La loratadina y sus 110 efectos adversos !!!

Data-Medicos 
Dermagic/Express No. 3-(107) 
27 Septiembre 2.001 / 27 September 2.001 

EDITORIAL ESPANOL 
================= 
Hola amigos de la red, DERMAGIC de nuevo con ustedes, en esta ocasion con EL TEMA: LA 
LORATADINA Y SUS 11O EFECTOS ADVERSOS. 

Hace unas semanas vi en mi oficina una paciente femenina de 10 años de edad, quien como unico 
tratamiento de control para una rinitis alergica estaba tomando LORATADINA diaria y llevaba 4 
meses seguidos haciendolo. Examenes de LABORATORIO revelaron aumento de las enzimas 
hepaticas. 

Este evento me llevo a indagar FUERTEMENTE ACERCA DE ESTA MOLECULA, pues los 
laboratorios encargados de mercadear el PRODUCTO JAMAS nunca JAMAS me mencionaron 
sobre tales efectos. 

Lo primero que hice fue consultar EL LIBRO DE MOSBY del año 1.996. y ENCONTRE en la 
seccion sobre EFECTOS ADVERSOS los 110 QUE ABAJO se describen. Impresionado por el 
hallazgo, PEDI A UN AMIGO DE LOS ESTADOS UNIDOS me enviara la INFORMACION 
del fabricante sobre el producto, DOCUMENTO que llego a mis manos la semana pasada y donde 
verdaderamente estan ALLI ESCRITOS TODOS ESOS EFECTOS ADVERSOS. 

El otro paso que tome fue el de RASTREAR toda la BASE DE DATOS sobre la LORATADINA 
en la RED, donde para mi sorpresa encontre pocos articulos sobre ESTOS EFECTOS, siendo el 
mas interesante, el reporte de la FDA sobre el PRODUCTO, donde hay un estudio BASTANTE 
OBJETIVO que realmente CONFIRMA que la LORATADINA puede producir daño hepatico, y 
que ha estado involucrada en alteraciones CARDIACAS y muerte. 

Para el año 1.992 fue reportado un alerta sobre la toxicidad de LA LORATADINA y su uso 
cronico. 

LA MOLECULA LORATADINA nace para los años 1.986-1987 con el nombre codigo de SCH 
29851 y el primer pais que la puso el mercado FUE BELGICA en febrero de 1.998, luego Canada 
en junio de 1.988. Para el año de 1.999 el producto habia sido aprobado en 94 paises incluyendo 
17 como producto de no prescripcion medica. 

En Estados Unidos fue aprobada en el año 1.993 PARA USO EXCLUSIVO en niños mayores de 
12 AÑOS DE EDAD y ADULTOS. (1996). Luego se extendio su USO a niños entre 6 Y 12 
AÑOS y 2 A 5 AñOS DE EDAD. Y fue el 26 de SEPTIEMBRE DEL AÑO 2000 cuando fue 
aprobada para su uso en niños de menores de 2 años de edad. 

REPITO, a partir DEL 26 DE SEPTIEMBRE DEL AÑO 2.000 LA FDA APROBO SUS USO 
EN NIÑOS MENORES DE 2 AÑOS. 

Solo encontre UN SOLO ESTUDIO DE LORATADINA EN NIÑOS ENTRE 6 MESES Y 17 
AñOS y lo mas curioso del caso es QUE DATA DEL AÑO 1989. Cuando la loratadina estaba 
dando sus primeros pasos en el mercado. 

El empaque original del producto LORATADINA PARA EL AÑO PASADO DECIA: 

La seguridad y efectividad de la LORATADINA en pacientes pediatricos por debajo de 2 años no 
ha sido aun establecida. 

Pero NOSOTROS la estuvimos prescribiendo en estos niños PROBABLEMENTE SIN saberlo. 

Y en el empaque ORIGINAL Y ACTUAL DEL PRODUCTO ESTAN LOS 110 EFECTOS 
ADVERSOS que se describen. 

OTRO ASPECTO MUY IMPORTANTE A RESALTAR es que las presentaciones de 
LORATADINA CON PSEUDOEFEDRINA estan aprobadas por la FDA PARA SER 
USADAS SOLO EN NIÑOS MAYORES DE 12 AÑOS Y ADULTOS.

En la investigacion encontre unas INTERESANTES REFERENCIAS bibliograficas SOBRE LOS 
ESTUDIOS COMPARATIVOS DE LA LORATADINA versus CETIRIZINA, 
FEXOFENADINA, EBASTINA Y BROMFENIRAMINA en relacion a EFECTIVIDAD. Todos 
ellos resultaron ser superiores a LORATADINA. 

Los laboratorios siempre nos dijeron QUE LA GRAN VENTAJA de la loratadina sobre sus 
competidores era LA AUSENCIA DE EFECTOS ADVERSOS. Lo cual no es VERDAD pues la 
LORATADINA como otras medicinas TIENE SUS VENTAJAS Y DESVENTAJAS, y apuesto 
que muchos de ustedes como yo JAMAS nunca JAMAS imaginaron que eran tantos, aunque el 
numero de pacientes reportados sea poco. 

Y mi paciente constituye UN EVIDENTE CASO DE QUE la loratadina y su uso prolongado puede 
dañar el higado. 

CONCLUSIONES: sobre la molecula loratadina y sus efectos adversos. 

