email protected]

OBJECTIVE: We assessed the pharmacokinetics and tolerability of 5 mg loratadine syrup (1 mg/mL) in children aged 2 to 5 years. METHODS: Two studies were undertaken. A single-dose, open-label bioavailability study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine. Plasma concentrations of loratadine and desloratadine were determined at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after a single administration of 5 mg loratadine syrup to 18 healthy children (11 male, 7 female; 12 black, 5 white, 1 other; mean age +/- SD, 3.8 +/- 1.1 years; mean weight +/- SD, 17.4 +/- 4.4 kg). In addition, a randomized, double-blind, placebo-controlled, parallel-group study was performed to assess the tolerability of 5 mg loratadine syrup after multiple doses. Loratadine (n = 60) or placebo (n = 61) was given once daily for 15 days to children with a history of allergic rhinitis or chronic idiopathic urticaria. In the loratadine group, 27 boys and 33 girls (52 white, 8 black) were enrolled, with a mean age +/- SD of 3.67 +/- 1.13 years and a mean weight +/- SD of 17.2 +/- 3.8 kg. In the placebo group, 27 boys and 34 girls (53 white, 7 black, 1 Asian) were enrolled, with a mean age +/- SD of 3.52 +/- 1.12 years and a mean weight +/- SD of 17.3 +/- 2.9 kg. Tolerability was assessed based on electrocardiographic results, occurrence of adverse events, changes in vital signs, and results of laboratory tests and physical examinations. RESULTS: The peak plasma concentrations of loratadine and desloratadine were 7.78 and 5.09 ng/mL, respectively, observed 1.17 and 2.33 hours after administration of loratadine; the areas under the plasma concentration-time curve to the last quantifiable time point for loratadine and desloratadine were 16.7 and 87.2 ng x h/mL, respectively. Single and multiple doses were well tolerated, with no adverse events occurring with greater frequency after multiple doses of loratadine than after placebo. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically meaningful changes in other tolerability assessments. CONCLUSION: Loratadine was well tolerated in this small, selected group of children aged 2 to 5 years at a dose providing exposure similar to that with the adult dose (ie, 10 mg once daily).

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15.) 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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16.) 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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17.) 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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18.) Second-generation antihistamines: the risk of ventricular arrhythmias.
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Clin Ther 1999 Feb;21(2):281-95 

DuBuske LM.

Brigham and Women's Hospital, Boston, Massachusetts, USA.

Some second-generation antihistamines, notably terfenadine and astemizole, have been associated with prolongation of the QT interval and the development of torsades de pointes, a potentially fatal ventricular arrhythmia. This rare adverse event has been associated with greatly elevated blood levels of these agents, resulting from drug overdose, hepatic insufficiency (dysfunction), or interactions with other drugs that inhibit their metabolism. This paper reviews the data concerning the effects of selected second-generation antihistamines on cardiac conduction, particularly the QT interval, to evaluate whether ventricular arrhythmias are a class effect of these agents. Electrocardiographic studies indicate that terfenadine and astemizole, but not loratadine or cetirizine, prolong the QT interval in laboratory animals. In vitro studies demonstrate that terfenadine and astemizole block the cardiac K+ channels, leading to delayed ventricular repolarization and QT-interval prolongation; in contrast, neither loratadine nor its metabolite, desloratadine, significantly inhibits cardiac K+ channels at clinically achievable blood levels. Studies in human volunteers confirm the absence of electrocardiographic effects of azelastine, cetirizine, fexofenadine, and loratadine administered at several times the recommended dose or concomitantly with agents that inhibit their metabolism and elimination. In conclusion, the data indicate that the potential to cause ventricular arrhythmias is not a class effect of second-generation antihistamines and that loratadine, cetirizine, azelastine, and fexofenadine are not associated with torsades de pointes or other ventricular arrhythmias.

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19.) 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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20.) 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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21.) 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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22.) 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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23.) 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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24.) Product Information of the desloratadine.
=============================================================
Product Information

Name of the medicinal product
-----------------------------
Azomyr (in Europe)

Marketing Authorisation Holder
------------------------------
SP Europe 
Rue de Stalle 73 
B-1180 Brussels 
Belgium

Active substance
-----------------
Desloratadine

International Nonproprietary Name or Common Name
-------------------------------------------------
Desloratadine


Pharmaco-therapeutic group
--------------------------
Antihistamine-H1 antagonist

ATC Code
--------
R06A X27


Therapeutic indication
-----------------------
It is indicated for relief of symptoms associated with seasonal allergic rhinitis

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25.) The real truth of the origin of the DESLORATADINE
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Biomed Report /After roller coaster ride, Sepracor has a new prescription.
============================================================ 
source: Boston Business Journal.
From the November 5, 1999 print edition


Ted Griffith 

Sepracor Inc. last year vaulted into the ranks of stock market high fliers, but this year life on Wall Street has been more rocky for the Marlborough company. 

