Data-Medicos
Dermagic/Express No. 3-(108)
Ocubre 2.001. October 2.001.
EDITORIAL ENGLISH
=================
HOLA amigos de la red DERMAGIC, de nuevo con ustedes, en esta ocasión con el
tema: REALMENTE EXISTEN GRANDES DIFERENCIAS ENTRE LA DESLORATADINA Y LORATADINA.
???
Antes de iniciar el tema, les comento que un día después de lanzada a la red el
tema LA LORATADINA Y SUS 11O EFECTOS ADVERSOS, en el servidor DERMLIST de BRASIL
se publico un caso de un
paciente masculino de 22 años de edad quien desarrollo
una HEPATITIS por droga debido al uso de LORATADINA, el testimonio
esta montado en esta revisión, lo cual ratifica que lo DE
LA TOXICIDAD HEPÁTICA DE ESTA MOLECULA no es un cuento de NAVIDAD.
Otro aspecto a señalar es la ratificación de que desde el año 1.996 ya se
conocían los efectos tóxicos de esta molécula en el HÍGADO, YA que el libro
Mosby los publico. Ustedes pueden observar la cantidad de efectos adversos que
para ese año ya se habían descrito, y también pueden leer LA INFORMACIÓN DEL
FABRICANTE SUMINISTRADA en las cajas de Loratadina en los Estados Unidos de
América, año 2000-2001, de modo que no hay margen de error.
El laboratorio MUY PROBABLEMENTE CONSCIENTE DE LOS EFECTOS ADVERSOS QUE HA
CAUSADO LA LORATADINA desde su salida al mercado, el 11 de mayo 2.001 se OPONE a
cambiar el estatus de la misma A VENTA LIBRE (OTC). En nuestro pais se VENDE
LIBREMENTE. También alega que el tratamiento de las alergias es complejo.
Como todos ustedes saben el 31 de Julio de este año DERMAGIC publico la primera
revisión de la DESLORATADINA, REVELANDO que una organización denominada PUBLIC
CITIZEN hace una publicación implicando al LABORATORIO fabricante de los
productos ALBUTEROL, LORATADINA CON PSUDOEFEDRINA Y DESLORATADINA como productos
con problemas de manufactura.
EL laboratorio IMPLICADO REBOTO los alegatos de CITIZEN
9 DÍAS DESPUÉS de la publicación
de DERMAGIC/EXPRESS EN todo el mundo. Pero hay que resaltar que el
alegato del LABORATORIO es en FAVOR DEL PRODUCTO ALBUTEROL, con respecto a la
LORATADINA CON PSEUDOEFEDRINA Y DESLORATADINA (AERIUS) NO SE PRONUNCIO. Ni se ha
pronunciado HASTA el día presente.
... Pero el 22 DE JUNIO 2.001, ya el LABORATORIO HABÍA
RECONOCIDO públicamente
que realmente existían problemas en sus fabricas y que se iba a
abocar a resolverlos, lo mas pronto posible, ESPEREMOS QUE ESTO YA se haya
cumplido.
Con respecto a la DESLORATADINA podemos decir lo siguiente de interes:
LA DESLORATADINA (AERIUS) ES EL MAYOR METABOLITO ACTIVO
DE LA LORATADINA (descarboethoxyloratadina)UNA VEZ ES metabolizada por el HÍGADO
(citocromo p450 y otros), de modo que LA LORATADINA EJERCE la mayoría
de sus efectos en el CUERPO HUMANO como desloratadina. Resumiendo LA
DESLORATADINA ES UNA SIMPLE LORATADINA sin metabolismo de primer paso,
probablemente con algún otro efecto. Esto es positivo pues la LIBERA DE SUS
EFECTOS SOBRE EL hígado, pero no la LIBERA de los OTROS efectos adversos que se
le atribuyen a la molécula LORATADINA.
Interesante hecho me encuentro al revisar TODA LA BASE DE DATOS SOBRE LA
DESLORATADINA donde no encuentro NINGÚN ASPECTO NEGATIVO sobre esta molécula, lo
mismo que OCURRIÓ CON LA LORATADINA y fíjense la CANTIDAD DE EFECTOS ADVERSOS
QUE LA FDA le ha reportado.
La desloratadina NO HA SIDO APROBADA EN ESTADOS UNIDOS
porque la patente de la LORATADINA VENCE en DICIEMBRE del 2.002, y es MENOS
COSTOSA, y también encontré un articulo interesante donde se COMENTA que LOS
BENEFICIOS DE ESTA MOLÉCULA SOBRE LA LORATADINA PARECEN SER MUY POCOS. Los
primeros EFECTOS ADVERSOS REPORTADOS son los mismos que para la loratadina, Y
ESTO ES UNA DEMOSTRACIÓN MAS DE QUE LA LORATADINA EJERCE LA MAYORÍA DE sus
efectos sobre el cuerpo COMO DESLORATADINA.
En nuestro país Venezuela SE INTRODUJO EL PRODUCTO DESLORATADINA (AERIUS) el dia
23 de AGOSTO 2.001 y a mi se me entrego una MONOGRAFÍA DEL PRODUCTO y en la
presentación del mismo hay un aspecto interesante que señalar:
Se me dijo que esta MOLÉCULA ES ENTRE 30 Y 50 VECES MAS
POTENTE que los otros antihistamínicos LO CUAL ES FALSO Y CARECE DE BASES
CIENTÍFICAS, pues NO EXISTE NINGÚN ESTUDIO PUBLICADO QUE AVALE estas
propiedades, y DUDO que lo exista PUES la DESLORATADINA ES EL METABOLITO ACTIVO
DE LA LORATADINA., COMO VA A SER 50 VECES MAS POTENTE QUE OTRO ????.
Esta información TOTALMENTE LEJANA A LA REALIDAD se hizo con la finalidad
COMERCIAL DE IMPLANTAR AERIUS como el mejor y nuevo antihistamínico DEL MUNDO,
cuando se trata simplemente de una LORATADINA SIN metabolismo de primer paso.
Desde la publicación DE DERMAGIC/EXPRESS (31 DE JULIO) sobre este tema
DESLORATADINA EL LABORATORIO FABRICANTE no se ha pronunciado PÚBLICAMENTE AL
RESPECTO.
Los HECHOS por fecha:
---------------------------------
1.) EL DÍA 13 DICIEMBRE 2000 EL LABORATORIO SHERING-P
envía a LA FDA petición para aprobación de DESLORATADINA. en 2
presentaciones.
2.) El dia 16 DE ENERO del 2.001 DESLORATADINA ES
aprobada por la Unión Europea para su
comercialización en Europa, EN
ALERGIAS ESTACIONALES fabricada por la compañía SEPRACOR comercializada POR
SHERING -P.
3.) EL día 25 DE ENERO 2.001 el laboratorio
SCHERING-P recibe una "PROBABLE" carta de aprobación para comercializar
DESLORATADINA.en estados Unidos. 9 MESES DESPUÉS este hecho NO SE HA HECHO
REALIDAD todavía.
4.) El día 3 DE MARZO 2.001 PUBLIC CITIZEN DENUNCIA
que el LABORATORIO SHERING-P tiene problemas con la FABRICACIÓN DE 3 DE SUS
PRODUCTOS, ALBUTEROL, LORATADINA CON PSUDOEFEDRINA Y DESLORATADINA.
5.) EL día 11 DE MAYO 2.001 el laboratorio
FABRICANTE SE OPONE A CAMBIAR EL STATUS DE LORATADINA A PRODUCTO de venta libre
(OTC)
6.) El DÍA 22 DE JUNIO 2.001 EL LABORATORIO
SHERING-P anuncia que facilitara las inspecciones de la FDA, que realmente hay
problemas en sus fabricas y que hará esfuerzos por corregirlos detallando el
plan de acción.
7.) EL 31 DE JULIO 2.001 DERMAGIC/EXPRESS
lanza a la red LA REVISIÓN DE DESLORATADINA develando LA VERDAD DE LOS HECHOS.
8.) EL 9 DE AGOSTO 2.001 EL LABORATORIO SHERING -P
RECUSA alegatos de PUBLIC CITIZEN con respecto a la droga ALBUTEROL,
no lo hace con DESLORATADINA Y LORATADINA CON PSEUDOEFEDRINA.
9.) EL MISMO 9 DE AGOSTO 2.001 SHERING-P
VUELVE ANUNCIAR LA APROBACIÓN DE LA UNIÓN EUROPEA de la DESLORATADINA para uso
en pacientes con URTICARIA IDIOPÁTICA, en ADULTOS Y NIÑOS MAYORES DE 12 AÑOS,
10.) 23 DE AGOSTO 2.001, DESLORATADINA COMIENZA A SER
comercializada en VENEZUELA, con los NOMBRES COMERCIALES DE AERIUS Y DESALEX,
diciéndo que el producto es 30-50 VECES MAS POTENTE QUE OTROS
ANTIHISTAMÍNICOS.
11.) EL DIA 5 OCTUBRE 2.001 EL LABORATORIO SHERING-P
de Venezuela llama a DERMAGIC/EXPRESS por teléfono y le INSINÚA que LAS
PUBLICACIONES SOBRE SUS MOLÉCULAS NIMESULIDE, LORATADINA Y DESLORATADINA TIENEN
"MALA INTENCIÓN".
- DERMAGIC/EXPRESS responde que son TOTALMENTE
CIENTÍFICAS Y APEGADAS A LA REALIDAD Y CON BASES BIBLIOGRÁFICAS PERFECTAMENTE
COMPROBABLES, Y QUE SE HICIERON PARA INFORMAR A LA COMUNIDAD NACIONAL E
INTERNACIONAL ASPECTOS DE INTERÉS sobre estas moléculas.
- DEMAGIC/EXPRESS ha REALIZADO REVISIONES DE OTRAS
MOLÉCULAS COMO FEXOFENADINA, TERBINAFINA ITRACONAZOLE, FINASTERIDE,
ISOTRETINOINA, MINOCICLINA y OTRAS, Y NUNCA JAMÁS los LABORATORIOS llamaron PARA
DECIR QUE LAS REVISIONES BIBLIOGRÁFICAS ERAN MAL INTENCIONADAS.
- DERMAGIC/EXPRESS RESPONDERÁ DE NUEVO CIENTÍFICAMENTE
CON OTRA REVISIÓN SOBRE EL NIMESULIDE Y SUS EFECTOS SOBRE EL CORAZÓN.
- DESDE EL 21 DE AGOSTO 2.001 A LOS VISITADORES DEL
LABORATORIO SHERING-P SE LES IMPIDIÓ LA ENTRADA A LA OFICINA DE
DERMAGIC/EXPRESS.
12.) 15 OCTUBRE, 2.001
DESLORATADINA SIGUE SIN SER APROBADA POR LA FDA, en LOS ESTADOS UNIDOS DE
AMÉRICA.
Una vez mas alerto a TODOS LOS PAÍSES Y MÉDICOS que PIDAN LA MONOGRAFÍA DEL
PRODUCTO AL LABORATORIO FABRICANTE y la lean con detenimiento y TOMEN sus
debidas precauciones antes de PRESCRIBIR EL PRODUCTO.
CONCLUSIONES:
--------------------------
1.) PUBLIC CITIZEN TENIA RAZÓN. !!!
2.) DESLORATADINA FUE APROBADA POR LA UNIÓN EUROPEA SOLO PARA EL TRATAMIENTO DE
ALERGIAS ESTACIONALES (RINITIS ALERGICA) Y URTICARIA IDIOPÁTICA EN ADULTOS Y
NIÑOS MAYORES DE 12 AÑOS.
3.) DESLORATADINA SIGUE SIN SER APROBADA POR LA FDA.
4.) LA TOXICIDAD HEPÁTICA DE LA LORATADINA ES UN HECHO COMPROBADO.
5.) LOS EVENTOS CARDIACOS PRODUCIDOS POR LA LORATADINA SON UNA REALIDAD.
6.) SE NECESITAN MAS ESTUDIOS OBJETIVOS
SOBRE LA DESLORATADINA PARA ENTENDER BIEN ESTA MOLÉCULA Y SUS VERDADEROS EFECTOS EN EL CUERPO HUMANO, pues si de los 110 efectos adversos QUE se le atribuyen a la LORATADINA,
si
les quitamos los hepáticos QUEDAN MAS DE 95 EFECTOS ADVERSOS reportados AL USO DE ESTA
MOLÉCULA. La pregunta es: QUIEN LOS PRODUCE, LA LORATADINA O LA DESLORATADINA, el metabolito activo. ???
En las referencias los hechos
Dr José Lapenta R.
EDITORIAL ENGLISH
=================
HELLLO friends of the net, DERMAGIC again with you, in this occasion with the
topic: BIG DIFFERENCES REALLY EXIST BETWEEN THE DESLORATADINE AND LORATADINE.
???
Before beginning the topic, I comment them that one day after having thrown to
the net the topic THE LORATADINE AND THEIR 11O ADVERSE EFFECTS, in the server
DERMLIST of BRAZIL I publishes a case of a 22 year-old
masculine patient who I develop a HEPATITIS for drug due to the use of
LORATADINE,
the testimony is mounted one in this revision, that which ratifies
that OF
THE HEPATIC TOXICITY OF THIS MOLECULE is not a story
of CHRISTMAS.
Another aspect to point out is the ratification that from the year 1.996 the
toxic effects of this MOLECULE were already known in the LIVER, since the Mosby
Book publishes them. You can observe the quantity of adverse effects that they
had been described already for that year, and you can also read THE MAKER'S
INFORMATION in the boxes of LORATADINE in the United States of America, year
2000-2001, so that there is not error margin.
The laboratory very PROBABLY AWARE OF THE ADVERSE EFFECTS THAT THE LORATADINE
has CAUSED from its exit to the market, May 11 2.001 is OPPOSED to change the
status the same one TO FREE SALE (OTC). in our country it is SOLD FREELY. He
also alleges that the treatment of the allergies is complex.
As all you know the July 31 of this year DERMAGIC I publish the first revision
of the DESLORATADINE, REVEALING that a denominated organization PUBLIC CITIZEN
makes a publication implying to the manufacturing LABORATORY of the products
ALBUTEROL, LORATADINE WITH PSEUDOEPHEDRINE AND DESLORATADINE like products with
manufacturing troubles.
THE IMPLIED laboratory REBUTS the allegations of
CITIZEN 9 DAYS after the publication of DERMAGIC/EXPRESS in the
entire world. But it is necessary to stand out that the allegation of the
LABORATORY is in FAVOR OF THE PRODUCT ALBUTEROL, with regard to the LORATADINE
WITH PSEUDOEPHEDRINE AND DESLORATADINA (AERIUS) he doesn't PRONOUNCE. Neither it
has been pronounced UNTIL the present day.
... But JUNE 22 2.001, the LABORATORY had already
RECOGNIZED openly that problems really existed in their factorys and
that it will meet to solve them, him but soon possible, let us HOPE THIS has
ALREADY been completed.
With regard to the DESLORATADINE we can say the following of interest:
THE DESLORATADINE (AERIUS) it is THE MAJOR ACTIVE
METABOLITE OF THE LORATADINE (descarboethoxyloratadin) when he is metabolized by
the LIVER (cytochrome p-450 enzymes and others), so that THE
LORATADINE EXERCISES most of its effects in the HUMAN BODY as DESLORATADINE.
Summarizing THE DESLORATADINE is A SIMPLE LORATADINE without metabolism of first
step, probably with some other effect. This is positive because it LIBERATES it
OF THEIR EFFECTS ON THE liver, but it doesn't LIBERATE it of the OTHER adverse
effects that are attributed to the LORATADINE molecule.