1.) Para el año 2.000 se reportan 55 casos de muertes por el uso de Loratadina. 
2.) Se han reportado 86 casos de arritmias ventriculares de los cuales 16 murieron. 
3.) Se han reportado 43 casos de convulsiones asociadas al uso de loratadina. 
4.) Se han reportado 103 casos de injuria hepatica asociada al uso de loratadina, que incluye 
anormal funcionamiento del higado, ictericia, hepatitis y necrosis hepatica. 
5.) Se han reportado 5 casos de insuficiencia hepatica de los cuales 4 necesitaron trasplante de 
higado. 
6.) Para el año 2000 dia 26 de septiembre es que la FDA aprueba su uso en niños menores de 2 
años. 
7.) Se han reportado 10 diferentes tipos de efectos adversos en relacion al uso de loratadina en 
niños de 2-5 años, a saber: Diarrea, Epistaxis, Faringitis, Influenza-like sintomas, Fatiga, Estomatitis, 
Desordenes dentales, Dolor de oidos, Infeciones virales, Rash. 
8.) Para el año 1.996 ya se habian REPORTADO LOS 110 EFECTOS ADVERSOS descritos en 
la revision y desde ese mismo años ya SE HABIAN REPORTADO LOS EFECTOS EDVERSOS 
SOBRE EL HIGADO. 
9.) Cetirizina, fexofenadina, bromfeniramina y evastina han resultado ser superiores a loratadina en 
cuanto a efectividad segun estudios publicados y NO SE LE DESCRIBEN TANTOS EFECTOS 
ADVERSOS. 
10.) la loratadina si tiene efectos sobre el sistema nervioso CENTRAL Y PRERIFERICO: a saber: 
somnolencia, Blefarospasmo, Vahidos, Disfonia, Hipertonia, Migraña, Parestesia, Tremor y vertigo. 
11.) Estos 110 efectos adversos NO FUERON INVENTADOS, y se reportaron en pacientes que 
estaban tomando el producto. La FDA obligo a los fabricantes a colocarlos en el empaque del 
producto desde 1.996. 

El objetivo FINAL de esta revision es ALERTAR a todos LOS MEDICOS que TODAS LAS 
MEDICINAS pueden PRODUCIR EFECTOS ADVERSOS, no hay PRODUCTOS 
PERFECTOS 

Y LA LORATADINA es uno de ellos... 

En las referencias los hechos... 

Saludos a todos. 

Dr. Jose Lapenta R. 

EDITORIAL ENGLISH 
================= 
Hello friends of the net, DERMAGIC again with you, in this occasion with THE TOPIC THE 
LORATADINE AND THEIR 11O ADVERSE EFFECTS. 

Some weeks ago I saw in my office a 10 year-old feminine patient who as only control treatment for 
an allergic rhinitis LORATADINE daily was taking, and she did it for 4 followed months. Exams of 
LABORATORY revealed increase of the hepatic enzymes. 

This event takes myself to investigate STRONGLY OF THIS MOLECULE, because the 
laboratories in charge of market the PRODUCT NEVER mentioned NEVER me on such effects. 

The first thing that I made was to consult THE MOSBY YEAR BOOK of 1.996, and I FOUND in 
the section about ADVERSE EFFECTS the 110 THAT BELOW are described. Impressed by the 
discovery, I REQUESTED TO A FRIEND OF THE UNITED STATES, he sent me the maker's 
INFORMATION on the product, DOCUMENT that I arrive to my hands last week and where 
they are truly THERE WRITINGS ALL THOSE ADVERSE EFFECTS. 

The other step that I takes was the one of SEARCHING the whole DATABASES on the 
LORATADINE in the NET, where it stops my surprise I found few articles on THESE EFFECTS, 
being the but interesting, the report of the FDA on the PRODUCT, where there is a QUITE 
OBJECTIVE study that CONFIRMS really that the LORATADINE can produce hepatic damage, 
and that it has been involved in HEART alterations. 

For the year 1.992 an alert was reported on the toxicity of THE LORATADINE and its chronic 
use. 

THE LORATADINE MOLECULE is born for the years 1.986-1987 with the name code of SCH 
29851 and the first country that it put it the market it was BELGIUM in February of 1.998, then 
Canada in June of 1.988. For the year of 1.999 the product had been approved in 94 countries 
including 17 as non prescription product. 

In United States it was approved in the year 1.993 FOR EXCLUSIVE USE in children bigger than 
12 YEARS OF AGE and ADULTS. (1996). Then their USE extended to children between 6 AND 
12 Years OF AGE, AND between 2-5 years old, and it was IN SEPTEMBER 26 OF THE 
YEAR 2000 when it was approved for their use in children from down to 2 years of age. 

And I REPEAT to SEPTEMBER 26 OF THE YEAR 2.000 THE FDA it APPROVED THEIR 
USE IN CHILDREN down to 2 years of age. 

Alone I found A SINGLE ESTUDY OF LORATADINE IN Children BETWEEN 6 MONTHS 
AND 17 Years and him but curious of the case it is THAT it DATES OF THE YEAR 1989. When 
the loratadine was taking its first steps in the market. 

The original packing of the product LORATADINE last year he SAID: 

The security and effectiveness of the LORATADINE in patient pediatric below 2 years it has not 
even been established. 

But WE were PROBABLY prescribing it in these children WITHOUT knowing it. 

And THE 110 ADVERSE EFFECTS that are described are in the ORIGINAL AND CURRENT 
packing OF THE PRODUCT. 

ANOTHER VERY IMPORTANT ASPECT OF STANDING OUT is that the presentations of 
LORATADINE WITH PSEUDOEPHEDRINE is approved by the FDA to BE USED ALONE 
IN CHILDREN OVER 12 YEARS OLD AND ADULTS in UNITED STATES. 