On March 8, Sepracor's stock climbed as high as $140.87, but then a few months later fell to a 52-week low of $55 on May 25. News that New Brunswick, N.J.-based Johnson & Johnson had decided not to help Sepracor sell an allergy drug contributed to Sepracor's stock tumble in the spring. 

In 1998, Sepracor's stock performance was stellar, with shares increasing more than 100 percent from $39.75 to $82.81. Just four years ago, stock in Sepracor was going for under $10. Media attention and the announcement of deals with major pharmaceutical companies helped drive the stock up in 1998. 

David Southwell, Sepracor's chief financial officer, now suggests the company is picking up momentum again. 

Southwell said he is optimistic about the coming months and investors will soon see plenty of good news from the company. At least some analysts agree with Southwell's sunny forecast for Sepracor, which specializes in developing improved versions of existing medicines. 

"The risk is decreasing going forward," said Sergio Traversa, an analyst with Mehta Partners, an investment research firm in New York City. "The news we're expecting is good news." 

A recent positive development for Sepracor was the announcement that Madison, N.J.-based Schering-Plough Corp. filed an application with the U.S. Food and Drug Administration for approval to sell what the company expects would be an improved version of the popular allergy drug Claritin. 

Sepracor developed the upgraded allergy drug, which is known as desloratadine, and would receive an undisclosed amount of royalties from Schering-Plough, provided the New Jersey company gets clearance to sell the drug. Claritin is one of the best-selling prescription medicines ever and generated $2.3 billion in revenue last year. 

The FDA is expected to announce its decision in about a year on whether desloratadine can be marketed in the United States. Schering Plough's announcement helped push Sepracor's stock higher, with investors betting the drug will get FDA approval. Sepracor shares opened last week at $72.75 and closed Friday at $83.18, up 14 percent. 

Southwell said the improved version of Claritin is just one reason to be hopeful about Sepracor. 

"It's going to be an action-packed time for us," the chief financial officer said. "The disappointments we had earlier in the year have largely been resolved. The middle of the year was disappointing. Now, though, we're expecting a good balance of the year and a great next year." 

Among other things, Sepracor is involved with developing an improved version of the antidepressant Prozac. 

There is a catch with the Prozac deal, however--the U.S. Federal Trade Commission is looking into the agreement between Sepracor and the maker of Prozac, Indianapolis-based Eli Lilly & Co. Back in December, Eli Lilly announced it would pay Sepracor as much as $90 million for Sepracor's modified version of Prozac. Sepracor's version is supposed to cause fewer side effects than Prozac. 

But the FTC has requested information about the agreement between Sepracor and Eli Lilly, apparently to determine if Eli Lilly is improperly using the patent process to extend its exclusive rights to Prozac. Southwell said he is confident that the FTC will ultimately allow Eli Lilly's deal with Sepracor to go forward. 

Aside from the improved Prozac that's under development, Southwell said the company will work on developing other compounds. He said Sepracor plans to test a number of new drugs on people throughout next year. The company is also selling an asthma drug called Xopenex, which was approved by the FDA in early 1999. 

In theory, Sepracor's business plan appears to be a brilliant one. The company takes highly popular prescription drugs, such as Prozac and Claritin, and alters them so that they are potentially better than the originals. The new version could be more powerful or have fewer side effects than its predecessor. 

In addition, the improved version offers a company a new way of extending exclusive rights to a lucrative market for a popular drug. In the case of Claritin, for instance, Schering-Plough has a series of patents, the first of which expires in 2002. But Sepracor's improved version has patent protection until 2014, according to Reuters. 

"If the business model works, Sepracor will be a $10 billion company," said Traversa, the Mehta Partners analyst. 

So far, however, Sepracor has yet to translate its good idea into profits. 

In the first nine months of 1999, Sepracor reported a net loss of $122.7 million, or $3.73 per share, compared with a net loss of $58.9 million, or $2.10 per share, during the same period last year. 

TED GRIFFITH, health care and biotechnology reporter for the Boston Business Journal, can be reached by e-mail at [email protected]. 


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26.) The real truth of the origin of the FEXOFENADINE AND DESLORATADINE, they have a single name: SEPRACOR.
-------------------------------------------------------------
ALLEGRA® (fexofenadine HCI) 
============================================================ 
SOURCE: the web site of sepracor.