The desloratadine has not BEEN APPROVED IN UNITED
STATES because the patent of the LORATADINE EXPIRES in DECEMBER of
the 2.002, and it is LESS EXPENSIVE, and I also found a I a interesting article
where it is COMMENTED that THE BENEFITS OF THIS MOLECULE ON THE LORATADINE SEEM
to BE VERY FEW. The first REPORTED ADVERSE EFFECTS are the same ones that for
the LORATADINE, AND THIS is A DEMONSTRATION THAT THE LORATADINE EXERCISES most
OF their effects on the body LIKE DESLORATADINE.
In our country venezuela THE PRODUCT DESLORATADINE was INTRODUCED (AERIUS) the
day 23 of AUGUST 2.001 and to my I am given a MONOGRAPH OF THE PRODUCT and in
the presentation of the same one there is an interesting aspect that to point
out:
I was said to me, that this MOLECULE is BETWEEN 30 AND
50 TIMES BUT POTENT that the other antihistamine drugs THAT WHICH is
FALSE AND it LACKS SCIENTIFIC BASES, because it doesn't EXIST ANY PUBLISHED
STUDY THAT it ENDORSES these properties. and I DOUBT that it exists him THEN the
DESLORATADINE it is THE ACTIVE METABOLITE OF THE LORATADINE., WHY it will BE 50
TIMES BUT POTENT THAN OTHERS ????.
This COMPLETELY DISTANT information TO THE REALITY was made with the COMMERCIAL
purpose OF IMPLANTING AERIUS like the best and new antihistame drug IN THE
WORLD, when it is simply a LORATADINE WITHOUT metabolism of first step.
From the publication DE DERMAGIC/EXPRESS (JULY 31)on this topic DESLORATADINE
THE MANUFACTURING LABORATORY has not been pronounced OPENLY in this respect.
The FACTS for date:
------------------------------
1.) The DAY 13 DECEMBER 2000 THE LABORATORY SHERING-P
sends to THE FDA petition for for approval of DESLORATADINE. in 2
presentations.
2.) The day 16 OF JANUARY of the 2.001 DESLORATADINE it
is approved by the European union for their commercialization in
Europe, IN SEASONAL ALLERGIES manufactured by the company SEPRACOR marketed BY
SHERING -P.
3.) THE day 25 OF JANUARY 2.001 the laboratory
SCHERING-P recive a "APPROVABLE" letter to market DESLORATADINE in
United states. 9 MONTHS LATER this fact REALITY has not still BEEN MADE.
4.) The day 3 OF MARCH PUBLIC CITIZEN it DENOUNCES that
the LABORATORY SHERING-P has problems with the PRODUCTION OF 3 OF ITS
PRODUCTS, ALBUTEROL, LORATADINE WITH PSUDOEPHEDRINE AND DESLORATADINE.
5.) THE day 11 OF MAY 2.001 the
MANUFACTURING laboratory is OPPOSED to CHANGE THE STATUS OF LORATADINE TO
PRODUCT of free sale (OTC).
6.) THE day 22 OF JUNE THE LABORATORY SHERING-P
announces that it FACILITATED THE FDA the inspections, that there are
truly problems in its factorys and that he will make efforts to correct them
detailing the action plan.
7.) The day 31 OF JULY DERMAGIC/EXPRESS throws
to the net THE REVISION ABOUT DESLORATADINE REVEALING THE TRUTH OF THE FACTS.
8.) The day AUGUST 9 THE LABORATORY SHERING -P REBUTS
the allegations of PUBLIC CITIZEN with regard to the drug ALBUTEROL,
he doesn't make it with DESLORATADINE AND LORATADINE WITH PSEUDOEPHEDRINE.
9.) THE SAME one AUGUST 9 SHERING-P RETURNS to ANNOUNCE
THE APPROVAL OF THE EUROPEAN UNION of the DESLORATADINE for use in
patient with IDIOPATHIC URTICARIA, in ADULTS AND bigger CHILDREN of 12 YEARS.
10.) The day AUGUST 23, DESLORATADINE BEGINS to be
marketed in VENEZUELA, with the BRAND NAMES OF AERIUS AND DESALEX,
saying to me that the product is 30-50 TIMES BUT POTENT THAN OTHER
ANTIHISTAMINICS.
11.) THE DAY 5 OCTOBER 2.001 THE LABORATORY SHERING-P
of Venezuela calls to DERMAGIC/EXPRESS and it INSINUATES him that THE
PUBLICATIONS ABOUT THEIR MOLECULES NIMESULIDE, LORATADINE, AND DESLORATADINE
HAVE "BAD INTENTION".
- DERMAGIC/EXPRESS responds that they are COMPLETELY
SCIENTIFIC AND ATTACHED TO THE REALITY AND WITH PERFECTLY VERIFIABLE
BIBLIOGRAPHICAL BASES, AND THAT they were MADE to INFORM TO THE MEDIC COMMUNITY
NATIONAL AND INTERNATIONAL ASPECTS OF INTEREST ON these molecules.
-DERMAGIC/EXPRESS has CARRIED OUT REVISIONS OF OTHER
MOLECULES LIKE FEXOFENADINE, TERBINAFINE, ITRACONAZOLE, FINASTERIDE,
ISOTRETINOIN, MINOCYCLINE and OTHERS, AND the LABORATORIES NEVER called NEVER to
SAY THAT THE BIBLIOGRAPHICAL REVISIONS were WITH "BAD INTENTION".
-DERMAGIC/EXPRESS WILL RESPOND SCIENTIFICALLY AGAIN
WITH A NEW REVISION ABOUT NIMESULIDE AND THEIR EFFECTS ON THE HEART.
- SINCE AUGUST 2.001 21 TO THE VISITORS OF THE
LABORATORY SHERING-P were IMPEDED THE ENTRANCE TO THE DERMAGIC/EXPRESS'S OFFICE.
12.) 15 OCTOBER 2.001
, DESLORATADINE CONTINUES WITHOUT being APPROVED
BY THE FDA, in THE UINITES STATES DE AMÉRICA.
Once but I alert ALL THE COUNTRIES AND DOCTORS that REQUEST THE MONOGRAPH FROM
THE PRODUCT TO THE MANUFACTURING LABORATORY and read it thoroughly and TAKE
their due cautions before PRESCRIBING THE PRODUCT.
CONCLUSIONS:
-------------------------
1.) PUBLIC CITIZEN HAD REASON. !!!
2.) DESLORATADINE was APPROVED BY THE EUROPEAN UNION ALONE FOR THE TREATMENT OF
SEASONAL ALLERGIES (ALLERGIC RINITIS) AND IDIOPATHIC URTICARIA IN ADULTS AND
bigger CHILDREN OF 12 YEARS.
3.) DESLORATADINE CONTINUES WITHOUT being APPROVED BY THE FDA.
4.) THE HEPATIC TOXICITY OF THE LORATADINE is A PROVEN FACT.
5.) THE CARDIAC EVENTS PRODUCED BY LORATADINE ARE A REALITY.
6.) MORE OBJECTIVE STUDIES are NEEDED ON THE
DESLORATADINA to UNDERSTAND THIS MOLECULE AND THEIR TRUE EFFECTS WELL IN THE HUMAN BODY, because if of the 110 adverse effects THAT are attributed to the
LORATADINE, we remove them the hepatic ones they are MORE THAN 95 ADVERSE EFFECTS reported TO
THE USE OF THIS MOLECULE. The question is: WHO PRODUCES THEM, THE LORATADINE OR THE DESLORATADINE, the active metabolite. ???
In the references the facts
Dr José Lapenta R.
=============================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
=============================================================
0.) A new case of hepatic TOXICITY from loratadine, testimony
1.) In vitro characterization of the inhibition profile of loratadine,
desloratadine, and 3-oh-desloratadine for five human cytochrome p-450 enzymes.
2.) Effect of desloratadine and loratadine on rhinovirus-induced intercellular
adhesion molecule 1 upregulation and promoter activation in respiratory
epithelial cells.
3.) Evaluation of the Interaction of Loratadine and desloratadine with
P-glycoprotein.
4.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and
anti-inflammatory drug.
5.) Desloratadine.
6.)[A new antihistamine. Inhibiting inflammation in rhinorrhea and nasal
congestion].
7.) Pharmacokinetic and safety profile of desloratadine and fexofenadine when
coadministered with azithromycin: a randomized, placebo-controlled,
parallel-group study.
8.) Desloratadine: A new, nonsedating, oral antihistamine.
9.) Once-daily desloratadine improves the signs and symptoms of chronic
idiopathic urticaria: a randomized, double-blind, placebo-controlled study.
10.) The pharmacologic profile of desloratadine: a review.
11.) Desloratadine: a new approach in the treatment of allergy as a systematic
disease--pharmacology and clinical overview. Introduction.
12.) Desloratadine in the treatment of chronic idiopathic urticaria.
13.) Desloratadine activity in concurrent seasonal allergic rhinitis and asthma.
14.) Decongestant efficacy of desloratadine in patients with seasonal allergic
rhinitis.
15.) Evaluation of the pharmacokinetics and electrocardiographic
pharmacodynamics of loratadine with concomitant administration of ketoconazole
or cimetidine.
16.) Therapeutic options in allergic disease: antihistamines as systemic
antiallergic agents.
17.( Preclinical pharmacology of desloratadine, a selective and nonsedating
histamine H1 receptor antagonist. 2nd communication: lack of central nervous
system and cardiovascular effects.
18.) Preclinical pharmacology of desloratadine, a selective and nonsedating
histamine H1 receptor antagonist. 1st communication: receptor selectivity,
antihistaminic activity, and antiallergenic effects.
19.) Anticholinergic effects of desloratadine, the major metabolite of
loratadine, in rabbit and guinea-pig iris smooth muscle.
20.) Desloratadine - first clinical data in rhinitis revealed
21.) SCHERING-PLOUGH SUBMITS U.S. MARKETING APPLICATIONS
FOR TWO NEW FORMULATIONS OF DESLORATADINE
22.) European Committee Recommends Approval of Desloratadine for Chronic
Idiopathic Urticaria
23.) Quality of life improves in seasonal allergic rhinitis patients treated
with desloratadine
24.) Efficacy and Tolerability of Once-Daily 5mg Desloratadine, an H1-Receptor
Antagonist, in Patients with Seasonal Allergic Rhinitis Assessment during the
Spring and Fall Allergy Seasons
25.) Schering-Plough Announces European Union Approval of Desloratadine
26.) DESLORATADINE
27.) SCHERING-PLOUGH REPORTS DESLORATADINE RECEIVES FDA "APPROVABLE" LETTER
28.) SCHERING-PLOUGH ANNOUNCES EUROPEAN UNION APPROVAL OF DESLORATADINE FOR
TREATMENT OF CHRONIC IDIOPATHIC URTICARIA
29.) PUBLIC CITIZEN
30.) SCHERING-PLOUGH REBUTS PUBLIC CITIZEN ALLEGATIONS
31.) LORATADINE INFORMATION FROM MOSBY YEAR BOOK. 1.996
32.) The original packing information of the product CLARITIN® brand of
loratadine 2.000-2.001
33.) SCHERING-PLOUGH DISAGREES WITH FDA ADVISORY PANEL’S RECOMMENDATION
REGARDING CLARITIN (LORATADINE)
34.) SCHERING-PLOUGH PROVIDES UPDATE ON MANUFACTURING ISSUES
AND FDA INSPECTIONS OF U.S. MANUFACTURING FACILITIES
=============================================================
=============================================================
0.) A new case of hepatic TOXICITY from loratadine, testimony
=============================================================
Source: DERMLIST Brasil, Dr Mauro Siqueira.
1. DR. MAURO SIQUEIRA
Subject: Loratadina - aconteceu comigo!
Caro Dr. Jose Lapenta:
Há cerca de 3 meses um meu paciente de 22 anos de idade apresentou uma forte
dermatite e euprescrevi LORATADINA por seis dias....algumas semanas depois veio
com queixas de astenia e palidez, a provas hepaticas estavam
fortemente alteradas. A pesquisa de hepatite A, B e C resultou negativa e as
outras possiveis causas do quadro foram afastadas pelo hepatologista. O
diagnostico foi hepatite medicamentosa e a unica causa era a loratadina!
Grato pelo alerta!
Mauro Siqueira
=============================================================
1.) In vitro characterization of the inhibition profile of loratadine,
desloratadine, and 3-oh-desloratadine for five human cytochrome p-450 enzymes.
=============================================================
Drug Metab Dispos 2001 Sep;29(9):1173-5
Barecki ME, Casciano CN, Johnson WW, Clement RP.
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research
Institute, Lafayette, New Jersey.
The purpose of this study was to evaluate loratadine, desloratadine, and
3-OH-desloratadine as inhibitors of certain human liver cytochrome P-450
enzymes. Pooled human liver microsomes were used to determine whether
loratadine, desloratadine, and 3-OH-desloratadine were inhibitors of cytochrome
P-450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4. Loratadine did not inhibit CYP1A2 or
CYP3A4 at concentrations up to 3829 ng/ml, which is approximately 815-fold
greater than the expected maximal human plasma concentration (4.7 +/- 2.7 ng/ml)
following the recommended dose of 10 mg/day. Loratadine inhibited CYP2C19 and
CYP2D6 with IC(50) values of approximately 0.76 &mgr;M [291 ng/ml; K(i)
congruent with 0.61 &mgr;M (234 ng/ml)] and 8.1 &mgr;M [3100 ng/ml; K(i)
congruent with 2.7 &mgr;M (1034 ng/ml)], respectively, which are approximately
62 and 660 times the expected loratadine therapeutic exposure concentration.
Neither desloratadine nor 3-OH-desloratadine inhibited CYP1A2, CYP2C9, CYP2C19,
CYP2D6, or CYP3A4 greater than 25% at concentrations of 3108 or 3278 ng/ml,
respectively. These results suggest that loratadine and the active metabolites
desloratadine and 3-OH-desloratadine are unlikely to affect the pharmacokinetics
of coadministered drugs which are metabolized by these five cytochrome P-450
enzymes.
=============================================================
2.) Effect of desloratadine and loratadine on rhinovirus-induced intercellular
adhesion molecule 1 upregulation and promoter activation in respiratory
epithelial cells.
=============================================================
J Allergy Clin Immunol 2001 Aug;108(2):221-8
Papi A, Papadopoulos NG, Stanciu LA, Degitz K, Holgate ST, Johnston SL.
University Medicine, University of Southampton, Southampton, UK.
BACKGROUND: Rhinoviruses have been recently associated with the majority of
asthma exacerbations for which current therapy is inadequate. Intercellular
adhesion molecule 1 (ICAM-1) has a central role in airway inflammation in
asthma, and it is the receptor for 90% of rhinoviruses. Rhinovirus infection of
airway epithelium induces ICAM-1. Desloratadine and loratadine are compounds
belonging to the new class of H(1)-receptor blockers. Anti-inflammatory
properties of antihistamines have been recently documented, although the
underlying molecular mechanisms are not completely defined. OBJECTIVE: We have
investigated the effects of desloratadine and loratadine on rhinovirus-induced
ICAM-1 expression, mRNA upregulation, and promoter activation. METHODS: Cultured
primary bronchial or transformed (A549) respiratory epithelial cells were
pretreated with desloratadine and loratadine for 16 hours and infected with
rhinovirus type 16 for 8 hours. ICAM-1 surface expression was evaluated with
flow cytometry, and ICAM-1 mRNA was evaluated with specific RT-PCR. In A549
cells promoter activation was evaluated with a chloramphenicol acetyltransferase
assay, and binding activity of nuclear factor kappa B in nuclear extracts was
evaluated with an electrophoretic mobility shift assay. RESULTS: Desloratadine
and loratadine (0.1-10 micromol/L) inhibited rhinovirus-induced ICAM-1
upregulation in both primary bronchial or transformed (A549) respiratory
epithelial cells. In A549 cells the 2 compounds showed a dose-dependent
inhibition with similar efficacy (inhibitory concentration of 50%, 1
micromol/L). Desloratadine and loratadine also inhibited ICAM-1 mRNA induction
caused by rhinovirus infection in a dose-dependent manner, and they completely
inhibited rhinovirus-induced ICAM-1 promoter activation. Desloratadine also
inhibited rhinovirus-induced nuclear factor kappa B activation. Desloratadine
and loratadine had no direct effect on rhinovirus infectivity and replication in
cultured epithelial cells. CONCLUSION: These effects are unlikely to be mediated
by H(1)-receptor antagonism and suggest a novel mechanism of action that may be
important for the therapeutic control of virus-induced asthma exacerbations.