In the investigation I found some bibliographical INTERESTING REFERENCES ON THE 
COMPARATIVE STUDIES OF THE LORATADINE versus CETIRIZINE, FEXOFENADINE, 
EBASTINE AND BROMPHENIRAMINE in relation to EFFECTIVENESS. All they turned out 
to be superior to LORATADINE. 

The laboratories always told us THAT THE GREAT ADVANTAGE of the loratadine on their 
competitors was THE ABSENCE OF ADVERSE EFFECTS. That which is not TRUE the 
LORATADINE like other medicines HAS THEIR ADVANTAGES AND DISADVANTAGES, 
and I bet that many of you as me NEVER imagined never NEVER that they were so many, although 
the one numbers of reported patients it is a little. 

And my patient constitutes AN EVIDENT CASE THAT the loratadine and her chronic use can 
damage the liver. 

CONCLUSIONS: on the molecule loratadine and their adverse effects. 

1.) for the year 2.000 55 cases of deaths are reported by the use of Loratadine. 
2.) 86 cases of ventricular arrhythmias have been reported of which 16 died. 
3.) 43 cases of convulsions associated to the loratadine use have been reported. 
4.) 103 cases of hepatic injury associated to the loratadine use have been reported that includes 
abnormal function of the liver, jaundice, hepatitis and hepatic necrosis. 
5.) 5 cases of hepatic failure have been reported of which 4 needed liver transplant. 
6.) For the year 2000 day 26 of September is that the FDA approves its use in children smaller than 
2 years. 
7.) 10 different types of adverse effects have been reported in relation to the loratadine use in 2-5 
year-old children: diarrhea, epistaxis, pharyngitis, influenza-like symptoms, fatigue, stomatitis, tooth 
disorder, earache, viral infection and rash. 
8.) For the year 1.996 THE 110 ADVERSE EFFECTS had already BEEN REPORTED described 
in the revision and from that same years THE EDVERSE EFFECTS had already BEEN 
REPORTED ON THE LIVER. 
9.) Cetirizine, fexofenadine, bromfeniramine and evastine have turned out to be superior to loratadine 
as for effectiveness according to published studies and they are not DESCRIBED SO MANY 
ADVERSE EFFECTS. 
10.) The loratadina she has effects on the CENTRAL an PERIFERIC nervous system: somnolence, 
blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia, tremor and vertigo. 
11.) These 110 adverse effects were not INVENTED, and they were reported in patients that were 
taking the product. The FDA forces the LABORATORIES to place them in the packing of the 
product from 1.996. 

The FINAL objective of this revision is to ALERT all THE DOCTORS that ALL THE 
MEDICINES can PRODUCE ADVERSE EFFECTS, there are not PERFECT PRODUCTS 

And THE LORATADINE belongs one to them... 

In the references the facts... 

Greetings to all 

Dr. Jose Lapenta R. 
================================================================== 
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
================================================================== 
1.) THE 110 ADVERSE EFFECTS OF THE LORATADINE / ENGLISH 
1.) LOS 110 EFECTOS ADVERSOS DE LA LORATADINA / SPANISH 
2.) PEDIATRIC USE OF THE LORATADINE / ENGLISH 
2.) USO PEDIATRICO DE LA LORATADINA / SPANISH 
3.) LORATADINE, EXECUTIVE SUMMARY FDA REPORT 
4.) Loratadine toxicity. 
5.) Double-blind comparison of cetirizine and loratadine in children ages 2 to 6 years with perennial 
allergic rhinitis. 
6.) Clinical pharmacology of the H1-receptor antagonists cetirizine and loratadine in children. 
7.) Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. 
8.) Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child: 
what are the options? 
9.) The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children 
aged 2 to 5 years. 
10.) Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, and placebo in 
the treatment of seasonal allergic rhinitis. The Ebastine Study Group. 
11.) Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 
120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic 
rhinitis. 
12.) Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: effects after 
controlled ragweed pollen challenge in an environmental exposure unit. 
13.) Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative 
clinical trial. 
14.) Evaluation of the potential cardiotoxicity of the antihistamines terfenadine, astemizole, loratadine, 
and cetirizine in atopic children. 
15.) Onset of action and efficacy of terfenadine, astemizole, cetirizine, and loratadine for the relief of 
symptoms of 
16.) Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine, 
loratadine, and placebo for seasonal allergic rhinitis. 
17.) [Severe adverse effect of the anti-allergy drug loratadine--warning against prolonged use of 
non-prescription drugs]. 
18.) Loratadine (SCH29851) 40 mg once daily versus terfenadine 60 mg twice daily in the treatment 
of seasonal allergic rhinitis. 
19.) Suppression of histamine-induced wheal response by loratadine SCH 29851) over 28 days in 
man. 
19.) FEXOFENADINE, FDA SUMMARY REPORT 
20.) CETIRIZINE, FDA SUMMARY REPORT 
21.) loratadine in childrens with skin alergic diseases. 
============================================================= 
============================================================= 
1.) THE 110 ADVERSE EFFECTS OF THE LORATADINE /ENGLISH 
============================================================= 
Sources: 
1.) The Mosby year book 1996. 
2.) Information given by the laboratory inside the box(1999-2000) 

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 

1.) Headache. 
2.) Somnolence. 
3.) Fatigue. 
4.) Dry Mouth. 

Adverse events reported in placebo-controlled chronic idiopathic urticaria trials were 
similar to those reported in allergic rhinítis studies. 