... Sepracor's patents relating to fexofenadine are licensed or assigned worldwide to Hoechst Marion Roussel, Inc. The fexofenadine product was developed and marketed by Hoechst Marion Roussel, Inc. as ALLEGRA® brand fexofenadine hydrochloride. 
In September, Sepracor and Hoechst Marion Roussel, Inc., (now Aventis), settled all patent issues between the two companies involving the nonsedating antihistamine developed and marketed by Hoechst Marion Roussel. Under the terms of a U.S. agreement, Sepracor and Hoechst Marion Roussel have settled an ongoing arbitrated patent interference involving their U.S. patent properties, and Hoechst Marion Roussel now owns the Sepracor patent properties. 

Hoechst Marion Roussel has also obtained an exclusive license to various other Sepracor U.S. patent applications related to fcxofenadine. Sepracor will receive royalties on fexofenadine sales in the U.S. upon expiration of Hoechst Marion Roussel's composition of matter patent in mid- February 2001. 

Under the terms of a separate ex-U.S. agreement, Hoechst Marion Roussel has obtained an exclusive license to Sepracor's patents that had been the subject of litigation in Europe, as well as various other patent oppositions between the two companies outside the U.S. Under this agreement, all legal actions outside the U.S. have been settled and Sepracor will receive royalties on fexofenadine products effective March 1, 1999, in countries where it has issued patents.

Desloratadine ... An active metabolite of the world's best-selling nonsedating antihistamine, Schering's CLARITIN®. 
In October 1999, Schering submitted a New Drug Application for desloratadine to the FDA. In addition, Schering-Plough also submitted a centralized Marketing Authorization Application (MAA) for desloratadine to the European Medicines Evaluation Agency of the European Union (EU). Approval of this centralized Marketing Authorization would result in unified labeling for desloratadine that would be valid in all 15 EU member states. 

Schering will pay royalties to Sepracor on sales of desloratadine beginning at product launch in countries where patents have been issued. Royalties will escalate over time and upon achievement of certain sales and other milestones. 

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27.) Cohen, Milstein, Hausfeld & Toll, P.L.L.C. Files Class Action Suit Against Schering-Plough Corporation 
=============================================================
Source: specializing in class action law

The following notice is issued by the law firm of Cohen, Milstein, Hausfeld & Toll, P.L.L.C., on behalf of its client, who filed a class action lawsuit on March 8, 2000, in the United States District Court for the District of New Jersey, on behalf of purchasers of Schering-Plough Corporation (NYSE:SGP) during the period between July 25, 2000 and February 15, 2001, inclusive.

The Complaint alleges that defendants named above violated Sections 10(b) and 20(a) of the Securities Exchange Act of 1934 and Rule 10b-5 promulgated thereunder. During the Class Period, Schering-Plough issued three earnings releases highlighting the Company's purported success and growth. The Complaint alleges that these three releases contained statements that were materially false and misleading because they failed to disclose certain material facts, including, inter alia:

-- (a) that the Company was experiencing manufacturing difficulties at its plants in Union, NJ, Kenilworth, NJ, Manati, Puerto Rico and Las Piedras, Puerto Rico, such that it was distracted from producing products at the levels budgeted for the respective plants;

-- (b) that the Company's manufacturing policies and procedures at its plants in Union, NJ, Kenilworth, NJ, Manati, Puerto Rico and Las Piedras, Puerto Rico, did not comply with applicable FDA regulations regarding the manufacture of pharmaceutical products;

-- (c) that the Company's manufacturing problems were more widespread and severe than the previously-announced problems at the aerosol plant;

-- (d) given the Company's manufacturing difficulties, the risk that the FDA would force the Company to curtail its operations and delay FDA approval of desloratadine so that the Company could correct the problems was much greater than defendants had disclosed; and

-- (e) that based on past practices and policies of the FDA and the nature and extent of the identified deficiencies, it was certain that the FDA would conduct a follow-up inspection of the New Jersey facilities.

The Complaint further alleges that defendants' failure to disclose the extent of its exposure to its manufacturing problems, falsely implied that there were no known impediments to receiving approval for its most-important new drug, desloratadine, which was in the final stage of the FDA's review process. Desloratadine, which is to be marketed as Claritin, is scheduled to be the successor drug to Claritin, once the patent for Claritin expires in December 2002.

After the market had closed on February 15, 2001, Schering-Plough finally disclosed the extent of the problems it was experiencing with its manufacturing practices and announced that it would be reducing sales and earnings expectations for the first quarter of 2001 and for the full-year 2001. The Company also warned that the FDA was requiring that all of its manufacturing deficiencies be resolved before the FDA would grant final approval of desloratadine.

Wall Street was shocked by the Company's February 15, 2001 announcement. In extremely heavy after-hours trading, the price of Schering-Plough common stock fell nearly $10 per share, after closing earlier in the day at $48.32. On February 16, 2001, the day after the announcement, the Schering-Plough's common stock opened up for trading at $38.25.