=============================================================
3.) Evaluation of the Interaction of Loratadine and desloratadine with
P-glycoprotein.
=============================================================
Drug Metab Dispos 2001 Aug;29(8):1080-3 Books, LinkOut
Wang Ej, Casciano CN, Clement RP, Johnson WW.
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute,
Lafayette, New Jersey.
The absorption of many drugs is affected by their interaction with ATP-binding
cassette (ABC) transporters. The most extensively studied of these ABC
transporters is the proein product of MDR1 (multidrug resistance) that encodes a
170-kDa integral plasma membrane phosphorylated glycoprotein known as
P-glycoprotein (P-gp). The purpose of this study was to determine, using two
different methods, whether the nonsedating antihistamine loratadine (L) and its
active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting
human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with
or without L, DL, and several positive controls. The IC(50) of loratadine (~11
&mgr;M) was ~160 times the maximum observed plasma concentration (C(max))
following a dose of 10 mg. The IC(50) of desloratadine (~43 &mgr;M) was ~880
times the C(max) following a dose of 5 mg. The positive control, cyclosporin A,
had an IC(50) of ~1 &mgr;M. ATP hydrolysis activity was measured in the membrane
fraction prepared from MDR cells presenting P-gp, which were exposed to various
concentrations of test compounds. Known substrates of P-gp demonstrated clear,
repeatable, concentration-dependent increases in ATP hydrolysis activity. L
caused an increase in ATPase activity above basal levels. L had a V(max) about
200% basal activity and K(m) of ~3 &mgr;M for P-gp. In contrast, DL had no
significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less
than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than
L (4 times). DL therefore is not a significant inhibitor of P-gp and should not
cause clinical drug interactions with agents that are P-gp substrates.
=============================================================
4.) Pharmacology and clinical efficacy of desloratadine as an anti-allergic and
anti-inflammatory drug.
Expert Opin Investig Drugs 2001 Mar;10(3):547-60
=============================================================
Agrawal DK.
Center for Allergy, Asthma and Immunology, Creighton University School of
Medicine, Omaha, NE 68178, USA. [email protected]
Desloratadine is a biologically active metabolite of the second-generation
antihistamine loratadine. Desloratadine is a highly selective peripheral H1
receptor antagonist that is significantly more potent than loratadine. Results
of in vitro and in vivo studies have suggested that desloratadine has
anti-allergic effects that are unrelated to its ability to antagonise the
effects of histamine. Desloratadine inhibits the expression of cell adhesion
molecules, inhibits the generation and release of inflammatory mediators and
cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation.
Studies in animals indicate that desloratadine does not cross the blood-brain
barrier and therefore does not cause sedation and does not impair cognition or
psychomotor performance. Desloratadine has an excellent overall safety profile.
It has no effect on QRS and QTc intervals and does not cause arrhythmias.
Desloratadine is not associated with any significant changes in gastrointestinal
function. In clinical studies, oral desloratadine is rapidly absorbed and
bioavailability is not affected by ingestion with food or grapefruit juice. The
half-life of desloratadine in humans is 27 h; the linear kinetic profile is
unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein
or organic anion transport polypeptide and the drug does not appear to be
metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It
therefore may be safely administered with ketoconazole, erythromycin,
fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both
nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including
nasal congestion. Desloratadine also provides significant relief of SAR symptoms
in patients with co-existing asthma and is effective in the treatment of chronic
idiopathic urticaria. Desloratadine improves quality of life and is
well-tolerated.
=============================================================
5.) Desloratadine.
=============================================================
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.
=============================================================
6.)[A new antihistamine. Inhibiting inflammation in rhinorrhea and nasal
congestion].
=============================================================
MMW Fortschr Med 2001 Apr 5;143(14):47
[Article in German]
Publication Types:
News
=============================================================
=============================================================
7.) Pharmacokinetic and safety profile of desloratadine and fexofenadine when
coadministered with azithromycin: a randomized, placebo-controlled,
parallel-group study.
=============================================================
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.
=============================================================
8.) Desloratadine: A new, nonsedating, oral antihistamine.
=============================================================
J Allergy Clin Immunol 2001 Apr;107(4):751-62 Related
Geha RS, Meltzer EO.
Boston Children's Hospital and Harvard Medical School, Enders Building, Room
809, 300 Longwood Ave., Boston, MA 02115, USA.
Desloratadine is a new, selective, H(1)-receptor antagonist that also has
anti-inflammatory activity. In vitro studies have shown that desloratadine
inhibits the release or generation of multiple inflammatory mediators, including
IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the
TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of
cell adhesion molecules, plateletactivating factor-induced eosinophil
chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol
myristate acetate-induced superoxide generation in vitro. In animals
desloratadine had no effect on the central nervous, cardiovascular, renal, or
gastrointestinal systems. Desloratadine is rapidly absorbed, has
dose-proportional pharmacokinetics, and has a half-life of 27 hours. The
absorption of desloratadine is not affected by food, and the metabolism and
elimination are not significantly affected by the subject's age, race, or sex.
There are no clinically relevant interactions between desloratadine and
erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a
significant substrate of the P-glycoprotein transport system. Once daily
administration of desloratadine rapidly reduces the nasal and nonnasal symptoms
of seasonal allergic rhinitis, including congestion. In patients with seasonal
allergic rhinitis and concomitant asthma, desloratadine treatment was also
associated with significant reductions in total asthma symptom score and use of
inhaled beta(2)-agonists. Use of desloratadine in patients with chronic
idiopathic urticaria was associated with significant reductions in pruritus,
number of hives, size of the largest hive, and interference with sleep and daily
activities. Clinical experience in over 2300 patients has shown that the adverse
event profile of desloratadine is similar to that of placebo; desloratadine has
no clinically relevant effects on electrocardiographic parameters, does not
impair wakefulness or psychomotor performance, and does not exacerbate the
psychomotor impairment associated with alcohol use.
=============================================================
9.) Once-daily desloratadine improves the signs and symptoms of chronic
idiopathic urticaria: a randomized, double-blind, placebo-controlled study.
=============================================================
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.
=============================================================
10.) The pharmacologic profile of desloratadine: a review.
=============================================================
Allergy 2001;56 Suppl 65:7-13
Henz BM.
Department of Dermatology and Allergy, Charite Humboldt University, Berlin,
Germany.
Desloratadine is a new agent for the treatment of diseases such as seasonal
allergic rhinitis and chronic urticaria. The pharmacologic profile of
desloratadine offers particular benefits in terms of histamine H1-receptor
binding potency and H1 selectivity. Desloratadine has a half-life of 21-24 h,
permitting once-daily dosing. No specific cautions are required with respect to
administration in renal or hepatic failure, and food or grapefruit juice have no
effect on the pharmacologic parameters. No clinically relevant racial or sex
variations in the disposition of desloratadine have been noted. In combination
with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and
Cmax of desloratadine were increased to a small extent, but no clinically
relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10
days), no significant adverse events were observed, despite the sustained
elevation of plasma desloratadine levels. Specifically, desloratadine had no
effects on the corrected QT interval (QTc) when administered alone, at high
dose, or in combination with ketoconazole or erythromycin. Preclinical studies
also show that desloratadine does not interfere with HERG channels or cardiac
conduction parameters even at high dose. Desloratadine is nonsedating and free
of antimuscarinic/anticholinergic effects in preclinical and clinical studies.
Novel antiallergic and anti-inflammatory effects have also been noted with
desloratadine, a fact which may be relevant to its clinical efficacy.
=============================================================
11.) Desloratadine: a new approach in the treatment of allergy as a systematic
disease--pharmacology and clinical overview. Introduction.
=============================================================
Allergy 2001;56 Suppl 65:5-6
Bonini S.
University of Naples, Italy.
Publication Types:
Review
Review, tutorial
=============================================================
=============================================================
12.) Desloratadine in the treatment of chronic idiopathic urticaria.
=============================================================
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.
=============================================================
13.) Desloratadine activity in concurrent seasonal allergic rhinitis and asthma.
=============================================================
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.
=============================================================
14.) Decongestant efficacy of desloratadine in patients with seasonal allergic
rhinitis.
=============================================================
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.
=============================================================
15.) Evaluation of the pharmacokinetics and electrocardiographic
pharmacodynamics of loratadine with concomitant administration of ketoconazole
or cimetidine.
=============================================================
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.
=============================================================
16.) Therapeutic options in allergic disease: antihistamines as systemic
antiallergic agents.
=============================================================
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.
=============================================================
17.( Preclinical pharmacology of desloratadine, a selective and nonsedating
histamine H1 receptor antagonist. 2nd communication: lack of central nervous
system and cardiovascular effects.
=============================================================
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.
=============================================================
18.) Preclinical pharmacology of desloratadine, a selective and nonsedating
histamine H1 receptor antagonist. 1st communication: receptor selectivity,
antihistaminic activity, and antiallergenic effects.
=============================================================
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.
=============================================================
19.) Anticholinergic effects of desloratadine, the major metabolite of
loratadine, in rabbit and guinea-pig iris smooth muscle.
=============================================================
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.
=============================================================
20.) Desloratadine - first clinical data in rhinitis revealed
=============================================================
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
============================================================
21.) SCHERING-PLOUGH SUBMITS U.S. MARKETING APPLICATIONS
FOR TWO NEW FORMULATIONS OF DESLORATADINE
============================================================
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.
=============================================================
22.) European Committee Recommends Approval of Desloratadine for Chronic
Idiopathic Urticaria
=============================================================
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.
=============================================================
23.) Quality of life improves in seasonal allergic rhinitis patients treated
with desloratadine
=============================================================
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.
=============================================================
24.) Efficacy and Tolerability of Once-Daily 5mg Desloratadine, an H1-Receptor
Antagonist, in Patients with Seasonal Allergic Rhinitis Assessment during the
Spring and Fall Allergy Seasons
=============================================================
[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.
============================================================
25.) Schering-Plough Announces European Union Approval of Desloratadine
============================================================
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.
============================================================
26.) DESLORATADINE
============================================================
Source: Prescribing Points July 2001
Desloratadine, a newly licensed antihistamine, has recently been turned down by
the Oxford Radcliffe Medicines Advisory Committee for inclusion in the hospital
formulary. The following paper outlines the data that was presented to the
Committee. It is hoped that before next years hayfever season we will be able
produce a complete review of hayfever treatment with Mr Grant Bates at the RI
and the help of one or two GPs.
Pharmacological action
Desloratadine is a potent, selective, non-sedating histamine H1-receptor
antagonist with antiallergic and anti-inflammatory properties. It is the major
metabolite of loratadine. Following oral administration, loratadine is
metabolised to desloratadine and a number of less active metabolites that
compete for the H1 receptor.
Indication
Desloratadine is indicated for the relief of symptoms associated with seasonal
allergic rhinitis (SAR) in adults and children over 12 years. Unlike the other
six non-sedating antihistamines, desloratadine is not currently licensed for the
treatment of urticaria.
Efficacy
A review of the treatment of seasonal allergic rhinitis by the National
Prescribing Centre concluded that oral antihistamines relieve ocular symptoms,
rhinorrhoea, sneezing and nasal irritation but have little or no effect on nasal
congestion. The review stated that there is no difference in efficacy between
any of the antihistamines in terms of efficacy, however response to a particular
agent may vary between individuals. The choice of non-sedating agent should be
based on relative safety, individual response and patient preference1. This
review did not include desloratadine or fexofenadine.
In addition to its anti-histamine actions, desloratadine is reported to exhibit
anti-inflammatory properties. In vitro desloratadine inhibits a wide range of
mediators including IL-4, IL-6, IL-8, IL-13 and P-selectin at therapeutic
concentrations2. The anti-inflammatory activity of desloratadine against IL-6
and IL-8 has been shown to be of the same order of magnitude as dexamethasone3.
In trials involving patients with moderate to severe SAR, desloratadine
conferred rapid and sustained relief of nasal congestion. Pooled results from
four randomised, parallel group, double blind placebo controlled studies (1982
patients) showed a significant improvement (25%) in nasal congestion scores at
both 2 days and 15 days (p<0.05)5. Fexofenadine has also been shown to reduce
nasal congestion in some studies. There is no evidence to show that this
improvement in nasal congestion will reduce the need for topical nasal
steroids.
Tolerability
In studies the incidence of side effects is comparable to placebo. No clinically
relevant effects, including cardiovascular effects have been reported5 (see
table 2). In a placebo controlled study to assess the effects of desloratadine
on driving performance, there was no significant difference from placebo4.
Table 2: Adverse drug reactions reported for desloratadine reported by >2%
patients
Adverse event Placebo
(n=661) Desloratadine 5mg
(n=659) Desloratadine 7.5mg
(n=662)
All events 83 (12.6) 111 (16.8) 102 (15.4)
Headache 26 (3.9) 38 (5.8) 36 (5.4)
Fatigue 10 (1.5) 17 (2.6) 17 (2.6)
Somnolence 15 (2.3) 14 (2.1) 18 (2.7)
Dry mouth 12 (1.8) 21 (3.2) 14 (2.1)
Summary
The choice of non-sedating antihistamine should be based on relative safety,
individual response and patient preference. The most commonly prescribed agents
in Oxfordshire are loratadine and cetirizine and these should be considered
first line non-sedating antihistamines.
Desloratidine was not accepted onto the formulary by the Medicines Advisory
Committee mainly due the fact that loratidine will to come off patent in the
near future and thus is likely to be considerably cheaper. It was also felt that
the benefits of desloratidine are likely to be small. Patients with nasal
congestion may require a steriod nasal spray to control symptoms in addition to
oral antihistamines Prescribing Points June 1999 Vol 8.4).
Antihistamine Expenditure Chart
References
1. National Prescribing Centre. Treatment of seasonal allergic rhinitis (hay
fever). MeReC Bulletin 1998; 9(3): 9-12.
2. Molet S et al. Inhibitory activity of loratadine and desloratadine on
histamine-induced activation of endothelial cells. Clin Exp Allergy 1997; 27:
1167-1174.
3. Lippert U et al. Pharmacological modulation of IL-6 and IL-8 secretion by the
H1antagonist desloratadine and dexamethasone by human mast and basophilic cell
lines. Exper Dermatol 1995; 4: 272-276.
4. Vuurman EFMP et al. Desloratadine does not impair actual driving performance:
a three-way crossover comparison with diphenhydramine and placebo. Unpublished
data on file 2000.
5. Nayak A et al. Decongestant effects of desloratadine in patients with
seasonal allergic rhinitis. J Allergy Clin Immunology 2000; 105(1):
Ali Harris
Clinical Effectiveness Pharmacist, RI
=============================================================
27.) SCHERING-PLOUGH REPORTS DESLORATADINE RECEIVES FDA "APPROVABLE" LETTER
=============================================================
KENILWORTH, N.J., Jan. 25, 2001 – In response to inquiries and a media report,
Schering-Plough Corporation (NYSE: SGP) confirmed today that it received an
"approvable" letter for its nonsedating antihistamine desloratadine on Jan. 19,
2001, from the U.S. Food and Drug Administration (FDA). The product is subject
to final approval by the FDA.
Schering-Plough Corporation is a research-based company engaged in the
discovery, development, manufacturing and marketing of pharmaceutical products
worldwide.