ADVERSE EVENTS OCCURRINg WITH A FREOUENCY OF =2 > 2% IN LORATADINE 
SYRUP-TREATED PATIENTS (6-12 YEARS 0LD IN LACEBO-CONTROLLED TRIAL 
AND MORE FHEOUENTLY THAN THE PLACEBO GROUP 

5.) Nervousness. 
6.) Wheezing. 
7.) Fatigue. 
8.) Hyperkinesia. 
9.) Abdominal Pain. 
10.) Conjunctivitis. 
11.) Dysphonia. 
12.) Malasise. 
13.) Upper Respirator Tract Infection. 

In addition to those adverse events the folloving adverse events nave been reported in loratadine 
clinical trials in adult and padiatric palients: 

AUTONOMIC NERVOUS SYSTEM: 

14.) alterad lacrimation. 
15.) alterad salivation. 
16.) flushing. 
17.) hypoesthesia. 
18.) impotence. 
19.) Increased sweating 
20.) thirst. 

BODY AS A WHOLE: 

21.) angioneutotic edema. 
22.) asthenia. 
23.) back pain. 
24.) blurred vision. 
25.) chest pain. 
26.) earache. 
27.) eye pain. 
28.) fever. 
29.) leg cramps. 
30.) malaise. 
31.) rigors. 
32.) tinnitus. 
33.) viral infection. 
34.) weight gain. 

CARDIOVASCULAR SYSTEM: 

35.) hypertension 
36.) hypotension. 
37.) palpitations. 
38.) supraventricular tachyarrhythmias. 
39.) syncope. 
40.) tachycardia. 

CENTRAL AND PERIPHERAL NERVOUS SYSTEM: 

41.) blepharospasm. 
42.) dizziness. 
43.) dysphonia 
44.) hypertonia 
45.) migraine. 
46.) paresthesia. 
47.) tremor. 
48.) vertigo. 

GASTROINTESTINAL SYSTEM: 

49.) alterad taste. 
50.) anorexia. 
51.) constipation 
52.) diarrhea 
53.) dyspepsia. 
54.) flatulence. 
55.) gastritis. 
56.) hiccup. 
57.)increased appetite. 
58.) nausea. 
59.) stomatitis. 
60.) toothache. 
61.) vomiting. 

MUSCULOSKELETAL SYSTEM: 

62.) arthralgia 
63.) myalgia. 

PSYCHIATRICS: 

64.) agitation 
65.) amnesia. 
66.) anxiety. 
67.) confusion. 
68.) decreased libido. 
69.) depression. 
70.) impaired concentration. 
71.) insomnia. 
72.) irritability. 
73.) paroniria. 

REPRODUCTIVE SYSTEM: 

74.) Breast pain. 
75.) dysmenorrhea. 
76.) menorrhagia. 
77.) vaginitis. 

RESPIRATORY SYSTEM: 

78.) bronchitis. 
79.) bronchospasm. 
80.) coughinq. 
81.) dyspnea. 
82.) epistaxis. 
83.) hemoptisis. 
84.) laryngitis. 
85.) nasal dryness. 
86.) pharyngitis. 
87.) sinusitis. 
88.) sneezing. 

SKIN AND APPENDAGES: 

89.) dermatitis. 
90.) dry hair. 
91.) dry skin. 
92.) photosensitivity reaction. 
93.) pruritus. 
94.) purpura. 
95.) rash. 
96.) urticaria. 

URINARY SYSTEM: 

97.) altered micturition. 
98.) urinary discoloration. 
99.) urirary incontinence. 
100.) urinary retention. 

Ir addilion, Ihe following spontaneous adverse avents have been reported rarely during file marketing 
of loratadine: 
(not reported percentages) 

101.) abnormal hepatic function. 
102.) jaundice. 
103.) hepatitis. 
104.) hepatic necrosis 

OTHERS: 

105.) alopecia. 
106.) anaphylaxis. 
107.) breast enlargement. 
108.) erythema multiforme. 
109.) peripheral edema. 
110.) seizures. 

ADVERSE EFFECTS IN CHILDRENS BETWEEN 2-5 YEARS OLD 
--------------------------- 

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: 

1.) diarrhea. 
2.) epistaxis. 
3.) pharyngitis. 
4.) influenza-like symptoms. 
5.) fatigue. 
6.) stomatitis. 
7.) tooth disorder. 
8.) earache. 
9.) viral infection. 
10.)rash. 


============================================================ 
1.) LOS 110 EFECTOS ADVERSOS DE LA LORATADINA / SPANISH 
============================================================ 
Fuentes: 
1.) THe Mosby Year Book. (1996) 
2.) Informacion suministrada por el fabricante dentro de las cajas del producto (1.999 - 2001) 

EFECTOS ADVERSOS REPORTADOS CON UNA INCIDENCIA MAYOR AL 2% EN 
ESTUDIOS PLACEBO-CONTROL SOBRE RINITIS ALERGICA EN PACIENTES DE 12 
AÑOS DE EDAD Y MAYORES. 

1.) Dolor de Cabeza. 
2.) Somnolencia 
3.) Fatiga. 
4.) Sequedad bucal. 

Estos efectos adversos fueron similares en el grupo de Urticaria cronica tratados con loratadina. 


EFECTOS ADVERSOS PRESENTADOS CON INCIDENCIA DE 2% O MAYOR EN 
PACIENTES ENTRE 6 Y 12 AÑOS DE EDAD, ESTUDIOS PLACEBO-CONTROL, CON 
JARABE DE LORATADINA, ( MAS FRECUENTEMENTE PRESENTADOS QUE EN EL 
GRUPO PLACEBO) 


5.) Nerviosismo. 
6.) Fatiga. 
7.) Jadeos. 
8.) Hiperquinesia. 
9.) Dolor Abdominal. 
10.) Conjuntivitis. 
11.) Disfonia. 
12.) Malestar 
13.) Infeccion del tracto respiratorio superior. 