The plaintiff's counsel -- Cohen, Milstein, Hausfeld & Toll, P.L.L.C. -- has significant experience in prosecuting investor class actions and actions involving financial fraud. The firm has offices in Washington, D.C. and Seattle, Washington and is active in major litigation pending in federal and state courts throughout the nation.

The firm's reputation for excellence has been recognized on repeated occasions by courts which have appointed the firm to lead positions in complex multi-district or consolidated litigation. Cohen, Milstein, Hausfeld & Toll, P.L.L.C. has taken a lead role in numerous important cases on behalf of defrauded investors, and has been responsible for a number of outstanding recoveries which, in the aggregate, total hundreds of millions of dollars or more.

If you purchased shares of Schering-Plough Corporation during the Class Period, you may move the Court no later than April 17, 2001 to serve as lead plaintiff for the Class. In order to serve as lead plaintiff, you must meet certain legal standards.

If you have any questions about this notice or the action, or with regard to your rights, please contact either of the following:

Steven J. Toll, Esq. or Robert Smits 
Cohen, Milstein, Hausfeld & Toll, P.L.L.C. 
1100 New York Avenue, N.W. 
Suite 500 - West Tower 
Washington, D.C. 20005 
Telephone: 888-240-0775 or 202-408-4600 
E-mail address: [email protected] or [email protected]

For more information, please contact us at [email protected].

If you have any information which would be helpful to the prosecution of this case, please Alert Us.

============================================================
28.) INSPECTION REPORT March 1, 2001 about Schering-Plough Corporation
============================================================
CHRONOLOGY AND REPEATED MANUFACTURING DEFECTS WITH IMPORTANT DRUGS LIKE  LORATADINE WITH PSEUDOEPHEDRINE (CLARITIN-D), DESLORATADINE (AERIUS- NEOCLARITIN-CLARINEX).

source: Public Citizen's Health Research Group

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. 


THE FEXOFENADINE CARDIAC TROUBLES: A REAL TRUTH
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FEXOFENADINE and arrhythmias.
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29.) Fexofenadine-induced QT prolongation: a myth or fact?
=============================================================
Br J Dermatol 2000 Jun;142(6):1260-1 

Dhar S, Hazra PK, Malakar S, Mistri G.

Publication Types: 
Letter 
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30.)lengthening and life-threatening arrhythmias associated with fexofenadine.
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Br J Gen Pract 2000 Feb;50(451):148 

Craig-McFeely PM, Freemantle SL, Pearce GL, Shakir SA.

Publication Types: 
Letter 
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31.) Fexofenadine and prolonged QT intervals.
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Nursing 1999 Sep;29(9):72 

Shuster J.

Temple University, Philadelphia, Pa., USA.

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32.) Prolonged QTc time and ventricular arrhythmia with fexofenadine.
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Am J Cardiol 1999 Nov 15;84(10):1278-9 Related Articles, Books 


Comment on: 
Am J Cardiol. 1999 May 15;83(10):1451-4 


Kashyap AS, Kashyap S.

Publication Types: 
Comment 
Letter 
=============================================================

=============================================================
33.) QT lengthening and life-threatening arrhythmias associated with fexofenadine.
=============================================================
Lancet 1999 Mar 20;353(9157):980 


Comment in: 
Lancet. 1999 Aug 21;354(9179):683 
Lancet. 1999 Jun 12;353(9169):2072-3 

Pinto YM, van Gelder IC, Heeringa M, Crijns HJ.

Publication Types: 
Letter 

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34.) QT lengthening and arrhythmias associated with fexofenadine.
=============================================================
Lancet 1999 Jun 12;353(9169):2072-3 
Comment on: 
Lancet. 1999 Mar 20;353(9157):980 

Giraud T.

Publication Types: 
Comment 
Letter 

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35.) LORATADINE, FEXOFENADINE AN CETIRIZINE ADVERSE EFECTS
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Source: The FDA

EXECUTIVE SUMMARY

ABBREVIATIONS:
-------------
AE= Adverse Event
BID= Twice Daily
CDER= Center for Drug Evaluation and Research
NDA= New Drug Application
OTC=Over-The-Counter
OPDRA=Office Of Post-Marketing Drug Assessment
QD=Once Daily
SAE=Serious Adverse Event
WR=Written Request
AERS=Adverse Event Reporting System

LORATADINE 
----------
There are five approved formulations of loratadine: 

NDA 19-658: Loratadine 10 mg (Claritin) tablets, approved April, 1993.

NDA 20-704: Loratadine Zydis (Claritin RediTabs), approved December, 1993.

NDA 19-670: Loratadine 5 mg/pseudoephedrine 120 mg (Claritin-D 12 Hour Extended Release tablets, approved November, 1994.

NDA 20-470: Loratadine 10 mg/pseudoephedrine 240 mg (Claritin-D 24 Hour Extended Release) tablets, approved August, 1996.