DISCLOSURE NOTICE: The information in this press release includes certain
forward-looking information relating to the potential approval of a new product.
Due to market factors, governmental regulations and legislation, the regulatory
review process, manufacturing issues, patent positions and litigation, trade
buying patterns, among other things, the potential approval of desloratadine and
its market potential are subject to risks and uncertainties. For further details
and a discussion of these and other risks and uncertainties, see the company’s
Securities and Exchange Commission filings, including the company’s 1999 annual
report on Form 10-K.
=============================================================
28.) SCHERING-PLOUGH ANNOUNCES EUROPEAN UNION APPROVAL OF DESLORATADINE FOR
TREATMENT OF CHRONIC IDIOPATHIC URTICARIA
=============================================================
KENILWORTH, N.J., Aug. 9, 2001 ¾ Schering-Plough Corporation (NYSE: SGP) today
announced that the European Commission of the European Union (EU) has granted
marketing authorization for desloratadine 5 mg tablets as a once-daily,
nonsedating treatment for the symptoms of chronic idiopathic urticaria (CIU)
such as itching or hives in adults and children 12 years of age and older.
Desloratadine received EU approval for the treatment of seasonal allergic
rhinitis (SAR) in January 2001 and is marketed in the EU under the brand names
AERIUS and NEOCLARITYN.
Commission approval of the centralized application for desloratadine in CIU
results in a single Marketing Authorization with unified labeling that is
immediately valid in all 15 EU-Member States as well as in Iceland and Norway.
The Commission’s decision follows the product’s recommendation for approval in
April 2001 by the EU’s Committee for Proprietary Medicinal Products (CPMP) of
the European Agency for the Evaluation of Medicinal Products (EMEA).
"Since its EU approval in January, desloratadine has gained rapid acceptance in
several major European markets as a significant new therapy for the treatment of
seasonal allergies," said Roch F. Doliveux, president, Schering-Plough
International. "The approval of desloratadine in the treatment of CIU represents
another important step in our efforts to expand and enhance its clinical
profile."
Affecting an estimated 15 to 25 percent of people at least once in their lives,
urticaria is a reaction to a variety of substances, including food, drugs and
topical agents, and characterized by an eruption of itchy, swollen lesions on
the skin. An estimated 25 percent of urticaria patients develop CIU, which is
defined as a case that lasts for a period of at least six weeks and has no
identifiable cause. Up to 20 percent of prescription antihistamine use in the EU
can be attributed to CIU therapy.
Desloratadine is a highly potent H-1 receptor antagonist that effectively
controls the symptoms of SAR and CIU with nonsedating relief for a full 24
hours. In clinical trials the most common side effects were headache, dry mouth
and fatigue, with an incidence rate similar to placebo.
Schering-Plough is a research-based company engaged in the discovery,
development, manufacturing and marketing of pharmaceutical products worldwide.
=============================================================
29.) PUBLIC CITIZEN
=============================================================
source PUBCLIC CITIZEN
March 1, 2001
Tommy Thompson, Secretary,
Department of Health and Human Services
200 Independence Avenue, SW
Washington, D.C. 20201
Dear Secretary Thompson:
During the past 15 months, 59 million asthma inhalers manufactured by
Schering-Plough for treating acute attacks of asthma had to be recalled because
of dangerously sloppy manufacturing procedures which resulted in many units
failing to contain the active ingredient, albuterol (brand name Proventil(1)).
We have obtained a confidential external audit by the AAC Consulting Group of
Rockville, Maryland, contracted for by Schering-Plough, conducted at
Schering-Plough's manufacturing facility at Kenilworth NJ, where these
life-sustaining products were manufactured. This audit took place from February
28, 2000 to April 14, 2000(2). The auditors were extremely critical of the
general attitude of management personnel who described to them--- "an imbalance
between quality and production, leaning considerably toward production". They
also found serious specific problems with the quality control of the production
of the asthma inhalers such as the fact that "An in-process assay for the active
ingredient in Proventil is not performed." Managers told the auditors that
"aerosol products are a major money maker for the company". But, the auditors
concluded, "significant manufacturing problems have been experienced with this
product class, which is indicative of insufficient technical expertise and
managerial oversight...."
In addition, we have obtained the summary of a very recent 31-day FDA inspection
of the same plant completed January 19th of this year in which FDA inspectors
found a persistence of many of the same kinds of problems with the quality of
manufacturing uncovered one year ago during the private audit of Schering. The
FDA investigators concluded that "The process validation for many products fails
to support claims that manufacturing processes were capable of consistently
producing products with the same quality, purity and safety."(3)
We urge you to launch an investigation into criminal charges against
Schering-Plough based on the possibility that the company knowingly shipped
millions of the 59 million units of albuterol-containing asthma drug eventually
recalled between the time the company became aware of the seriously flawed
manufacturing processes and the time the recall was finally accomplished. We
also urge that you investigate the company for continuing to ship other
prescription drug products while fully aware of the serious violations of FDA
good manufacturing practice (GMP) regulations during their production.
The current quality control problems found in that manufacturing plant during
the recent FDA inspection are so serious that there has been a "temporary
interruption of some production lines"(4) and it will not be allowed by the FDA
to gain approval or start shipping its new allergy drug, Clarinex, a metabolite
of the active ingredient in its top-selling Claritin, which it had previously
planned to ship very soon. During that inspection, FDA investigators found that
"There was no assurance that the manufacturing process, parameters, equipment or
protocols...conducted at multiple sites for the production of Clarinex
(Desloratidine tablets, 5 mg) are equivalent or capable of producing product of
the same quality." No other new Schering-Plough products will be approved until
these serious manufacturing problems are resolved.
SCHERING'S PRIORITY OF PRODUCTION OVER QUALITY: A FORM OF CONTEMPT FOR THE
SAFETY OF PATIENTS
Added to the findings of Schering-Plough's own consultants and the results of
the FDA's most recent inspection of the Kenilworth NJ facility, is the fact that
the FDA has issued at least five Warning Letters to the company since June, 1998
detailing serious GMP problems in its manufacturing facilities in New Jersey,
Puerto Rico, and Ireland.
Table 1 below summarizes the five Warning Letters directed at various
Schering-Plough plants since June 29, 1998 for serious deviations from GMP
guidelines.
Table 1 Warning Letters Issued to Schering-Plough by the Food and Drug
Administration for Good Manufacturing Practice Guideline Deficiencies for the
Production of Human Drugs Since June 1998
Date Facility Drug(s) Involved Examples of Problems Noted in Warning Letters
6/29/98 (5) Las Piedras, Puerto Rico Theo-Dur,
Claritin 10 mg Extension of expiration period for Theo-Dur, an asthma drug.
Failure to investigate variability in Claritin 10 mg tablets, an antihistamine.
10/23/98 (6) Kenilworth and Union, New Jersey Proventil Inhaler, Claritin D,
Diprolene Oint., Nasonex Nasal Spray Proventil Inhaler, an important asthma
drug, failing pressure results.
Claritin D, a combination antihistamine-decongestant, dissolution rate
problems.
Diprolene Ointment, a topical steroid, out of specification assay results.
Nasonex Nasal Spray, used for allergy, failed to conform to all specifications.
11/23/98 (7) Innishannon, County Cork, Ireland Intron A Intron A is an
injectable used to treat a variety of disorders including some cancers and
chronic hepatitis C. Failure to establish appropriate procedures to insure that
Intron A is sterile.
7/21/99 (8) Kenilworth and Union, New Jersey Vanceril DS Inhaler, Proventil
Inhaler Vanceril Inhaler, used to treat chronic asthma, failure to follow test
procedures and failure to meet specifications.
Proventil Inhaler, also for asthma, there was failure to properly test the
content of canisters.
5/8/00 (9) Manati, Puerto Rico Garamycin Ophthalmic Solution,
Vancenase AQ, Nasonex Nasal Garamycin is an antibiotic used to treat eye
infections. There was failure to perform adequate investigation into the cause
of out of specifications results for stability testing for some batches of the
drug.
Vancenase AQ and Nasonex Nasal suspension are used for allergy treatment. There
were deviations from protocol for the Uniformity of Spray Content Assays for
these products.
Six months before the FDA began their most recent inspection of the Kenilworth
NJ facility on November 1, 2000, Schering-Plough's consultants, AAC Consulting
Group, noted in their audit of this plant on April 27, 2000:
Upper management needs to demonstrate its long term commitment to product
quality, such as through increased staffing/budget resource allocations and
investments in new equipment, in order to supplant the traditional emphasis on
production and firmly establish a company culture in which quality is, in fact,
the number one priority.(10)
AAC Consulting found that "Most units fail to have documentation demonstrating
that operators are qualified in all required critical tasks. Some areas also
lack approved training procedures." The consultants noted that although
Schering-Plough's upper management had recently placed some emphasis on quality
" there is staff concern that this commitment to quality may not be long
term."(11)
The consultants asked supervisors, managers, and operators if they perceived a
real change in the company's commitment to improving product quality since the
aerosol recalls and problems with the FDA in late 1999. The consultants
observed:
Most managers/supervisors have adopted a wait and see attitude, to determine if
upper management will "walk the talk" with respect to long term commitment to
product quality. They state that for many years they have been under significant
pressure to get production out and don't feel they have had enough time or
people to do a quality job. They indicated that there has been in the past a
continual push for increased production and decreased down time sometimes at the
expense of quality work and GMP compliance. They believe there has been an
imbalance between quality and production, leaning considerably toward the side
of production.(12)
After five Warning Letters for serious GMP violations in a period of only two
years and an audit conducted by outside consultants of the Kenilworth NJ
facility, a plant that had previously had been issued two Warning Letters,
serious GMP violations were found seven months later by the FDA. The first point
in the FDA's report referred to the quality of products produced at this
facility. The FDA inspectors observed:
The Quality Control Unit failed to assure that drug products were manufactured
in compliance with cGMPs and therefore have the safety, quality, and purity that
they purport, or are represented to possess.(13)
CHRONOLOGY AND REPEATED MANUFACTURING DEFECTS WITH IMPORTANT DRUGS
Appendix 1, at the end of this document, is the chronological sequence of
important events in the Schering-Plough affair.
ALBUTEROL (PROVENTIL) ASTHMA INHALERS
------------------------------------
Two of the Warning Letters, 10/23/98 and 7/21/99, involve manufacturing problems
with albuterol (PROVENTIL) aerosol inhalers. Albuterol is a drug of vital
importance for asthmatics. It is frequently used to stop acute asthma attacks.
The 7/21/99 Warning Letter also reveals meetings and communications between
Schering-Plough and the FDA's Center for Drug Evaluation and Research (CDER). On
6/25/99, CDER informed Schering-Plough's Vice President for Worldwide Regulatory
Affairs of a four phase prior approval program for the release of albuterol
inhalers by the company.
Defective manufacturing of albuterol led to almost 60 million canisters of this
drug being recalled because some canisters did not contain the active
ingredient. The first recall took place on 9/9/99 and involved 190,679 units of
the drug. The second, on 3/29/00, recalled 58,936,179 canisters of albuterol.
Schering-Plough knew of problems with the production of albuterol inhalers
during the July 30, 1998 inspection of the Kenilworth NJ facility that resulted
in the October 23, 1998 Warning Letter. By late June of 1999, the company had to
agree to prior approval by the FDA before any albuterol inhalers could be
distributed by the company.
The AAC Consulting Group began their audit at Kenilworth NJ on February 28, 2000
and submitted its final report to Schering-Plough on April 27, 2000. After two
Warning Letters and two recalls involving albuterol inhalers, the consultants
made the following observations regarding the manufacturing of albuterol
inhalers:
Evaluation of this manufacturing area disclosed significant changes in both
procedures and record keeping practices. Overall, these were found to be
positive, but some observations did reflect potential problem areas and perhaps
even some degree of over-reaction to the recent aerosol product recalls.(14)
It is our understanding, based on interviews with supervisors and managers, that
aerosol products are a major money make for the company. In addition,
significant manufacturing problems have been experienced with this product
class, which is indicative of insufficient technical expertise and managerial
oversight. This production area does not have the visibility and importance from
an organizational standpoint that it needs in order to quickly and effectively
recover from past problems, maintain satisfactory regulatory compliance, attract
and retain necessary expertise, and grow in the future.(15)
Some components, such as aerosol valves from 3M Neotechnic, are received for
testing already pre-sampled by the vendor. There is no assurance that the
samples provided to Schering were collected by the vendor according to accepted
sampling procedures and are representative of the entire lot.(16)
Updating aerosol test procedures should be given the highest priority in light
of past problems with this product class and the intense scrutiny Schering
operations in this area is currently undergoing by FDA.(17)
An in-process assay for the active ingredient in Proventil is not performed.
Reportedly, R&D has been trying for several years without success to shorten the
Proventil final release assay procedure, so that it is suitable for in-process
testing.(18)
An in-process assay method for Proventil should be developed and validated as
soon as possible so that the active ingredient is quantified in-process as is
done for all other Schering aerosol products.(19)
The AAC audit was completed six months before the FDA's most recent inspection
of Kenilworth NJ. Still the FDA observed deficiencies in the manufacture of
albuterol inhalers:
Aerosol Manufacturing Line 76 with the online stress testing heating blocks was
validated in that the two validation attempts have failed to meet the validation
protocol acceptance criteria.(20)
Validation Summary Report #Val-9-184, (validation for the use of the heating
blocks for on-line stress testing for Proventil/Albuterol) was inadequate in
that 1 out of 3 original Validation Batches, #9-BBS-640, was rejected for
excessive downtime and rejected canisters (purged cans). An additional
Validation Batch, #9-BBS-643, was also rejected due to out-of-specification leak
test results.(21)
A second validation attempt of the heating blocks for on-line stress testing was
executed under Validation Summary Report #VAL-00-48. This validation was
inadequate in that Validation Batch #'s 0-BBS-572m 0-BBS-573 & 0-BBS-574 failed
to meet the process validation acceptance criteria for total content of
Albuterol. Additionally, the rinse method utilized by the laboratory to retest
the total content of Albuterol per canister was never validated.(22)
The Product Quality Review (PQR) methods for the Delivery of Albuterol through
the Actuator and Particle Size for Proventil Aerosol Inhaler were inadequate in
that the methods exhibit various unidentified extraneous peaks. PQR Methods for
Total Content of Albuterol per Can Assay and Estimation of Degradation Products
were also inadequate in that there was a lack of resolution between typical
unknown peaks from neighboring active or placebo peaks. These methods were used
to test and release product batches, as well as stability samples, from
10/11/99-12/7/00.(23)
LORATADINE WITH PSEUDOEPHEDRINE (CLARITIN D)
---------------------------------------------
Problems with the production of the antihistamine loratadine in combination with
pseudoephedrine (CLARITIN D) were identified in the July 30, 1998 inspection of
the Kenilworth NJ plant that resulted in the October 23, 1998 Warning Letter.