Otros efectos adversos presentados en estudios de pacientes adultos y niños con el uso de la 
loratadina: 

SISTEMA NERVIOSO AUTONOMO: 

14.) Alteracion lacrimal. 
15.) Salivacion Alterada. 
16.) Flushing. 
17.) Hipoestesia. 
18.) Impotencia. 
19.) Incremento de la Sudoracion 
20.) sed 

CUERPO como TOTALIDAD: 

21.) Edema angioneurotico. 
22.) Astenia. 
23.) Dolor de espalda. 
24.) Vision Borrosa. 
25.) Dolor en el pecho. 
26.) Dolor de oidos. 
27.) Dolor Ocular. 
28.) Fiebre. 
29.) Calambre en las piernas. 
30.) Malestar general. 
31.) Rigores. 
32.) Tinitus. 
33.) Infeccion Viral. 
34.) Aumento de peso. 

SISTEMA CARDIOVASCULAR: 

35.) Hipertension. 
36.) Hipotension. 
37.) Palpitaciones. 
38.) Taquiarritmias supraventriculares. 
39.) Sincope. 
40.) Taquicardia. 

SISTEMA NERVIOSO CENTRAL Y PERIFERICO: 

41.) Blefarospasmo. 
42.) Vahidos. 
43.) Disfonia. 
44.) Hipertonia. 
45.) Migraña. 
46.) Parestesia. 
47.) Tremor. 
48.) Vertigo. 

SISTEMA GASTROINTESTINAL: 

49.) Alteracion del gusto. 
50.) Anorexia. 
51.) Constipacion. 
52.) Diarrea. 
53.) Dispepsia. 
54.) Flatulencia. 
55.) Gastritis. 
56.) Hipo. 
57.) Aumento del apetito. 
58.) Nauseas. 
59.) Estomatitis. 
60.) Dolor en los dientes. 
61.) Vomitos. 

SISTEMA MUSCULO-ESQUELETICO: 

62.) Artralgia. 
63.) Milgia. 

PSIQUIATRICOS: 

64.) Agitacion. 
65.) Amnesia. 
66.) Ansiedad. 
67.) Confusion. 
68.) Disminucion de la libido. 
69.) Depresion. 
70.) Disminucion de la concentracion. 
71.) Imsonio. 
72.) Irritabilidad. 
73.) Paroniria. 

SISTEMA REPRODUCTIVO: 

74.) Dolor en las mamas. 
75.) Dismenorrea. 
76.) Menorragia. 
77.) Vaginitis. 

SISTEMA RESPIRATORIO: 

78.) Bronquitis. 
79.) Broncoespasmo. 
80.) tos. 
81.) Disnea. 
82.) Epistaxis. 
83.) Hemoptisis. 
84.) Laringitis. 
85.) Sequedad nasal. 
86.) Faringitis. 
87.) Sinusitis. 
88.) Estornudos. 

PIEL Y APENDICES: 

89.) Dermatitis. 
90.) Cabello seco. 
91.) Piel seca. 
92.) Reaccion de fotosensibilidad. 
93.) Prurito. 
94.) Purpura. 
95.) Rash. 
96.) Urticaria. 

SISTEMA URINARIO: 

97. Alteracion en la miccion. 
98.) Decoloracion de la orina. 
99.) Incontinencia urinaria. 
100.) Retencion de orina. 

En adicion, los siguientes efectos adversos espontaneos han sido reportados raramente (no se 
reportan porcentajes) con el uso de loratadina: 

101.) Funcion hepatica anormal. 
102.) Ictericia. 
103.) Hepatitis. 
104.) Necrosis Hepatica. 

OTROS: 

105.) Alopecia. 
106.) Anafilaxia. 
107.) Agrandamiento de las mamas. 
108.) Eritema multiforme. 
109.) Edema periferico. 
110.) Convulsiones. 

EFECTOS ADVERSOS EN NIÑOS DE 2 A 5 AñOS DE EDAD: 

66 pacientes pediatricos entre 2 y 5 años de edad recibieron 5 mgrs de loratadina 1 vez al dia en un 
estudio placebo-control, doble ciego durante 14 dias, no se encontraron efectos adversos 
inesperados en el perfil de seguridad de la loratadina. Las reacciones adversas mas comunmente 
encontradas mas que el el grupo placebo en el 2-3 % de los pacientes fueron: 

1.) Diarrea. 
2.) Epistaxis. 
3.) Faringitis. 
4.) Influenza-like sintomas. 
5.) Fatiga. 
6.) Estomatitis. 
7.) Desordenes dentales. 
8.) Dolor de oidos. 
9.) Infeciones virales. 
10.) Rash. 


============================================================= 
2.) PEDIATRIC USE OF THE LORATADINE / ENGLISH 
============================================================= 
Source: 
1.) Information given by the laboratory inside the box. (2.000) 

Pediatric Use: 

The satety of LORATADINE 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 effectiveness of 
LORATADIN for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria in this 
pediatric age group is based on an extrapolation of the demonstrated efficacy of LORATADINE in 
adults in these conditions and the likelihood that the disease course, pathophysiology and the drug's 
effect are substantially similar to that on the adults. The recommended dose for the pediatric 
population is based on cross study comparison of the pharmacokinetics of LORATADINE 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 LORATADIN in pediatric patients under 2 years of age nave not 
been established. 