NDA 20-641: Loratadine 10 mg/10 mL (Claritin) Syrup, approved October, 1996.

The single ingredient Claritin tablet products are currently labeled for use in children age 6 years and above. Claritin Syrup was recently approved (September 26, 2000) for use in children down to age 2 years. The two Claritin-D formulations are approved for use in adults and children 12 years of age and older.

The NDA reviews for the single ingredient loratadine formulations showed that at the labeled dose of 10 mg once daily, the most commonly reported events from placebo-controlled clinical trials included headache, dry mouth, and somnolence (8% for loratadine vs. 6% for placebo vs. 22% for clemastine4 1 mg BID). Other safety information in the prescription package insert of potential relevance in an OTC setting include recommendations for dosing adjustment in renal failure (because of reduced loratadine clearance) and avoidance of the combination loratadine- pseudoephedrine products (Claritin-D) in patients with cardiac disease as well as hepatic insufficiency. Clinical pharmacology studies reported in the package insert and conducted in normal volunteers revealed no evidence of QTc prolongation at doses of loratadine up to four times the labeled dose. Drug interaction studies reported in the package insert have demonstrated increased plasma loratadine and descarboethoxyloratadine5 levels associated with coadministration of erythromycin, cimetidine, and ketoconazole. No significant effects on the QTc interval were observed in these studies. 

As of April, 2000, the AERS database contained 4081 adverse event reports in association with products containing loratadine,including 55 reports with death as an outcome. The most prevalent event categories were for "drug ineffectiveness," "drug interaction," "headache," and "palpitations." Among the serious events, three categories were identified as potential areas of concern: ventricular arrhythmias and sudden death, seizures, and hepatotoxicity. These adverse events are further evaluated below. 

There were a total of 86 cases of ventricular arrhythmias, including 16 deaths, reported in association with loratadine use. Careful review of these reports by FDA staff revealed that there were confounding factors present in the majority of cases that precluded a definitive conclusion that loratadine was causally related to the reported adverse event. These confounding factors included use of concomitant medications that might be associated with arrhythmias and pre-existing cardiovascular disease. It remains unclear whether concomitant cardiovascular disease is predictive of an arrhythmic event in association with loratadine or simply reflects the type of patient more likely to have been prescribed loratadine, given the known association of other "non-sedating" antihistamines (i.e, terfenadine and astemizole) with ventricular arrhythmias. 

There were a total of 43 cases of seizures reported in association with loratadine use. Careful review of these reports by FDA staff suggested that a causal association with loratadine was possible or likely in 26 of the cases. Seizures are currently included as an adverse event in the loratadine prescription package insert. A review of the professional labeling of several currently marketed OTC antihistamines suggests that as a class, antihistamine products may rarely be associated with seizures.

Rare occurrences of liver-related events have been reported, including abnormal hepatic function, jaundice, hepatitis, and hepatic necrosis, and are currently included in the loratadine prescription package insert. In AERS, there were a total of 103 cases of hepatic injury reported in association with loratadine use. Of these, there were five cases of hepatic failure, of which four required liver transplantation. Careful review of these reports by FDA staff revealed that there were confounding factors in 3 of the 5 cases of hepatic failure that precluded a definitive conclusion that loratadine was causally related. These confounding factors included use of concomitant medications that might be associated with liver failure and recent foreign travel. To further evaluate the potential association between loratadine and hepatic failure, OPDRA reviewers undertook substantial efforts to establish a comparative background rate for occurrence of hepatic failure, which is known to occur "spontaneously" (i.e., without an identifiable cause) and which is not uncommonly reported in association with use of a wide variety of drugs. The reporting rate for hepatic failure in association with use of loratadine was several fold lower than the calculated background rate of hepatic failure (i.e., 1 per million person years). In considering these data, it is important to remember that underreporting of adverse events is a well recognized limitation of spontaneous reporting systems. Although there is no clear causal relationship between loratadine use and the occurrence of hepatic failure, the possibility that loratadine use may very rarely result in hepatic failure cannot be excluded. 

Soon after approval and marketing of Claritin-D 24 Hour Extended Release Tablets in 1996, numerous reports of tablets becoming lodged in the patient’s esophagus were received. Some of these cases were serious in nature and required endoscopic removal of the tablet, which had adhered tightly to the esophageal mucosa. This problem was thought to be related to the tablet coating and possibly the shape and size of the tablet. The tablet coating and shape were changed in December 1998. No such serious adverse events have been reported for the new formulation.

A careful review of the published literature for loratadine did not provide additional insight regarding the primary areas of safety concern, nor did it identify new adverse events that were not observed in the other safety databases.