Eighteen months later AAC Consulting continued to find problems with the
production of Claritin-D:
Previously filed validation reports for Claritin-D (Once-a-Day), with the same
product ID (GJKS), were performed in 1993. The protocols and final reports were
reviewed and approved by production and quality in 1995. One of the batches
manufactured failed final blend specifications, but this validation was approved
by management nearly two years later. There was no statement as to the batch's
disposition.(24)
The annual product review for Claritin-D 24 reflected 45 of 752 finished tablet
batches were rejected. Of those there were 35 rejected for high moisture, 5 for
variable loratadine content. This would seem to reflect that the process is not
validated. There also were 44 batches that had low granulation yield based on
product hang-up in the equipment. This same issue has been seen with other
products and it is not apparent that there has been a for cause investigation
done to determine why product is hanging up in the equipment. There also were
307 batches that had low yield. This has caused variance and MRB reports. It
appears that the specs may not be appropriate and/or the process is not
validated. Addressing this issue could cut down on a lot of unnecessary
investigation time.(25)
The FDA also continued to find deficiencies in the production of Claritin-D in
their most recent inspection of the Kenilworth NJ plant:
Validation of the Claritin D-24hr. ER Tablet process, using a drug substance
from a new source (Schering, Singapore) was not adequate in that only one batch
was manufactured. Change Authorization #CA-99-248 allows for the use of this
alternate source. The new drug substance was used to manufacture batch #'s
0-DCS-257 through 0-DCS-340, approximately 95 batches.(26)
The current revalidation Protocol, #VAL-0-61, for Claritin D-24 hr. ER Tablet
Cores contained incorrect acceptance criteria, but was signed and approved by
Validation, QC, and Manufacturing Departments. Specifications for two finished
product tablet tests were erroneously included as the acceptance criteria for
the tablet cores.(27)
DESLORATADINE (CLARINEX)
------------------------
Desloratadine (CLARINEX) is Schering-Plough's replacement for its overpriced
antihistamine loratadine (CLARITIN). Desloratadine is the major metabolic
breakdown product of loratadine. It appears from the FDA's recent Kenilworth NJ
inspection that there are serious problems with the production of desloratadine
that will prevent final approval of the drug. The FDA observed the following in
their recent inspection:
There was no assurance that the manufacturing process, parameters, equipment, or
protocols and acceptance criteria, conducted and generated at multiple sites for
the production of Clarinex (Desloratadine Tablets, 5 mg) are equivalent, or
capable of producing product of the same quality.
The test method transfer from Schering, Kenilworth to Schering, Puerto Rico
failed to demonstrate that accurate and reliable results could be obtained from
the QC laboratory.
There was insufficient comparability data for the drug substance, Desloratadine,
manufactured at the firm's Ireland and Singapore sites to assure equivalence of
the drug substance supply.(28)
In conclusion, it is clear that there are an extraordinary variety of serious
problems at the Schering-Plough manufacturing plant in Kenilworth, New Jersey
which threaten the safety of drugs already shipped out of the facility and
bespeak the need for extreme caution in allowing any further products to be
shipped from that plant. In addition, we hope you insist that the FDA
investigate the possibility of criminal behavior on the part of those
Schering-Plough officials who may have knowingly shipped defective
pharmaceutical products for use in unsuspecting patients. We expect a prompt
response to this urgent request.
Sincerely,
Larry Sasich, Pharm.D., MPH
Research Associate
Sidney M. Wolfe, M.D., Director
Public Citizen's Health Research Group
Appendix 1 Chronological Sequence of Events
Date Action Drugs Mentioned Documentation
5/7/98 Inspection - Las Piedras, PR From the 6/29/98 Warning Letter
6/29/98 Warning Letter - Las Piedras, PR Theo-Dur Claritin 10 mg
www.fda.gov/foi/warning_letters/d1423b.pdf accessed 2/19/01
7/30/98 Inspection - Kenilworth and Union, NJ From 10/23/98 Warning Letter
10/23/98 Warning Letter - Kenilworth and Union, NJ
"Current regulations specify that drug products failing to meet standards or
specifications and any other relevant quality control criteria shall be
rejected. Reprocessing may be performed, provided certain criteria are met
according to written procedures. The practice of partial releases, no matter how
stringent the re-sampling, raises doubt as to the safety and efficacy of the
product being released. It is not acceptable to substitute testing over adequate
control of a process." Claritin-D, Diprolene Oint, Proventil Inhaler, Nasonex
Nasal Spray www.fda.gov/foi/warning_letters/m2366n.pdf accessed 2/19/01
11/23/98 Warning Letter - County Cork, Ireland Intron A
www.fda.gov/foi/warning_letters/m2327n.pdf accessed 2/19/01
5/28/99 Inspection Union and Kenilworth, NJ From 7/21/99 Warning Letter
6/7/99 Teleconference in NJ between S-P and CDER concerning Proventil and
Vanceril inhalers. From 7/21/99 Warning Letter
6/17/99 Meeting at FDA between S-P and CDER to discuss conditions under which
S-P may resume shipment of Proventil Inhalers. From 7/21/99 Warning Letter
6/25/99 CDER letter to Dr. Alexander Giaquinto, Sr. VP, Worldwide Regulatory
Affairs detailing a four-phase proposal for the release of Proventil Aerosol.
S-P must strictly adhere to the proposal to continue distributing Proventil
Inhalers. This amounts to "prior approval" by the FDA. From 7/21/99 Warning
Letter
7/21/99 Warning Letter - Union and Kenilworth, NJ
The 6/15/99 response to the 10/23/98 Warning Letter was not satisfactory. Drug
products failing to meet established standards or specifications and any other
relevant quality control criteria shall be rejected. Retesting later is not an
acceptable practice. Vanceril
Proventil www.fda.gov/foi/warning_letters/m2818n.pdf accessed 12/19/01
9/9/99 Class I Recall Warrick Pharmaceuticals Albuterol Aerosol. 190, 679. AL,
CT, FL, GA, KY, MD, MA, NJ, NY, NC, OH, PA, RI, TN, VA, WV. Some units fail to
contain active ingredient.
The recall affects a lot that was distributed between late April and early May
1999. Schering-Plough Press Release 9/9/99
12/2/99 Class II Recall - Vanceril Double Strength Aerosol. 82,029 units
nationwide. Some units may not contain active drug. Drug was distributed in
November 1999.
"The cause of the problem has been identified as inadequate batch start-up
practices that occurred for a short period during filling of the subject lots.
The company has taken corrective actions to prevent a recurrence."
Schering-Plough Press Release 12/2/99
3/28/00 Inspection - Manati, PR 5/8/00 Warning Letter
3/29/00 Class II Recall Proventil/Albuterol inhalers, 58,936,179; Vanceril 84
mcg, 831,594 units; Vanceril 42 mcg, 5,274,819 units; Vancenase, 2,706,424 units
nationwide, PR, and Canada. Some canisters may not have active ingredient.
This recall relates to an aerosol manufacturing problem that had been previously
identified in October 1999.
Does not involve any inhaler manufactured after September 30, 1999. These
inhalers would have an expiration date of Oct 2001 or later. Schering-Plough
Press Release 3/29/00
4/27/00 AAC Consulting Group audit of Kenilworth, NJ. Audit began 2/28/00
AAC found that an in-process assay for the active ingredient in Proventil is not
performed. AAC Audit Report
5/8/00 Warning Letter - Manati, PR Garamycin Ophthalmic Solution, Vancenase,
Nasonex Diprolene Gel
Celestone Injection www.fda.gov/foi/warning_letters/m3847n.pdf accessed 2/19/01
1/19/01 FDA 483 Observations of Kenilworth, NJ
The Product Quality Review (PQR) methods for the Delivery of Albuterol through
the Actuator and Particle Size for Proventil Aerosol Inhaler were inadequate in
that the methods exhibit various unidentified extraneous peaks. PQR Methods for
the Total Content of Albuterol pr Can Assay and Estimation of Degradation
Products were also inadequate in theat there was a lack of resolution between
typical unknown peaks from neighboring active or placebo peaks. These methods
were used to test and release product batches, as well as stability samples,
from 10/11/99-12/07/00. (page 12) FDA 483 Inspection Report
--------------------------------------------------------------------------------
1. The first recall, 9/9/99, involved 190,000 units and the second, 3/29/00,
involved 58.9 million units. Some units manufactured by Schering in the same New
Jersey facility were sold under the name of their subsidiary, Warrick, as
generic albuterol. In a Q & A accompanying the second recall, Schering-Plough
explained that the purpose of the recall was to "address the remote possibility
that an aerosol container may not contain active drug" and said, in an
extraordinary and reckless understatement of what could be a life-threatening
situation, "Proventil and Warrick brand albuterol patients using a canister
without active drug will not obtain their usual relief from asthma symptoms."
2. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000. Final report
is dated April 27, 2000.
3. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1.
4. Schering-Plough press release, February 15, 2001.
5. Warning Letter addressed to Mr. Francisco R. Rodriquez, General Manager,
Schering-Plough Products Inc., Las Piedras, Puerto Rico from Samuel Jones,
District Director, Puerto Rico District, Food and Drug Administration dated June
29, 1998.
6. Warning Letter addressed to Mr. John E. Nine, President, Technical
Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ
07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District
Director, New Jersey District dated October 23, 1998.
7. Warning Letter addressed to Colman Casey, Ph.D., Managing Director,
Schering-Plough (Brinny) Co., Innishannon, Couny Cork, Ireland from Jerome A.
Donlan, M.D., Ph.D., Acting Director, Office of Compliance and Biologics
Quality, Center for Biologics Evaluation and Research, Food and Drug
Administration dated November 23, 1998.
8. Warning Letter addressed to Mr. John E. Nine, President, Technical
Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ
07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District
Director, New Jersey District dated July 21, 1999.
9. Warning Letter addressed to Mr. John E. Nine, President, Technical
Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ
07033-0503 from Mildred R. Barber, District Director, Food and Drug
Administration dated May 2, 2000.
10. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 6.
11. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 5.
12. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 76.
13. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1.
14. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 36.
15. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 65.
16. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 91.
17. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page106.
18. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page106.
19. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page106.
20. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.
21. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.
22. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.
23. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 12.
24. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 9.
25. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit
Report, AAC Consulting Group, February 28, 2000 April 14, 2000, page 85.
26. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 2.
27. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.
28. Department of Health and Human Services, Food and Drug Administration. Form
FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000
Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 15.
=============================================================
30.) SCHERING-PLOUGH REBUTS PUBLIC CITIZEN ALLEGATIONS
=============================================================
KENILWORTH, N.J., Aug. 9, 2001 –Schering-Plough Corporation (NYSE: SGP) today
issued the following response to allegations made by the Public Citizen activist
group regarding recalls conducted in 1999 and 2000 of the company’s albuterol
inhaler products for asthma.
Schering-Plough is confident that all of its products on the market are safe and
effective. The health and safety of patients who use our products remain our No.
1 priority.
The company is extremely disturbed that the letter by Public Citizen
misrepresented data and drew unfounded conclusions, which could unnecessarily
alarm asthma patients. Schering-Plough emphasized that asthma patients should
continue to take their medications as prescribed.
Contrary to Public Citizen’s allegations, in all adverse event reports involving
deaths where an albuterol canister was tested by the company, the canister was
shown to contain active ingredient. Further, every inhaler involved in a
patient’s claim of injury that has been tested by the company has been shown to
date to contain active ingredient.
Schering-Plough knows of no death or injury to a patient shown to have been
caused by an inhaler lacking active ingredient. While there are some lawsuits
claiming otherwise, the company is contesting them vigorously.
Schering-Plough is committed to manufacturing products of the highest quality
and took extraordinary measures in 1999 and 2000 to ensure that all of its
inhalers in the marketplace were safe and effective. In all instances, the
company acted promptly and responsibly with respect to the above product
recalls, and in consultation with the U.S. Food and Drug Administration (FDA).
Asthma is a very serious disease and causes more than 5,400 deaths in the United
States annually. Under FDA regulations, adverse event reports are routinely
reported to the FDA. Public Citizen’s allegations are based on a flawed analysis
of a small number of events, which does not address event rates that occur with
similar asthma rescue inhaler products.
Schering-Plough is a research-based company engaged in the discovery,
development, manufacturing and marketing of pharmaceutical products worldwide.
=============================================================
31.) LORATADINE INFORMATION FROM MOSBY YEAR BOOK. 1.996
=============================================================
CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY
------------------------------------------------------
CATEGORIES: Allergies; Antihistamines; FDA Approved 1993 Apr; FDA Class 1S
("Standard Review"); Lacrimation; Non-Sedating Antihistamines; Patent Expiration
1998 Aug; Pregnancy Category B; Respiratory & Allergy Medications; Rhinitis;
Rhinorrhea; Sales > $500 Million; Sneezing; Top 100 Drugs; Urticaria
BRAND NAMES: Claritin; Clarityne*; Fristamin*; Lisino*
* Foreign brand name outside U.S.
FORMULARIES: BC/BS; Medi-Cal
COST OF THERAPY: $58.06 (Rhinitis; Tablet; 10 mg; 1/day; 30 days)
PRIMARY ICD9: 477.9 (Allergic Rhinitis, Cause Unspecified)
DESCRIPTION
-----------
Claritin Tablets contain 10 mg micronized loratadine, an antihistamine, to be
administered orally. They also contain the following inactive ingredients: corn
starch, lactose, and magnesium stearate.
Loratadine is a white to off-white powder not soluble in water, but very soluble
in acetone, alcohol, and chloroform. It has a molecular weight of 382.89, and
empirical formula of C22H23CIN2O2; its chemical name is ethyl
4-(8-chloro-5,6-dihydro-11H-benzo(5,6)cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate.
CLINICAL PHARMACOLOGY
---------------------
Loratadine is a long-acting tricyclic antihistamine with selective peripheral
histamine H1-receptor antagonistic activity.
Human histamine skin wheal studies following single and repeated 10 mg oral
doses of Claritin Tablets have shown that the drug exhibits an antihistaminic
effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours and
lasting in excess of 24 hours. There was no evidence of tolerance to this effect
after 28 days of dosing with Claritin Tablets.
Pharmacokinetic studies following single and multiple oral doses of loratadine
in 115 volunteers showed that loratadine is rapidly absorbed and extensively
metabolized to an active metabolite (descarboethoxyloratadine). Approximately
80% of the total dose administered can be found equally distributed between
urine and feces in the form of metabolic products after 10 days. The mean
elimination half-lives found in studies in normal adult subjects (n=54) were 8.4
hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92
hours) for the major active metabolite (descarboethoxyloratadine). In nearly all
patients, exposure (AUC) to the metabolite is greater than exposure to parent
loratadine. Loratadine and descarboethoxyloratadine reached steady-state in most
patients by approximately the fifth dosing day. The pharmacokinetics of
loratadine and descarboethoxyloratadine are dose independent over the dose range
of 10 to 40 mg and are not significantly altered by the duration of treatment.
In vitro studies with human liver microsomes indicate that loratadine is
metabolized to descarboethoxyloratadine predominantly by P450 CYP3A4 and, to a
lesser extent, by P450 CYP2D6. In the presence of a CYP3A4 inhibitor
ketoconazole, loratadine is metabolized to descarboethoxyloratadine
predominantly by CYP2D6. Concurrent administration of loratadine with either
ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and
CYP3A4 inhibitor) to healthy volunteers was associated with significantly
increased plasma concentrations of loratadine (see DRUG INTERACTIONS section).
In a study involving twelve healthy geriatric subjects (66 to 78 years old), the
AUC and peak plasma levels (Cmax) of both loratadine and
descarboethoxyloratadine were significantly higher (approximately 50% increased)
than in studies of younger subjects. The mean elimination half-lives for the
elderly subjects were 18.2 hours (range = 6.7 to 37 hours) for loratadine and
17.5 hours (range = 11 to 38 hours) for the active metabolite.
In the clinical efficacy studies, Claritin Tablets were administered before
meals. In a single-dose study, food increased the AUC of loratadine by
approximately 40% and of descarboethoxyloratadine by approximately 15%. The time
to peak plasma concentration (Tmax) of loratadine and descarboethoxyloratadine
was delayed by 1 hour with a meal.
In patients with chronic renal impairment (creatinine clearance ú 30 ml/min)
both the AUC and peak plasma levels (Cmax) increased on average by approximately
73% for loratadine; and approximately by 120% for descarboethoxyloratadine,
compared to individuals with normal renal function. The mean elimination
half-lives of loratadine (7.6 hours) and descarboethoxyloratadine (23.9 hours)
were not significantly different from that observed in normal subjects.
Hemodialysis does not have an effect on the pharmacokinetics of loratadine or
its active metabolite (descarboethoxyloratadine) in subjects with chronic renal
impairment.