============================================================= 
2.) USO PEDIATRICO DE LA LORATADINA / SPANISH 
============================================================= 
Fuente: 
1.) Informacion suministrada por uno de los fabricantes dentro de la caja. (2.000) 

Uso pediatrico: 

La seguridad del Jarabe de LORATADINA a una dosis de 10 mgrs ha side demostrada en 188 
pacientes pediatricos entre 6 y 12 años de edad en estudios placebo control de 2 semanas de 
duracion. La efectividad de la LORATADINA para el tratamiento de la rinotis alergica estacional y 
urticaria idiopatica cronica en este grupo de edad pediatrico esta basado en una extrapolacion de la 
eficacia demostrada de la LORATADINA en adultos en estas condiciones y la probabilidad que el 
curso de la enfermedad, 
fisiopatologia, y efecto de la droga es similar que en el adulto. La dosis recomendada para la 
poblacion pediatrica esta basada en un estudio cruzado comparativo de la farmacoquinetica de la 
LORATADINA en adultos y niños y en el perfil de seguridad en ambos grupos, adultos y niños a 
dosis iguales o superiores que las recomendadas 

La seguridad y efectividad de la LORATADINA en pacientes pediatricos por debajo de 2 años no 
ha sido aun establecida. 

============================================================= 
3.) LORATADINE, FDA REPORT 
============================================================= 
Source: The FDA 

EXECUTIVE SUMMARY 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

============================================================= 
4.) Loratadine toxicity. 
============================================================= 
Am J Emerg Med 2000 Sep;18(5):639-40 

Gokel Y, Satar S, Sebe A. 

Publication Types: 
Letter 
============================================================= 
============================================================= 
5.) Double-blind comparison of cetirizine and loratadine in children ages 2 to 6 years with perennial 
allergic rhinitis. 
============================================================= 
Am J Ther 1999 May;6(3):149-55 

Sienra-Monge JJ, Gazca-Aguilar A, Del Rio-Navarro B. 

Pulmonology and Allergy Department, Hospital Infantil de Mexico Federico Gomez, Mexico. 

Antihistamines are the pharmacologic cornerstone of treatment for allergic rhinitis. The comparative 
effects of the newer, more specific H (1) -antagonists cetirizine and loratadine among younger 
patients are not well characterized. The efficacy and safety of cetirizine and loratadine were 
compared in a prospective, randomized, double-blind, longitudinal, parallel-group study of 80 
children, 2 to 6 years of age, with perennial allergic rhinitis caused by house dust mites or plant 
pollens (verified by a radioallergosorbent or skin test). Patients received cetirizine or loratadine at 
0.2 mg/kg once daily in the morning for 28 days. Histamine skin tests and eosinophil counts from 
nasal smears were performed at baseline and at the end of treatment. Individual rhinitis symptoms 
were assessed by the investigator at baseline and on day 28 and by parents at baseline and daily in 
symptom diaries. Global assessments were made by using a visual analog scale at baseline and at the 
end of treatment. Cetirizine produced significantly greater inhibition of the wheal response compared 
with loratadine (P <.0001). Eosinophil counts were improved to a comparable degree with both 
agents. Cetirizine and loratadine produced comparable improvements in symptoms and according to 
a global evaluation as assessed by the investigator at the end of treatment. Both agents produced 
substantial symptomatic relief according to patients' daily diary assessments; however, cetirizine was 
more effective than loratadine in relieving the symptoms of rhinorrhea, sneezing, nasal obstruction, 
and nasal pruritus (P <. 0001). Both treatments were well tolerated; two patients receiving cetirizine 
were dropped from the study because of adverse events. Cetirizine and loratadine provided 
effective, well-tolerated relief of the symptoms of perennial allergic rhinitis in small children. Cetirizine 
was more effective than loratadine in inhibiting the wheal response to histamine challenge and 
afforded greater reductions in most individual symptoms assessed daily by the parent. 

============================================================= 
6.) Clinical pharmacology of the H1-receptor antagonists cetirizine and loratadine in children. 
============================================================= 
Pediatr Allergy Immunol 2000 May;11(2):116-9 

Simons FE, Johnston L, Simons KJ. 

Health Sciences Clinical Research Center, Faculty of Medicine, University of Manitoba, Winnipeg, 
Canada. 

H1-receptor antagonists are widely used in children but are not as well-studied in children as they 
are in adults. Our objective was to determine the onset and duration of action and the relative 
potency of the H1-receptor antagonists cetirizine and loratadine in children. We performed a 
prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of 
cetirizine and loratadine using suppression of the histamine-induced wheal and flare as the primary 
outcome. In 15 allergic children, mean age 9 years, compared with baseline, cetirizine (10 mg) 
suppressed the wheals and flares significantly from 0.25 to 24 h, achieving nearly 100% of flare 
suppression from 2 to 24 h, inclusive, and loratadine (10 mg) suppressed the wheals and flares 
significantly from 0.75 to 24 h, inclusive. Cetirizine suppressed the wheals and flares significantly 
more than loratadine from 0.25 to 1 h, inclusive, and at 0.5, 1, 2, 3, 5, 6, 7, and 24 h, respectively. 
Placebo also suppressed the wheal and flare significantly at some assessment times. Cetirizine and 
loratadine both have excellent antihistaminic activity in children, with a rapid onset of action and a 
24-h duration of action in this population. 

============================================================= 
7.) Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. 
============================================================= 
Br J Clin Pharmacol 1999 Mar;47(3):307-13 

Comment in: 
Br J Clin Pharmacol. 2000 Apr;49(4):379-80 

de Abajo FJ, Rodriguez LA. 