For loratadine, a report prepared by the Therapeutic Products Programme of the Bureau of Licensed Products Assessment (Canadian regulatory authorities) dated June 22, 2000 was reviewed by the FDA review team.6 This document was prepared as part of an ongoing, comprehensive surveillance inquiry of all newer generation antihistamines presently marketed in Canada. A safety analysis of loratadine was included in this report, with the focus primarily being on cardiovascular risk. The data reviewed in the report included global safety data submitted by the drug sponsor, including all Canadian domestic as well as foreign adverse event reports, published case reports and clinical trials, and any new scientific information relevant to a benefit-risk assessment. The current marketing status of loratadine in Canada as well as internationally was also reviewed. A summary of the findings and conclusions of this report are provided below.

Loratadine was first marketed in February, 1988 in Belgium. Approval was granted in June, 1988 in Canada, where it became a non-prescription product in December, 1989. As of March, 1999, loratadine in some formulation had been approved and marketed in 94 countries worldwide, including in 17 as a non-prescription product. With the exception of the switch to non-prescription status in 1989, no significant regulatory action related to safety has been taken regarding loratadine in Canada since its approval. 

The most commonly reported cardiac-related adverse events in the databases reviewed in the Canadian report were palpitations and/or tachycardia. There were cases of documented cardiac arrhythmias, although most were confounded by concomitant medications and underlying cardiac disease. The report noted that loratadine does not significantly block HERG potassium channels under the same in vitro conditions in which terfenadine has been shown to block these important channels that are involved in cardiac repolarization. Therefore, the authors of this report concluded that a causal association of loratadine with ventricular arrhythmias was unlikely, both from a clinical as well as a scientific standpoint.

On the other hand, new information regarding the in vitro affinity of loratadine for an atrial ion channel was discussed in the report. Although considered very preliminary, the possibility that a primary atrial tachycardia could be triggered under certain rare conditions was discussed as an explanation for the confirmed cases of atrial arrhythmia in the database. The authors of this report concluded that these data alone could not support a labeling change. 

After careful consideration of the available data, the Canadian regulatory authorities recommended a risk management plan for loratadine. Specifically, the loratadine product monograph would be updated to include "tachycardia" under "Adverse Reactions," the adverse event databases would continue to be closely monitored by both the sponsor as well as the regulators, and the sponsor would be required to formally investigate the confounders "concomitant medications" and "underlying cardiac disease" on the cardiovascular safety of this drug product. Loratadine would remain a nonprescription product in Canada. 

In conclusion, a thorough review of all available safety data for loratadine failed to identify conclusive evidence of a causal relationship between use or loratadine and serious adverse events. Potential safety signals were noted for ventricular arrhythmias and liver failure; however, as described above, the data are inconclusive and suggest that if such events were causally-related to loratadine, they are extremely unusual . A potential association between loratadine use and seizures was observed, consistent with information contained in the current package insert, and likely consistent with a class effect. 


FEXOFENADINE
--------------------------

NDA 20-625 for Allegra capsules (fexofenadine 60 mg) was approved on July 31, 1996. Since then, two additional NDA’s for drug products containing the drug substance fexofenadine have been approved, Allegra-D tablets (with the decongestant, pseudoephedrine: NDA 20-786, approved December, 1997) and Allegra multiple strength tablets (fexofenadine 30, 60, and 180 mg: NDA 20-872, approved February, 2000). Single ingredient formulations of fexofenadineare approved for use in adults and in children age 6 years and older. The combination of fexofenadine and pseudoephedrine (Allegra-D) is approved for use in adults and children 12 years of age and older. 

The original reviews for these fexofenadine NDAs were assessed with respect to their safety findings. Overall, the placebo-controlled clinical trials included data from over 2000 patients age 12 years to adult. Adverse experiences occurring at a frequency of greater than >1.0% and which were more common in fexofenadine-treated patients compared to placebo included viral infection, nausea, dysmenorrhea, drowsiness (0.9% for placebo BID vs. 1.3 % for Allegra 60 mg BID), dyspepsia, and fatigue. Adverse experiences reported from Allegra-D trials reflected the contribution of the pseudoephedrine component. These adverse events noted in the preapproval clinical trials are adequately described in the "Adverse Experiences" section of the label for each of these drug products. 

A literature review revealed no case reports or citations describing unique or unexpected adverse events not already included in product labeling, or covered adequately by review of the AERS post-marketing database.

As of April 5, 2000, there were a total of 1768 adverse event reports in the AERS database associated with use of fexofenadine, 360 of which had a serious outcome and 18 of which resulted in death. The in-depth review of these data focused primarily on events that were serious and/or potentially life threatening. These included reports of ventricular arrhythmias and sudden death, seizures, and drug interactions.