In patients with chronic alcoholic liver disease the AUC and peak plasma levels
(Cmax) of loratadine were double while the pharmacokinetic profile of the active
metabolite (descarboethoxyloratadine) was not significantly changed from that in
normals. The elimination half-lives for loratadine descarboethoxyloratadine were
24 hours and 37 hours, respectively, and increased with increasing severity of
liver disease.
There was considerable variability in the pharmacokinetic data in all studies of
Claritin Tablets, probably due to the extensive first-pass metabolism.
Individual histograms of area under the curve, clearance, and volume of
distribution showed a log normal distribution with a 25-fold range in
distribution of healthy subjects.
Loratadine is about 97% bound to plasma proteins at the expected concentrations
(2.5 to 100 ng/ml) after a therapeutic dose. Loratadine does not affect the
plasma protein binding of warfarin and digoxin. The metabolite
descarboethoxyloratadine is 73% to 77% bound to plasma protein (at 0.5 to 100
ng/ml).
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue
distribution studies in mice and rats, and in vivo radioligand studies in mice
have shown that neither loratadine nor its metabolites readily cross the
blood-brain barrier. Radioligand binding studies with guinea pig pulmonary and
brain H1-receptors indicate that there was preferential binding to peripheral
versus central nervous system H1-receptors.
Clinical trials of Claritin Tablets involved over 10,700 patients who received
either Claritin Tablets or another antihistamine and/or placebo in double-bind
randomized controlled studies. In placebo-controlled trials, 10 mg once daily of
Claritin Tablets was superior to placebo and similar to clemastine (1 mg BID) or
terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic
rhinitis. In these studies, somnolence occurred less frequently with Claritin
Tablets than with clemastine and at about the same frequency as terfenadine or
placebo. In studies with Claritin Tablets at doses 2 to 4 times higher than the
recommended dose of 10 mg, a dose-related increase in the incidence of
somnolence was observed. Therefore, some patients, particularly those with
hepatic or renal impairment and the elderly, may experience somnolence.
Among those patients involved in double-blind, randomized controlled studies of
Claritin Tablets, approximately 1000 patients were enrolled in studies of
idiopathic chronic urticaria. In placebo-controlled clinical trials, Claritin
Tablets 10 mg once daily were superior to placebo in the management of
idiopathic chronic urticaria, as demonstrated by reduction of associated
itching, erythema, and hives. In these studies, the incidence of somnolence seen
with Claritin Tablets was similar to that seen with placebo.
In a study in which Claritin Tablets were administered at 4 times the clinical
dose for 90 days, no clinically significant increase in the QTc was seen on
ECGs.
INDICATIONS
------------
Claritin Tablets are indicated for the relief of nasal and non-nasal symptoms of
seasonal allergic rhinitis and for the management of idiopathic chronic
urticaria.
CONTRAINDICATION
------------------
Claritin Tablets are contraindicated in patients who are hypersensitive to this
medication or to any of its ingredients.
PRECAUTIONS
-----------
General: Patients with liver impairment or renal insufficiency (GFR < 30 ml/min)
should be given a lower initial dose (10 mg every other day) because they have
reduced clearance of Claritin Tablets.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In an 18-month
oncogenicity study in mice and a 2-year study in rats, loratadine was
administered in the diet at doses up to 40 mg/kg (mice) and 25 mg/kg (rats). In
the carcinogenicity studies, pharmacokinetic assessments were carried out to
determine animal exposure to the drug. AUC data demonstrated that the exposure
of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (active
metabolite) times higher than a human given 10 mg/day. Exposure of rats given 25
mg/kg of loratadine was 28 (loratadine) and 67 (active metabolite) times higher
than a human given 10 mg/day. Male mice given 40 mg/kg had a significantly
higher incidence of hepatocellular tumors (combined adenomas and carcinomas)
than concurrent controls. In rats, a significantly higher incidence of
hepatocellular tumors (combined adenomas and carcinomas) was observed in males
given 10 mg/kg and males and females given 25 mg/kg. The clinical significance
of these findings during long-term use of Claritin Tablets is not known.
In mutagenicity studies, there was no evidence of mutagenic potential in reverse
(Ames) or forward point mutation (CHO-HGPRT) assays, or in the assay for DNA
damage (Rat Primary Hepatocyte Unscheduled DNA Assay) or in two assays for
chromosomal aberrations (Human Peripheral Blood Lymphocyte Clastogenesis Assay
and the Mouse Bone Marrow Erythrocyte Micronucleus Assay). In the Mouse Lymphoma
Assay, a positive finding occurred in the nonactivated but not the activated
phase of the study.
Loratadine administration produced hepatic microsomal enzyme induction in the
mouse at 40 mg/kg and rat at 25 mg/kg, but not at lower doses.
Decreased fertility in male rats, shown by lower female conception rates,
occurred at approximately 64 mg/kg and was reversible with cessation of dosing.
Loratadine had no effect on male or female fertility or reproduction in the rat
at doses of approximately 24 mg/kg.
Pregnancy Category B: There was no evidence of animal teratogenicity in studies
performed in rats and rabbits at oral doses up to 96 mg/kg (75 times and 150
times, respectively, the recommended daily human dose on a mg/m2 basis). There
are, however, no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response,
Claritin Tablets should be used during pregnancy only if clearly needed.
Nursing Mothers: Loratadine and its metabolite, descarboethoxyloratadine, pass
easily into breast milk and achieve concentrations that are equivalent to plasma
levels with an AUCmilk/AUCplasma ratio of 1.17 and 0.85 for the parent and
active metabolite, respectively. Following a single oral dose of 40 mg, a small
amount of loratadine and metabolite was excreted into the breast milk
(approximately 0.03% of 40 mg over 48 hours). A decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother. Caution should be exercised when Claritin
Tablets are administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below the age of 12 years
have not been established.
Physicians GenRx
Drug names
LORATADINE
DRUG INTERACTION
Loratadine (10 mg once daily) has been safely coadministered with therapeutic
doses of erythromycin, cimetidine, and ketoconazole in controlled clinical
pharmacology studies. Although increased plasma concentrations (AUC 0-24 hrs) of
loratadine and/or descarboethoxyloratadine were observed following
coadministration of loratadine with each of these drugs in normal volunteers (n
= 24 in each study), there were no clinically relevant changes in the safety
profile of loratadine, as assessed by electrocardiographic parameters, clinical
laboratory tests, vital signs, and adverse events. There were no significant
effects on QTc intervals, and no reports of sedation or syncope. No effects on
plasma concentrations of cimetidine or ketoconazole were observed. Plasma
concentrations (AUC 0-24 hrs) of erythromycin decreased 15% with
coadministration of loratadine relative to that observed with erythromycin
alone. The clinical relevance of this difference is unknown. These above
findings are summarized in the following table (TABLE 1).
TABLE 1 - Loratadine, Drug Interactions
Effects on Plasma Concentrations (AUC 0-24 hrs) of Loratadine and
Descarboethoxyloratadine After 10 Days of Coadministration (Loratadine
10 mg) in Normal Volunteers
Loratadine Descarboethoxyloratadine
Erythromycin + 40% + 46%
(500 mg Q8h)
Cimetidine + 103% + 6%
(300 mg QID)
Ketoconazole + 307% + 73%
(200 mg Q12h)
There does not appear to be an increase in adverse events in subjects who
received oral contraceptives and loratadine.
ADVERSE REACTIONS
-----------------
Approximately 90,000 patients received Claritin Tablets 10 mg once daily in
controlled and uncontrolled studies. Placebo-controlled clinical trials at the
recommended dose of 10 mg once a day varied from 2 weeks' to 6 months' duration.
The rate of premature withdrawal from these trials was approximately 2% in both
the treated and placebo groups (TABLE 2).
TABLE 2 - Loratadine, Adverse Reactions
REPORTED ADVERSE EVENTS WITH AN INCIDENCE OF MORE THAN 2% IN
PLACEBO-CONTROLLED ALLERGIC RHINITIS CLINICAL TRIALS
PERCENT OF PATIENTS REPORTING
-----------------------------------------------------------------------
LORATADINE PLACEBO CLEMASTINE TERFENADINE
10 mg QD 1 mg BID 60 ng BID
n=1926 n=2545 n=536 n=684
-----------------------------------------------------------------------
Headache 12 11 8 8
Somnolence 8 6 22 9
Fatigue 4 3 10 2
Dry Mouth 3 2 4 3
-----------------------------------------------------------------------
Adverse events reported in placebo-controlled idiopathic chronic urticaria
trials were similar to those reported in allergic rhinitis studies.
Adverse event rates did not appear to differ significantly based on age, sex, or
race, although the number of non-white subjects was relatively small.
In addition to those adverse events reported above, the following adverse events
have been reported in 2% or fewer patients.
Autonomic Nervous System:
------------------------
Altered lacrimation, altered salivation, flushing, hypoesthesia, impotence,
increased sweating, thirst.
Body As A Whole:
--------------
Angioneurotic edema, asthenia, back pain, blurred vision, chest pain,
conjunctivitis, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus,
upper respiratory infection, weight gain.
Cardiovascular System:
---------------------
Hypertension, hypotension, palpitations, syncope, tachycardia.
Central and Peripheral Nervous System:
--------------------------------------
Blepharospasm, dizziness, dysphonia, hyperkinesia, migraine, paresthesia,
tremor, vertigo.
Gastrointestinal System:
-----------------------
Abdominal distress, altered taste, anorexia, constipation, diarrhea, dyspepsia,
flatulence, gastritis, increased appetite, nausea, stomatitis, toothache,
vomiting.
Musculoskeletal System:
----------------------
Arthralgia, myalgia.
Psychiatric:
------------
Agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired
concentration, insomnia, nervousness, paroniria.
Reproductive System:
-------------------
Breast pain, dysmenorrhea, menorrhagia, vaginitis.
Respiratory System:
------------------
Bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis,
nasal congestion, nasal dryness, pharyngitis, sinusitis, sneezing.
Skin and Appendages:
-------------------
Dermatitis, dry hair, dry skin, photosensitivity reaction, pruritus,
purpura, rash, urticaria.
Urinary System:
----------------
Altered micturition, urinary discoloration.
In addition, the following spontaneous adverse events have been reported
-------------
rarely during the marketing of loratadine:
abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis;
alopecia; anaphylaxis; breast enlargement; erythema multiforme; peripheral
edema; seizures; and supraventricular tachyarrhythmias.
DRUG ABUSE AND DEPENDENCE
-------------------------
There is no information to indicate that abuse or dependency occurs with
Claritin Tablets.
OVERDOSAGE
------------
Somnolence, tachycardia, and headache have been reported with overdoses greater
than 10 mg (40 to 180 mg). In the event of overdosage, general symptomatic and
supportive measures should be instituted promptly and maintained for as long as
necessary.
Treatment of overdosage would reasonably consist of emesis (ipecac syrup),
except in patients with impaired consciousness, followed by the administration
of activated charcoal to absorb any remaining drug. If vomiting is unsuccessful,
or contraindicated, gastric lavage should be performed with normal saline.
Saline cathartics may also be of value for rapid dilution of bowel contents.
Loratadine is not eliminated by hemodialysis. It is not known if loratadine is
eliminated by peritoneal dialysis.
Oral LD50 values for loratadine were greater than 5000 mg/kg in rats and mice.
Doses as high as 10 times the recommended clinical doses showed no effects in
rats, mice, and monkeys.
DOSAGE AND ADMINISTRATION
-------------------------
Adults and children 12 years of age and over: One 10 mg tablet daily.
In patients with liver failure or renal insufficiency (GFR < 30 ml/min), 10 mg
every other day should be the starting dose.
Physicians GenRx
HOW SUPPLIED
-------------
Claritin Tablets, 10 mg, white to off-white compressed tablets; impressed with
the product identification number "458" on one side; and "Claritin 10" on the
other; high density polyethylene plastic bottles of 100 (NDC 0085-0458-03) and
500 (NDC 0085-0458-06). Also available, Claritin Unit-of-Use packages of 14
tablets (7 tablets per blister card) (NDC 0085-0458-01) and 30 tablets (10
tablets per blister card) (NDC 0085-0458-05); and 10 x 10 tablet Unit
Dose-Hospital Pack (NDC 0085-0458-04).
Protect Unit-of-Use packaging and Unit Dose-Hospital Pack from excessive
moisture. Store between 2o and 30oC (36o and 86oF).
(Schering Corporation, 9/95, B-14386769) (95/09)
HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE:
-----------------------------------------
Tablet, Uncoated - Oral - 10 mg
14's $36.04 CLARITIN, Schering 00085-0458-01
30's $58.06 CLARITIN, Schering 00085-0458-05
100's $193.54 CLARITIN, Schering 00085-0458-03
100's $193.54 CLARITIN, U.D., Schering 00085-0458-04
500's $967.67 CLARITIN, Schering 00085-0458-06
=============================================================
32.) F-19649873 1711 PRODUCT /The original packing information of the product
INFORMATION CLARITIN® brand of loratadine 2.000-2.001
=============================================================
TABLETS, SYRUP, and RAPIDLY-DISINTEGRATING TABLETS
DESCRIPTION Loratadine is a white to off-white powder not soluble in water, but
very soluble in acetone, alcohol, and
chloroform. It has a molecular weight of 382.89, and empirical formula of
C22H23CIN2O2; its chemical name is ethyl
4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate
and has the
following structural formula:
CLARITIN Tablets contain 10 mg micronized loratadine, an antihistamine, to be
administered orally. It also contains
the following inactive ingredients: corn starch, lactose, and magnesium
stearate.
CLARITIN Syrup contains 1 mg/mL micronized loratadine, an antihistamine, to be
administered orally. It also contains
the following inactive ingredients: citric acid, edetate disodium, artificial
flavor, glycerin, propylene glycol, sodium benzoate,
sugar, and water. The pH is between 2.5 and 3.1.
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) contain 10 mg
micronized loratadine, an antihistamine,
to be administered orally. It disintegrates in the mouth within seconds after
placement on the tongue, allowing its contents
to be subsequently swallowed with or without water. CLARITIN REDITABS
(loratadine rapidly-disintegrating
tablets) also contain the following inactive ingredients: citric acid, gelatin,
mannitol, and mint flavor.
CLINICAL PHARMACOLOGY Loratadine is a long-acting tricyclic antihistamine with
selective peripheral histamine
H1-receptor antagonistic activity.
Human histamine skin wheal studies following single and repeated 10 mg oral
doses of CLARITIN have shown that the
drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a
maximum at 8 to 12 hours, and lasting in
excess of 24 hours. There was no evidence of tolerance to this effect after 28
days of dosing with CLARITIN.
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue
distribution studies in mice and rats,
and in vivo radioligand studies in mice have shown that neither loratadine nor
its metabolites readily cross the bloodbrain
barrier. Radioligand binding studies with guinea pig pulmonary and brain
H1-receptors indicate that there was
preferential binding to peripheral versus central nervous system H1-receptors.
Repeated application of CLARITIN REDITABS (loratadine rapidly-disintegrating
tablets) to the hamster cheek pouch
did not cause local irritation.
Pharmacokinetics: Absorption: Loratadine was rapidly absorbed following oral
administration of 10 mg tablets, once
daily for 10 days to healthy adult volunteers with times to maximum
concentration (Tmax) of 1.3 hours for loratadine and
2.5 hours for its major active metabolite, descarboethoxyloratadine. Based on a
cross-study comparison of single doses
of loratadine syrup and tablets given to healthy adult volunteers, the plasma
concentration profile of descarboethoxyloratadine
for the two formulations is comparable. The pharmacokinetics of loratadine and
descarboethoxyloratadine are
independent of dose over the dose range of 10 mg to 40 mg and are not altered by
the duration of treatment. In a singledose
study, food increased the systemic bioavailability (AUC) of loratadine and
descarboethoxyloratadine by approximately
40% and 15%, respectively. The time to peak plasma concentration (Tmax) of
loratadine and
descarboethoxyloratadine was delayed by 1 hour. Peak plasma concentrations
(Cmax) were not affected by food.