Area de Farmacovigilancia, Centro Nacional de Farmacobiologia, Madrid, Spain. 

AIMS: To quantify and compare the incidence of ventricular arrhythniias associated with the use of 
five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The 
effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were 
also examined. METHODS: We carried out a cohort study with a nested case-control analysis using 
the UK-based General Practice Research database (GPRD). The study cohort included persons 
aged less than 80 years old who received their first prescription for any of the five study drugs 
between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% 
confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as 
compared with non use. RESULTS: The study cohort included 197425 persons who received 
513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias 
were detected. Nine occurred during the current use of any antihistamine, resulting in a crude 
incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 
1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 
95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range 
of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular 
arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines 
(RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with 
P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study 
period with no single case of ventricular arrhythmias occurring in the presence of these two risk 
factors. CONCLUSIONS: The use of nonsedating antihistamines increases the risk of ventricular 
arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low 
requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk 
associated with terfenadine was no different from that with other nonsedating antihistamines. 

============================================================= 
8.) Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child: 
what are the options? 
============================================================= 
BioDrugs 2001;15(7):453-63 


Galant SP, Wilkinson R. 

Department of Paediatric Allergy/Immunology, University of California, Irvine, California, USA. 

Allergic rhinitis (AR) is the most common chronic condition in children and is estimated to affect up 
to 40% of all children. It is usually diagnosed by the age of 6 years. The major impact in children is 
due to co-morbidity of sinusitis, otitis media with effusion, and bronchial asthma. AR also has 
profound effects on school absenteeism, performance and quality of life. Pharmacotherapy for AR 
should be based on the severity and duration of signs and symptoms. For mild, intermittent 
symptoms lasting a few hours to a few days, an oral second-generation antihistamine should be used 
on an as-needed basis. This is preferable to a less expensive first-generation antihistamine because of 
the effect of the latter on sedation and cognition. Four second-generation antihistamines are currently 
available for children under 12 years of age: cetirizine, loratadine, fexofenadine and azelastine nasal 
spray; each has been found to be well tolerated and effective. There are no clearcut advantages to 
distinguish these antihistamines, although for children under 5 years of age, only cetirizine and 
loratadine are approved. Other agents include pseudoephedrine, an oral vasoconstrictor, for nasal 
congestion, and the anticholinergic nasal spray ipratropium bromide for rhinorrhoea. Sodium 
cromoglycate, a mast cell stabiliser nasal spray, may also be useful in this population. For patients 
with more persistent, severe symptoms, intranasal corticosteroids are indicated, although one might 
consider azelastine nasal spray, which has anti- inflammatory activity in addition to its antihistamine 
effect. With the exception of fluticasone propionate for children aged 4 years and older, and 
mometasone furoate for those aged 3 years and older, the other intranasal corticosteroids including 
beclomethasone dipropionate, triamcinolone, flunisolide and budesonide are approved for children 
aged 6 years and older. All are effective, so a major consideration would be cost and safety. For 
short term therapy of 1 to 2 months, the first-generation intranasal corticosteroids (beclomethasone 
dipropionate, triamcinolone, budesonide and flunisolide) could be used, and mometasone furoate 
and fluticasone propionate could be considered for longer-term treatment. Although somewhat more 
costly, these second-generation drugs have lower bioavailability and thus would have a better safety 
profile. In patients not responding to the above programme or who require continuous medication, 
identification of specific triggers by an allergist can allow for specific avoidance measures and/or 
immunotherapy to decrease the allergic component and increase the effectiveness of the 
pharmacological regimen. 

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

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

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

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

============================================================= 
10.) Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, and placebo in 
the treatment of seasonal allergic rhinitis. The Ebastine Study Group. 
============================================================= 
J Allergy Clin Immunol 2000 Jun;105(6 Pt 1):1101-7 

Ratner PH, Lim JC, Georges GC. 

Sylvana Research, San Antonio, TX, USA. 

BACKGROUND: Ebastine and loratadine are 2 nonsedating second-generation H(1) antihistamines 
with once-daily dosing. OBJECTIVE: We compared the efficacy and safety of ebastine 20 mg and 
10 mg, loratadine 10 mg, and placebo administered once daily for 4 weeks in controlling the 
symptoms of seasonal allergic rhinitis (SAR). METHODS: In a double-blind, placebo-controlled, 
randomized, parallel-group study, 565 patients with ragweed SAR, ages 12 to 70 years, received 
either ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, or placebo once daily for 4 weeks. 
Patients recorded morning and evening reflective scores (past 12 hours) as well as snapshot scores 
(at time of recording) for nasal discharge, congestion, sneezing, itching, and total eye symptoms. 
Total symptom score (TSS) is the sum of these 5 scores. RESULTS: Ebastine 20 mg produced 
significantly greater (P <.05) reductions from baseline compared with loratadine 10 mg over the 
entire treatment period in the mean daily reflective (42.5% vs 36.3%) and mean morning snapshot 
(40.3% vs 31.3%) TSS. The overall improvement in daily reflective and morning snapshot TSS was 
comparable between ebastine 10 mg and loratadine 10 mg and significantly better than placebo (P 
<.05). The total percent of patients with adverse events was similar among all 4 treatment groups (P 
=.78). CONCLUSION: Ebastine 20 mg given once daily was significantly superior to loratadine 10 
mg given once daily at improving the rhinitis total symptom score throughout the day and at 
awakening over a 4-week period. Ebastine 20 mg and 10 mg doses were both efficacious and well 
tolerated in the treatment of SAR. 