A total of 39 cases of ventricular arrhythmias, including 11 deaths have been reported in association with use of fexofenadine. A detailed review of these cases by FDA staff revealed that evaluation of a majority of the total cases and 8 of the 11 deaths were confounded by a history of cardiac disease and/or use of one or more concomitant medication possibly associated with arrthymias in the affected individual. Concomitant drugs included drugs that belong to classes known to be associated with prolongation of the QTc, in particular cisapride, macrolides, or antifungals. A definite causal association between use of fexofenadine and ventricular arrhythmias was not support by the data; however, the possibility of such rare events cannot be excluded.

A total of 30 cases of seizures associated with the use of fexofenadine were included in the AERS database. A detailed review of these cases by FDA staff revealed 17 cases of new onset seizures or increase in seizure frequency that were possibly associated with fexofenadine, by generally accepted epidemiological criteria. Seizure as an adverse event of fexofendine use is not listed in the current approved package insert. 

A careful review of reports of possible drug-drug interactions associated with fexofenadine disclosed 9 reports of cardiac dysrrhythmia associated with the co-administration of fexofenadine plus a macrolide antibiotic. The cause of the arrhythmia in these cases remains unexplained. Although clinical pharmacology studies have demonstrated that coadministration of a macrolide antibiotic or an azole antifungal increases plasma fexofenadine levels, elevated plasma fexofenadine levels have not been shown to have a significant effect on QTc. Conversely, fexofenadine has not been shown to increase plasma macrolide or azole levels, a mechanism by which QTc prolongation might occur. 

Three cases of coagulation abnormalities have been reported following co-administration of fexofenadine and warfarin. The mechanism of a possible drug interaction is unclear, although alteration of protein binding is one possibility.

Fexofenadine is the active metabolite of terfenadine, but lacks the pro-drug’s ability to inhibit the main subunit of the HERG potassium channel in vitro, which is felt to be the primary mechanism responsible for cardiac arrhythmias associated with terfenadine use. As the sole active metabolite of terfenadine, fexofenadine is predicted to have a non-cardiac adverse events profile reflective of terfenadine, and to be safe from a cardiac perspective. A full safety review of terfenadine, excluding cardiac events, was therefore conducted by DPADP to supplement the available post-marketing data available for fexofenadine. 

As of 20 March 2000, there were a total of 6,186 adverse event reports associated with the use of terfenadine in the AERS database. Many of the serious adverse events and deaths could be ascribed to cardiovascular causes, the consequence of toxicity unique to terfenadine and unlikely to be relevant for fexofenadine. Alopecia was the 2nd most common non-cardiac AE, and review of individual cases argues for a causal relationship to the drug. Alopecia has also been reported in association with fexofenadine use. There were 113 reports of seizures/convulsions associated with use of terfenadine As noted above, seizures have also been reported to occur in association with fexofenadine use, as they have with most first generation antihistamines. 

Review of the medical literature for terfenadine retrieved a total of 1095 references over 25 years (1975 – 2000). Review of the adverse events associated with the use of terfenadine reported in the medical literature generally mirrored the known cardiac toxicity of terfenadine and otherwise complemented the AERS/SRS search. No unique or unexpected adverse events attributable to terfenadine were reported in the medical literature.

In conclusion, a detailed review of all available safety data for fexofenadine did not reveal conclusive evidence of a causal association between fexofenadine use and serious and/or life threatening adverse events. A possible association between fexofenadine use and seizures was noted and this is not currently reflected in the package insert. A potential signal of ventricular arrhythmias in association with fexofenadine use was detected, however, the data were inconclusive and the known pharmacologic properties of fexofenadine argue against a causal link. 


CETIRIZINE
-----------------
Cetirizine is an active metabolite of hydroxyzine, a currently marketed prescription antihistamine. In clinical trials cetirizine has been associated with somnolence at a rate slightly greater than that seen with placebo (13.7% in adults, 4.2% in children at a dose of 10 mg.

There are two approved formulations of cetirizine: 

NDA 19-835: Cetirizine 5 mg (Zyrtec) tablets, approved December, 1995.

NDA 20-346: Cetirizine 1 mg/1 mL (Zyrtec Syrup), approved September, 1996.

Cetirizine tablets are currently labeled for use in adults and children age 12 years and above at a dose of 5 to 10 mg once daily. Cetirizine Syrup is approved for use in children down to age 2 years. Approved dosing for children age 6 to 11 years is 5 to 10 mg once daily and for children age 2 to 5 years is 2.5 mg (2.5 ml Zyrtec Syrup) once daily. 

The NDA reviews for these cetirizne formulations showed that at the labeled dose of 10 mg once daily, the most commonly reported events from placebo-controlled clinical trials included somnolence (13.7% for cetirizine vs. 6.3% for placebo), fatigue (5.9% vs. 2.6%), and dry mouth (5.0% vs. 2.3%). The frequency of reported psychiatric disorders after administration of cetirizine was twice that of placebo (18% compared to 9%) in placebo-controlled studies in adults. There was no gender difference.