Pharmacokinetic studies showed that CLARITIN REDITABS (loratadine
rapidly-disintegrating tablets) provide plasma
concentrations of loratadine and descarboethoxyloratadine similar to those
achieved with CLARITIN Tablets. Following
administration of 10 mg loratadine once daily for 10 days with each dosage form
in a randomized crossover comparison
in 24 normal adult subjects, similar mean exposures (AUC) and peak plasma
concentrations (Cmax) of loratadine
were observed. CLARITIN REDITABS (loratadine rapidly-disintegrating tablets)
mean AUC and Cmax were 11% and 6%
greater than that of the CLARITIN Tablet values, respectively.
Descarboethoxyloratadine bioequivalence was demonstrated
between the two formulations. After 10 days of dosing, mean peak plasma
concentrations were attained at
1.3 hours and 2.3 hours (Tmax) for parent and metabolite, respectively.
In a single-dose study with CLARITIN REDITABS (loratadine rapidly-disintegrating
tablets), food increased the AUC of
loratadine by approximately 48% and did not appreciably affect the AUC of
descarboethoxyloratadine. The times to peak
plasma concentration (Tmax) of loratadine and descarboethoxyloratadine were
delayed by approximately 2.4 and 3.7
hours, respectively, when food was consumed prior to CLARITIN REDITABS
(loratadine rapidly-disintegrating tablets)
administration. Parent and metabolite peak concentrations (Cmax) were not
affected by food.
In a single-dose study with CLARITIN REDITABS (loratadine rapidly-disintegrating
tablets) in 24 subjects, the AUC of
loratadine was increased by 26% when administered without water compared to
administration with water, while Cmax
was not substantially affected. The bioavailability of descarboethoxyloratadine
was not different when administered without water.
Metabolism: In vitro studies with human liver microsomes indicate that
loratadine is metabolized to descarboethoxyloratadine
predominantly by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by
cytochrome P450 2D6
(CYP2D6). In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is
metabolized to descarboethoxyloratadine
predominantly by CYP2D6. Concurrent administration of loratadine with either
ketoconazole, erythromycin (both CYP3A4
inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers
was associated with substantially
increased plasma concentrations of loratadine (see Drug Interactions section).
Elimination: Approximately 80% of the total loratadine dose administered can be
found equally distributed between
urine and feces in the form of metabolic products within 10 days. In nearly all
patients, exposure (AUC) to the metabolite
is greater than to the parent loratadine. The mean elimination half-lives in
normal adult subjects (n = 54) were 8.4
hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92
hours) for descarboethoxyloratadine.
Loratadine and descarboethoxyloratadine reached steady-state in most patients by
approximately the fifth dosing day.
There was considerable variability in the pharmacokinetic data in all studies of
CLARITIN Tablets and Syrup, probably
due to the extensive first-pass metabolism.
Special Populations: Pediatric: The pharmacokinetic profile of loratadine in
children in the 6- to 12-year age group
is similar to that of adults. In a single-dose pharmacokinetic study of 13
pediatric volunteers (aged 8 to 12 years) given
10 mL of CLARITIN Syrup containing 10 mg loratadine, the ranges of individual
subject values of pharmacokinetic parameters
(AUC and Cmax) were comparable to those following administration of a 10 mg
tablet or syrup to adult volunteers.
The pharmacokinetic profile of loratadine in children in the 2 to 5-year age
group (n = 18) is similar to that of adults. In
a single-dose pharmacokinetic study of pediatric subjects (age 2 to 5 years)
given 5 mL of CLARITIN Syrup containing
5 mg loratadine, the range of individual subject values of pharmacokinetic
parameters (AUC and Cmax) were comparable
to those following administration of a 10 mg tablet or syrup to adult volunteers
or children eight years of age and older.
Geriatric: In a study involving 12 healthy geriatric subjects (66 to 78 years
old), the AUC and peak plasma levels
(Cmax) of both loratadine and descarboethoxyloratadine were approximately 50%
greater than those observed in studies
of younger subjects. The mean elimination half-lives for the geriatric subjects
were 18.2 hours (range = 6.7 to 37 hours)
for loratadine and 17.5 hours (range = 11 to 38 hours) for
descarboethoxyloratadine.
Renal Impairment: In a study involving 12 subjects with chronic renal impairment
(creatinine clearance d 30 mL/min)
both AUC and Cmax increased by approximately 73% for loratadine and by 120% for
descarboethoxyloratadine, as compared
to six subjects with normal renal function (creatinine clearance e 80 mL/min).
The mean elimination half-lives of loratadine
(7.6 hours) and descarboethoxyloratadine (23.9 hours) were not substantially
different from that observed in normal subjects.
Hemodialysis does not have an effect on the pharmacokinetics of loratadine or
descarboethoxyloratadine in subjects
with chronic renal impairment.
Hepatic Impairment: In seven patients with chronic alcoholic liver disease, the
AUC and Cmax of loratadine were double
while the pharmacokinetic profile of descarboethoxyloratadine was not
substantially different from that observed in
other trials enrolling normal subjects. The elimination half-lives for
loratadine and descarboethoxyloratadine were 24
hours and 37 hours, respectively, and increased with increasing severity of
liver disease.
Clinical Trials: Clinical trials of CLARITIN Tablets involved over 10,700
patients, 12 years of age and older, who
received either CLARITIN Tablets or another antihistamine and/or placebo in
double-blind randomized controlled studies.
In placebo-controlled trials, 10 mg once daily of CLARITIN Tablets was superior
to placebo and similar to clemastine
(1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms
of allergic rhinitis. In these studies,
somnolence occurred less frequently with CLARITIN Tablets than with clemastine
and at about the same frequency as
terfenadine or placebo. In studies with CLARITIN Tablets at doses two to four
times higher than the recommended dose
of 10 mg, a dose-related increase in the incidence of somnolence was observed.
Therefore, some patients, particularly
those with hepatic or renal impairment and the elderly, or those on medications
that impair clearance of loratadine and
its metabolites, may experience somnolence. In addition, three
placebo-controlled, double-blind, 2-week trials in 188
pediatric patients with seasonal allergic rhinitis aged 6 to 12 years, were
conducted at doses of CLARITIN Syrup up to
10 mg once daily. In a double-blind, placebo-controlled study, the safety of 5
mg loratadine, administered in
5 mL of CLARITIN Syrup, was evaluated in 60 pediatric patients between 2 and 5
years of age. No unexpected adverse
events were observed.
Clinical trials of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets)
involved over 1300 patients who
received either CLARITIN REDITABS (loratadine rapidly-disintegrating tablets),
CLARITIN Tablets, or placebo. In placebocontrolled
trials, one CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) once
daily was superior to placebo
and similar to CLARITIN Tablets in effects on nasal and non-nasal symptoms of
seasonal allergic rhinitis.
Among those patients involved in double-blind, randomized, controlled studies of
CLARITIN Tablets, approximately
1000 patients (age 12 and older), were enrolled in studies of chronic idiopathic
urticaria. In placebo-controlled clinical
trials, CLARITIN Tablets 10 mg once daily were superior to placebo in the
management of chronic idiopathic urticaria, as
demonstrated by reduction of associated itching, erythema, and hives. In these
studies, the incidence of somnolence
seen with CLARITIN Tablets was similar to that seen with placebo.
In a study in which CLARITIN Tablets were administered to adults at four times
the clinical dose for 90 days, no clinically
significant increase in the QTc was seen on ECGs.
In a single-rising dose study in which doses up to 160 mg (16 times the clinical
dose) were studied, loratadine did not
cause any clinically significant changes on the QTc interval in the ECGs.
INDICATIONS AND USAGE CLARITIN is indicated for the relief of nasal and
non-nasal symptoms of seasonal allergic
rhinitis and for the treatment of chronic idiopathic urticaria in patients 2
years of age or older.
CONTRAINDICATIONS CLARITIN is contraindicated in patients who are hypersensitive
to this medication or to any of its
ingredients.
PRECAUTIONS General: Patients with liver impairment or renal insufficiency (GFR
< 30 mL/min) should be given a
lower initial dose (10 mg every other day). (See CLINICAL PHARMACOLOGY: Special
Populations.)
Drug Interactions: Loratadine (10 mg once daily) has been coadministered with
therapeutic doses of erythromycin,
cimetidine, and ketoconazole in controlled clinical pharmacology studies in
adult volunteers. Although increased plasma
concentrations (AUC 0-24 hrs) of loratadine and/or descarboethoxyloratadine were
observed following coadministration
of loratadine with each of these drugs in normal volunteers (n = 24 in each
study), there were no clinically relevant
changes in the safety profile of loratadine, as assessed by electrocardiographic
parameters, clinical laboratory tests, vital
signs, and adverse events. There were no significant effects on QTc intervals,
and no reports of sedation or syncope. No
effects on plasma concentrations of cimetidine or ketoconazole were observed.
Plasma concentrations (AUC 0-24 hrs) of
erythromycin decreased 15% with coadministration of loratadine relative to that
observed with erythromycin alone. The
clinical relevance of this difference is unknown. These above findings are
summarized in the following table:
Effects on Plasma Concentrations (AUC 0-24 hrs) of Loratadine and
Descarboethoxyloratadine
After 10 Days of Coadministration (Loratadine 10 mg) in Normal Volunteers
Loratadine Descarboethoxyloratadine
Erythromycin (500 mg Q8h) + 40% +46%
Cimetidine (300 mg QID) +103% + 6%
Ketoconazole (200 mg Q12h) +307% +73%
There does not appear to be an increase in adverse events in subjects who
received oral contraceptives and loratadine.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In an 18-month
carcinogenicity study in mice and a
2-year study in rats, loratadine was administered in the diet at doses up to 40
mg/kg (mice) and 25 mg/kg (rats). In the
carcinogenicity studies, pharmacokinetic assessments were carried out to
determine animal exposure to the drug. AUC
data demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6
(loratadine) and 18 (descarboethoxyloratadine)
times the exposure in adults and 5 (loratadine) and 20
(descarboethoxyloratadine) times the exposure in
children given the maximum recommended daily oral dose. Exposure of rats given
25 mg/kg of loratadine was
28 (loratadine) and 67 (descarboethoxyloratadine) times the exposure in adults
and 40 (loratadine) and 80 (descarboethoxyloratadine)
times the exposure in children given the maximum recommended daily oral dose.
Male mice given
40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined
adenomas and carcinomas) than
concurrent controls. In rats, a significantly higher incidence of hepatocellular
tumors (combined adenomas and carcinomas)
was observed in males given 10 mg/kg, and males and females given 25 mg/kg.
Exposure of rats given 10 mg/kg
of loratadine was 10 (loratadine) and 15 (descarboethoxyloratadine) times the
exposure in adults and 15 (loratadine) and
20 (descarboethoxyloratadine) times the exposure in children given the maximum
recommended daily oral dose. The
clinical significance of these findings during long-term use of CLARITIN is not
known.
In mutagenicity studies, there was no evidence of mutagenic potential in reverse
(Ames) or forward point mutation
(CHO-HGPRT) assays, or in the assay for DNA damage (rat primary hepatocyte
unscheduled DNA assay) or in two
assays for chromosomal aberrations (human peripheral blood lymphocyte
clastogenesis assay and the mouse bone marrow
erythrocyte micronucleus assay). In the mouse lymphoma assay, a positive finding
occurred in the nonactivated but
not the activated phase of the study.
Decreased fertility in male rats, shown by lower female conception rates,
occurred at an oral dose of 64 mg/kg
(approximately 50 times the maximum recommended human daily oral dose on a mg/m2
basis) and was reversible with
cessation of dosing. Loratadine had no effect on male or female fertility or
reproduction in the rat at an oral dose of
approximately 24 mg/kg (approximately 20 times the maximum recommended human
daily oral dose on a mg/m2 basis).
S 2 6 5 4 3
O OC2H5
Cl
N
N
C
FPO
Pregnancy Category B: There was no evidence of animal teratogenicity in studies
performed in rats and rabbits at oral
doses up to 96 mg/kg (approximately 75 times and 150 times, respectively, the
maximum recommended human daily
oral dose on a mg/m2 basis). There are, however, no adequate and well-controlled
studies in pregnant women. Because
animal reproduction studies are not always predictive of human response,
CLARITIN should be used during pregnancy
only if clearly needed.
Nursing Mothers: Loratadine and its metabolite, descarboethoxyloratadine, pass
easily into breast milk and achieve
concentrations that are equivalent to plasma levels with an AUCmilk/AUCplasma
ratio of 1.17 and 0.85 for loratadine and
descarboethoxyloratadine, respectively. Following a single oral dose of 40 mg, a
small amount of loratadine and descarboethoxyloratadine
was excreted into the breast milk (approximately 0.03% of 40 mg over 48 hours).
A decision should
be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the
mother. Caution should be exercised when CLARITIN is administered to a nursing
woman.
Pediatric Use: The safety of CLARITIN Syrup at a daily dose of 10 mg has been
demonstrated in 188 pediatric patients
6 to 12 years of age in placebo-controlled 2-week trials. The safety and
tolerability of CLARITIN Syrup at a daily dose of
5 mg has been demonstrated in 60 pediatric patients 2 to 5 years of age in a
double-blind, placebocontrolled,
2-week study. The effectiveness of CLARITIN for the treatment of seasonal
allergic rhinitis and chronic
idiopathic urticaria in children aged 2 to 12 years is based on an extrapolation
of the demonstrated efficacy of CLARITIN in
adults in these conditions and the likelihood that the disease course,
pathophysiology, and the drug's effect are substantially
similar to that of the adults. The recommended dose for the pediatric population
is based on cross-study comparison
of the pharmacokinetics of CLARITIN in adults and pediatric subjects and on the
safety profile of loratadine in both adults
and pediatric patients at doses equal to or higher than the recommended doses.
The safety and effectiveness of CLARITIN
in children under 2 years of age have not been established.
ADVERSE REACTIONS CLARITIN Tablets: Approximately 90,000 patients, aged 12 and
older, received CLARITIN
Tablets 10 mg once daily in controlled and uncontrolled studies.
Placebo-controlled clinical trials at the recommended
dose of 10 mg once a day varied from 2 weeks' to 6 months' duration. The rate of
premature withdrawal from these trials
was approximately 2% in both the treated and placebo groups.
REPORTED ADVERSE EVENTS WITH AN INCIDENCE OF MORE THAN 2% IN PLACEBO-CONTROLLED
ALLERGIC RHINITIS CLINICAL TRIALS IN PATIENTS 12 YEARS OF AGE AND OLDER
PERCENT OF PATIENTS REPORTING
LORATADINE PLACEBO CLEMASTINE TERFENADINE
10 mg QD 1 mg BID 60 mg BID
n = 1926 n = 2545 n = 536 n = 684
Headache 12 11 8 8
Somnolence 8 6 22 9
Fatigue 4 3 10 2
Dry Mouth 3 2 4 3
Adverse events reported in placebo-controlled chronic idiopathic urticaria
trials were similar to those reported in allergic
rhinitis studies.
Adverse event rates did not appear to differ significantly based on age, sex, or
race, although the number of nonwhite
subjects was relatively small.
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): Approximately 500
patients received
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in controlled
clinical trials of 2 weeks' duration. In these
studies, adverse events were similar in type and frequency to those seen with
CLARITIN Tablets and placebo.
Administration of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets)
did not result in an increased reporting
frequency of mouth or tongue irritation.
CLARITIN Syrup: Approximately 300 pediatric patients 6 to 12 years of age
received 10 mg loratadine once daily in
controlled clinical trials for a period of 8 to 15 days. Among these, 188
children were treated with 10 mg loratadine syrup
once daily in placebo-controlled trials. Adverse events in these pediatric
patients were observed to occur with type and
frequency similar to those seen in the adult population. The rate of premature
discontinuance due to adverse events
among pediatric patients receiving loratadine 10 mg daily was less than 1%.
ADVERSE EVENTS OCCURRING WITH A FREQUENCY OF e 2% IN LORATADINE SYRUP-TREATED
PATIENTS (6 TO 12
YEARS OLD) IN PLACEBO-CONTROLLED TRIALS, AND MORE FREQUENTLY THAN IN THE PLACEBO
GROUP
PERCENT OF PATIENTS REPORTING
LORATADINE PLACEBO CHLORPHENIRAMINE
10 mg QD 2-4 mg BID/TID
n = 188 n = 262 n = 170
------------------------
Nervousness 4 2 2
Wheezing 4 2 5
Fatigue 3 2 5
Hyperkinesia 3 1 1
Abdominal Pain 2 0 0
Conjunctivitis 2 <1 1
Dysphonia 2 <1 0
Malaise 2 0 1
Upper Respiratory
Tract Infection 2 <1 0
-----------------------
Sixty pediatric patients 2 to 5 years of age received 5 mg
-----------------------------------------------------------
loratadine once daily in a double-blind, placebo-controlled
clinical trial for a period of 14 days. No unexpected adverse events were seen
given the known safety profile of loratadine
and likely adverse reactions for this patient population. The following adverse
events occurred with a frequency of 2 to 3
percent in the loratadine syrup-treated patients (2 to 5 years old) during the
placebo-controlled trial, and more frequently than in the placebo group:
----------------------------------
diarrhea, epistaxis, pharyngitis, influenza-like symptoms,
fatigue, stomatitis, tooth disorder,
earache, viral infection, and rash.
In addition to those adverse events reported above (e 2%), the following adverse
events have been reported in at least
one patient in CLARITIN clinical trials in adult and pediatric patients:
Autonomic Nervous System:
------------------------
altered lacrimation, altered salivation, flushing, hypoesthesia, impotence,
increased
sweating, thirst.
Body as a Whole:
----------------
angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache,
eye pain, fever, leg
cramps, malaise, rigors, tinnitus, weight gain.
Cardiovascular System:
-----------------------
hypertension, hypotension, palpitations, supraventricular tachyarrhythmias,
syncope, tachycardia.
Central and Peripheral Nervous System:
-------------------------------------
blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia,tremor,
vertigo.
Gastrointestinal System:
------------------------
altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence,
gastritis, hiccup,
increased appetite, loose stools, nausea, vomiting.
Musculoskeletal System:
----------------------
arthralgia, myalgia.
Psychiatric:
-------------
agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired
concentration, insomnia,
irritability, paroniria.
Reproductive System:
--------------------
breast pain, dysmenorrhea, menorrhagia, vaginitis.
Respiratory System:
--------------------
bronchitis, bronchospasm, coughing, dyspnea, hemoptysis, laryngitis, nasal
dryness, sinusitis, sneezing.
Skin and Appendages:
---------------------
dermatitis, dry hair, dry skin, photosensitivity reaction, pruritus, purpura,
urticaria.
Urinary System:
---------------
altered micturition, urinary discoloration, urinary incontinence, urinary
retention.
In addition, the following spontaneous adverse events have
---------------------------------------------------------
been reported rarely during the marketing of
loratadine:
abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis;
alopecia; anaphylaxis; breast enlargement;
erythema multiforme; peripheral edema; thrombocytopenia; and seizures.
------------------------------------
DRUG ABUSE AND DEPENDENCE There is no information to indicate that abuse or
dependency occurs with CLARITIN.
OVERDOSAGE In adults, somnolence, tachycardia, and headache have been reported
with overdoses greater than
10 mg with the Tablet formulation (40 mg-180 mg). Extrapyramidal signs and
palpitations have been reported in children
with overdoses of greater than 10 mg of CLARITIN Syrup. In the event of
overdosage, general symptomatic and supportive
measures should be instituted promptly and maintained for as long as necessary.
Treatment of overdosage would reasonably consist of emesis (ipecac syrup),
except in patients with impaired
consciousness, followed by the administration of activated charcoal to absorb
any remaining drug. If vomiting is unsuccessful,
or contraindicated, gastric lavage should be performed with normal saline.
Saline cathartics may also be of value
for rapid dilution of bowel contents. Loratadine is not eliminated by
hemodialysis. It is not known if loratadine is eliminated
by peritoneal dialysis.
No deaths occurred at oral doses up to 5000 mg/kg in mice (approximately 1200
and 1400 times, respectively, the
maximum recommended daily oral dose in adults and children on a mg/m2 basis). No
deaths occurred at oral doses up
to 5000 mg/kg in matured rats (approximately 2400 and 2900 times, respectively,
the maximum recommended daily oral
dose in adults and children on a mg/m2 basis). However, lethality occurred in
juvenile rats at an oral dose of 125 mg/kg
(approximately 100 and 70 times, respectively, the maximum recommended daily
oral dose in adults and children on a
mg/m2 basis). No deaths occurred at oral doses up to 1280 mg/kg in monkeys
(approximately 2100 and 1500 times,
respectively, the maximum recommended daily oral dose in adults and children on
a mg/m2 basis).
DOSAGE AND ADMINISTRATION Adults and children 6 years of age and over: The
recommended dose of CLARITIN is
one 10 mg tablet or reditab, or 2 teaspoonfuls (10 mg) of syrup once daily.
Children 2 to 5 years of age: The recommended dose of CLARITIN Syrup is 5 mg (1
teaspoonful) once daily.
In adults and children 6 years of age and over with liver failure or renal
insufficiency (GFR < 30 mL/min), the starting
dose should be 10 mg (one tablet or two teaspoonfuls) every other day. In
children 2 to 5 years of age with liver failure
or renal insufficiency, the starting dose should be 5 mg (one teaspoonful) every
other day.
Administration of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets):
Place CLARITIN REDITABS
(loratadine rapidly-disintegrating tablets) on the tongue. Tablet disintegration
occurs rapidly. Administer with or without
water.
HOW SUPPLIED CLARITIN Tablets: 10 mg, white to off-white compressed tablets;
impressed with the product identification
number "458" on one side and "CLARITIN 10" on the other; high-density
polyethylene plastic bottles of 100 (NDC 0085-0458-03)
and 500 (NDC 0085-0458-06). Also available, CLARITIN Unit-of-Use packages of 30
tablets (10 tablets per blister card)
(NDC 0085-0458-05); and 10 x 10 tablet Unit Dose-Hospital Pack (NDC
0085-0458-04).
Protect Unit-of-Use packaging and Unit Dose-Hospital Pack from excessive
moisture.
Store between 2° and 30°C (36° and 86°F).
CLARITIN Syrup: Clear, colorless to light-yellow liquid, containing 1 mg
loratadine per mL; amber glass bottles of
16 fluid ounces (NDC 0085-1223-01).
Store between 2° and 25°C (36° and 77°F).
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets): CLARITIN REDITABS
(loratadine rapidly-disintegrating
tablets), 10 mg, white to off-white blister-formed tablet; impressed with the
letter "C" on one side; Unit-of-Use
polyvinyl chloride blister packages of 30 tablets (three laminated foil pouches,
each containing one blister card of
10 tablets) supplied with Patient's Instructions for Use (NDC 0085-1128-02).
Keep CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) in a dry
place.
Store between 2° and 25°C (36° and 77°F). Use within 6 months of opening
laminated foil pouch, and immediately
upon opening individual tablet blister.
Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 9/00 B-19649873
19628477T
CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) are manufactured
for Schering Corporation by
Scherer DDS, England.
U.S. Patent Nos. 4,282,233 and 4,371,516.
Copyright © 1997, 1998, 1999, 2000, Schering Corporation. All rights reserved.
CLARITIN®
brand of loratadine
TABLETS, SYRUP, and
RAPIDLY-DISINTEGRATING TABLETS
=============================================================
33.) SCHERING-PLOUGH DISAGREES WITH FDA ADVISORY PANEL’S RECOMMENDATION
REGARDING CLARITIN (LORATADINE)
=============================================================
KENILWORTH, N.J., May 11, 2001 – Schering-Plough Corporation (NYSE: SGP) today
said it strongly believes that CLARITIN (loratadine), the company’s nonsedating
antihistamine, should remain a prescription product following a non-binding
recommendation by the joint meeting of the U.S. Food and Drug Administration’s
(FDA) Nonprescription Drugs Advisory Committee and the Pulmonary–Allergy Drugs
Advisory Committee, which examined questions relating to the possible use of
CLARITIN in an over-the-counter (OTC) setting.
The panel voted 19 to 4 to recommend that loratadine has a safety profile
acceptable for OTC marketing. The panel also had serious concerns regarding
appropriate OTC labeling. Additional issues on the lack of use studies as well
as patient access were noted.
In making its recommendation, the panel rejected testimony from the leading
medical and consumer associations, including the American Academy of Asthma,
Allergy and Immunology (AAAAI) and the American Academy of Otolaryngic Allergy
(AAOA) and the patient-advocacy group Allergy and Asthma Network/Mothers of
Asthmatics, groups that spoke in support of maintaining the prescription status
of second-generation antihistamines, including loratadine.
In his presentation today before the joint advisory committees, Robert J.
Spiegel, M.D., chief medical officer of Schering-Plough and senior vice
president, medical affairs, said "We believe that prescription status of these
medications is necessary to protect and optimize public health."
Today’s hearing was prompted by a petition to switch CLARITIN from prescription
to OTC status, which was brought by the health insurance company WellPoint/Blue
Cross of California. Schering-Plough maintains that such a switch would force
patients to self-diagnose, self-treat and pay the entire cost of their allergy
medications, thus raising serious questions about quality of care and costs for
patients.
In opposing the switch, Schering-Plough has also said it believes there are
significant legal and public policy issues that would be raised if the FDA were
to require a switch without drug-sponsor support. An Rx-to-OTC switch over a
sponsor’s objections would constitute an unprecedented departure from past
agency policy and implicate the sponsor’s statutory and constitutional rights.
The company emphasized that the advisory panel’s action today constitutes a
recommendation that is not binding on the FDA, which may accept or reject the
recommendation, modify it, request additional information, or take no action.
Schering-Plough is a research-based company engaged in the discovery,
development, manufacturing and marketing of pharmaceutical products worldwide.
============================================================
34.) SCHERING-PLOUGH PROVIDES UPDATE ON MANUFACTURING ISSUES
AND FDA INSPECTIONS OF U.S. MANUFACTURING FACILITIES
============================================================
KENILWORTH, N.J., June 22, 2001 ¾ Schering-Plough Corporation (NYSE: SGP) today
reported that the U.S. Food and Drug Administration (FDA) has completed
inspections conducted during May and June at the company’s manufacturing
facilities in Kenilworth and Union, New Jersey, and Las Piedras and Manati,
Puerto Rico, and has issued new inspection reports (Form FDA-483), which cited
some continuing and some additional deficiencies concerning compliance with
current Good Manufacturing Practices (cGMP). Depending on when the Form FDA-483
was received, Schering-Plough has either responded to or is in the process of
responding to these observations and is continuing to discuss these matters with
FDA. The company cannot predict the outcome of these issues or the timing of any
resolution.
These most recent FDA inspections follow general cGMP inspections conducted at
the company’s New Jersey and Puerto Rico facilities in late 2000 and early 2001.
As reported by Schering-Plough on February 15, 2001, FDA had conducted
inspections of these facilities and had issued Form FDA-483s citing cGMP
deficiencies, primarily relating to production processes, controls and
procedures. In late 2000 and early 2001, the company submitted written responses
to FDA’s inspection reports.
In the months since FDA’s initial inspections of the New Jersey and Puerto Rico
facilities, Schering-Plough believes it has moved aggressively and deliberately
in an effort to resolve these manufacturing issues. The company also believes
that progress has been made, but recognizes that additional work remains to be
done.
On May 1, 2001, Schering-Plough submitted to FDA a comprehensive cGMP Work Plan
designed to take a broad, systemic approach to all aspects of manufacturing and
serve as a blueprint for quality and compliance initiatives.
Also on May 1 and continuing into June, FDA conducted reinspections of the
company’s New Jersey and Puerto Rico manufacturing facilities, and subsequently
issued new inspection reports. Schering-Plough has either responded to or is in
the process of responding to these observations.
In its response letter to FDA on one site’s observations, the company emphasized
that it takes each of the observations very seriously. Schering-Plough noted in
its letter that the Form FDA-483 observations are not meant to reflect (because
that is not their purpose):
- The major changes that have been made in the entire Schering-Plough corporate
structure;
- The substantial resources devoted to keeping the company’s cGMP commitments to
FDA;
- The large amount of cGMP work being undertaken; and
- The deep resolve of the company to continue this progress until its
commitments are fully met.
Schering-Plough believes that the manufacturing issues identified by FDA will be
addressed in the cGMP Work Plan now being implemented. The plan encompasses all
FDA-regulated manufacturing sites, consolidates all ongoing cGMP actions and
addresses six key areas: quality assurance, facilities and equipment, materials
management, production, laboratories, and packaging and labeling. The plan
covers all product lines and takes a uniform approach to quality, production and
maintenance at all FDA-regulated manufacturing sites.
Under this plan, Schering-Plough has undertaken major structural and
organizational changes. A new Worldwide Quality Operations unit has been formed
and given the authority and independence to address quality issues throughout
the company. This unit is responsible for all quality-related issues, including
technology transfer, validation, investigation, change authorization policies
and other quality-related procedures, protocols and documentation. The Quality
function at all FDA-regulated sites reports directly to this new unit.
In order to address its manufacturing issues, the company is making extensive
improvements to its operations, including:
-- In quality control and production, some 500 people will be added to
strengthen these areas. The company is about half-way to this goal, and has
recruited a number of senior level executives from outside the company;
-- In the area of equipment requalification and revalidation, the company has
recruited highly qualified executives, scientists and consultants to improve
revalidation studies and set up a validation review board to oversee the
requalification of manufacturing equipment and the revalidation of processes and
support systems;
-- In certain production areas where appropriate, equipment and manufacturing
lines are being upgraded, notably in aerosol production and tablet
manufacturing;
-- In global quality control, improved electronic document management and
laboratory information systems are being installed; and
-- A GMP Review Board has been formed, which includes three prominent former FDA
officials. This Board is overseeing progress on the company’s cGMP compliance
efforts and providing periodic reports to FDA.
DISCLOSURE NOTICE: The information in this press release includes certain
"forward-looking" statements relating to the company’s plans and activities
designed to resolve cGMP deficiencies identified by FDA in its inspections of
the company’s New Jersey and Puerto Rico manufacturing facilities. The
resolution of the issues with FDA is subject to substantial risks and
uncertainties. Many factors could cause actual results to differ materially from
the company’s forward-looking statements, including that the timing, scope and
duration of a resolution of the manufacturing and cGMP issues will depend on the
ability of the company to assure FDA of the quality and reliability of its
manufacturing systems and controls, and the extent of remedial and prospective
obligations undertaken by the company. Other risk factors include that any
failure to meet cGMP can result in delays in the release of products, seizure or
recall of products, suspension or revocation of the authority necessary for the
production and sale of products, fines and other civil or criminal sanctions.
For further details and a discussion of these and other risks and uncertainties,
see the company’s Securities and Exchange Commission filings, including the
company’s 2000 annual report on Form 10-K and subsequent quarterly report on
Form 10-Q.
Schering-Plough Corporation is a research-based company engaged in the
discovery, development, manufacturing and marketing of pharmaceutical products
worldwide.
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DATA-MÉDICOS/DERMAGIC-EXPRESS No 3-(108) /2.001 DR. JOSÉ LAPENTA R.
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