A total of four clinical pharmacology studies were conducted prior to approval to ascertain the potential effect of cetirizine on cardiac repolarization, specifically QTc. There was no evidence of QTc prolongation in three of these studies at doses up to six times the labeled dose of 10 mg for up to 7 days. A fourth study showed a 9.1 msec increase in QTc with cetirizine (ketoconazole alone showed an increase of 8.3 msec in the same study, the co-administration of the two was associated with a QTc of 17.4 msec). The validity of this finding has been questioned due to the absence of a known PK interaction between cetirizine and ketonconazole, the absence of preclinical data demonstrating an impact of cetirizine on QTc, and concerns about the reproducibility of this finding. There was no evidence of ECG changes supportive of a QTc effect in either the adult or the pediatric phase 3 controlled clinical trials conducted for product approval. 

Additional drug-drug interaction studies have disclosed no significant impact of coadministration of ketoconazole or the macrolide antibiotics erythromycin or azithromycin on cetirizine levels. 

Other safety information from the approved package insert of potential relevance in an OTC setting include recommendations for dosing adjustment in patients with renal failure and hepatic insufficiency, and in geriatric patients (each because of reduced clearance of cetirizine in that patient population). 

As of March, 2001, the AERS database contained a total of 3096 adverse event reports in association with products containing cetirizine. The most prevalent event categories were "drug ineffective" and adverse event terms encoding psychiatric events. Specifically, 39.3% of adverse reaction reports (n = 1216) for cetirizine included one or more nervous system or psychiatric terms. These included sedation (306), headache (107), insomnia (98), syncope (54), agitation (49), nervousness (48), convulsions (44), confusion (41), anxiety (40), paresthesia (38), tremor (38), abnormal dreams (37), depersonalization (34), malaise (34), depression (32), hyperkinetic syndrome (27), abnormal thinking (26), loss of consciousness (25), and hallucinations (23). There were 16 deaths, four of which were possibly attributable to a primary nervous system or psychiatric event. One patient committed suicide when he became confused, depressed and had hallucinations after taking cetirizine.

Among the serious events, three categories were identified as potential areas of concern: convulsions/seizures, ventricular arrhythmias, and thrombocytopenia. 

As of April 2000, there were 16 reports of new onset seizures temporally related to cetirizine administration. In 11 other cases, there was exacerbation of seizures after initiating treatment with cetirizine. Data are incomplete, but there was a positive dechallenge in 13 patients and a positive rechallenge in 4 patients, suggestive of causality. 

As of April 2000, there were 27 cases of ventricular arrhythmias, sudden cardiac death and QT prolongation temporally associated with cetirizine administration. About 50% if the patients had pre-existing cardiac disease or were taking a concomitant medication that could prolong the QT interval. Four patients were taking a medication that could induce an arrhythmia in a patient with pre-existing QT prolongation. Torsades de pointes was reported in 3 patients and ventricular tachycardia in 6 patients. Asymptomatic prolongation of the QT interval was noted in 4 patients and symptomatic prolongation in 6 patients. There were 5 fatalities in this group. The majority of these patients were adult women. In four patients, the event occurred the same day that treatment with cetirizine was initiated. Based on a careful review of these cases by FDA it appears that a causal relationship may be present between cetirizine and cardiac arrhythmias, however, the data are by no means conclusive. 

There were 11 cases of thrombocytopenia possibly associated with cetirizine. Seven cases were domestic and four were non-US. Seven of these cases were reported solely as thrombocytopenia, the remainder as ITP, TTP, or pancytopenia. The lowest platelet count reported was 1000, with three of the four cases reporting nadir levels less than 10,000. The outcomes include one death and seven patients that were hospitalized. Cetirizine and hydroxyzine have known cross-reactivity with the piperazines, and thrombocytopenia associated with piperazines has been reported in the literature. Based on a careful review of these data by FDA staff it appears that there may be a causal relationship between cetirizne and rare reports of thrombocytopenia; however,the data are not conclusive.

The published literature did not provide additional insight regarding the primary areas of safety concern.

In conclusion, an extensive review of adverse event reports associated with use of cetirizine revealed possible associations between cetirizine and sedation, neuropsychiactric events, including seizures, cardiac arrhthmias, and thrombocytopenia There is a preponderance of neuropsychiatric adverse events, particularly sedation, which may exceed the rate of reporting of similar events for loratadine and fexofenadine The data are inconclusive with regard to a causal relationship between cetirizine and arrhythmias and thromobcytopenia

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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(102)  31/07/2.001 DR. JOSE LAPENTA R. 
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