============================================================= 
11.) Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 
120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic 
rhinitis. 
============================================================= 
Clin Exp Allergy 2000 Jun;30(6):891-9 

Van Cauwenberge P, Juniper EF. 

Department of Otorhinolaryngology, University Hospital, Ghent, Belgium. 
[email protected] 

BACKGROUND: As there have been no previously published studies, this multinational, 
double-blind, randomized, placebo-controlled, parallel group study compared the efficacy, safety 
and impact on quality of life (QoL) in seasonal allergic rhinitis patients (SAR) of fexofenadine and 
loratadine (with placebo), when administered once daily. METHODS: Six hundred and eighty-eight 
SAR patients were randomized to receive fexofenadine HCl 120 mg, loratadine 10 mg or placebo, 
once daily for 2 weeks. The key parameters were the change from baseline in: mean 24-h reflective 
total symptom scores (TSS); sum of four individual symptom scores, excluding nasal congestion; 
instantaneous TSS; individual symptom scores including nasal congestion; and Rhinoconjunctivitis 
Quality of Life Questionnaire (RQLQ). Adverse events were recorded. RESULTS: Mean 24-h 
reflective and instantaneous TSS were significantly reduced by both fexofenadine HCl (both P </= 
0.0001) and loratadine (P </= 0.001 and P </= 0.005, respectively) compared with placebo (n = 
639). Among individual symptom scores, fexofenadine HCl was significantly better than loratadine in 
improving 24-h reflective itchy, watery, red eyes, as well as relieving nasal congestion (P </= 0.05 
for both). Fexofenadine HCl was also significantly better than loratadine (P </= 0.03) and placebo 
(P </= 0.005) in improving QoL, and the differences were of a magnitude considered to be clinically 
relevant. Loratadine had no statistically significant effect on QoL compared with placebo. The 
incidence of adverse events was low and similar across all treatment groups. CONCLUSION: 
Fexofenadine HCl and loratadine administered once daily are effective and well tolerated in SAR. In 
this study, fexofenadine HCl was significantly more effective than loratadine in relieving eye 
symptoms and nasal congestion. Furthermore, fexofenadine was significantly better than loratadine in 
improving QoL. 

============================================================= 
12.) Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: effects after 
controlled ragweed pollen challenge in an environmental exposure unit. 
============================================================= 
J Allergy Clin Immunol 1998 May;101(5):638-45 

Comment in: 
J Allergy Clin Immunol. 1999 Apr;103(4):715 

Day JH, Briscoe M, Widlitz MD. 

Department of Medicine, Queens University, Kingston, Ontario, Canada. 

BACKGROUND: Allergic rhinitis affects nearly one in 10 Americans. Cetirizine is a newer 
once-daily selective H1-antagonist. In traditional clinical trials, cetirizine has been shown to be safe 
and effective for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic 
urticaria. OBJECTIVE: To better characterize the efficacy and onset of action of cetirizine in a more 
controlled but clinically relevant setting, this agent was compared with loratadine and placebo in 
patients with symptomatic seasonal allergic rhinitis undergoing controlled pollen challenge in an 
environmental exposure unit (EEU). METHODS: This was a double-blind, randomized, 
parallel-group study. After screening, patients were exposed to ragweed pollen (primed) in the EEU 
(up to six exposures), and those with qualifying symptom scores were randomized to controlled 
pollen exposure (two periods of 5.5 to 6.5 hours over 2 days) and once-daily treatment with 10 mg 
cetirizine (n = 67), 10 mg loratadine (n = 67), or placebo (n = 68). The mean ragweed pollen level 
was 3480 +/- 350 grains/m3 (standard deviation). The primary efficacy variables were the total 
symptom complex (TSC) and the major symptom complex (MSC) scores. Symptoms were 
evaluated every half hour in the EEU throughout the study. RESULTS: Cetirizine produced a 36.7% 
mean reduction in TSC scores overall versus 15.4% with loratadine and 12.0% with placebo (p < or 
= 0.01). Cetirizine also produced a 37.4% mean reduction in MSC scores overall versus 14.7% 
with loratadine and 6.7% with placebo (p < or = 0.01). Onset of action as assessed by reductions in 
TSC and MSC scores versus placebo was evident within 1 hour with cetirizine (p < or = 0.02) and 
3 hours with loratadine (p < or = 0.03). The incidence of treatment-related side effects was similar 
among groups, with headache reported most commonly in each group. CONCLUSION: Cetirizine 
is well tolerated and effective in reducing symptoms of seasonal allergic rhinitis in patients undergoing 
controlled pollen challenge. 

============================================================= 
13.) Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative 
clinical trial. 
============================================================= 
J Clin Pharmacol 1998 Apr;38(4):382-9 

Druce HM, Thoden WR, Mure P, Furey SA, Lockhart EA, Xie T, Galant S, Prenner BM, 
Weinstein S, Ziering R, Brandon ML. 

Department of Clinical Research, Whitehall-Robins Healthcare, Madison, New Jersey 07940-0871, 
USA. 

A double-blind, randomized, placebo-controlled, parallel-group, multicenter study was conducted to 
compare the effectiveness of an extended-release formulation of a classical antihistamine, 
brompheniramine, and a second-generation compound, loratadine, in the treatment of allergic rhinitis. 
Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg twice daily (n = 112), 
loratadine 10 mg once daily (n = 112), or placebo twice daily (n = 114) for 7 days. Study 
medications were blinded using a double-dummy technique. Subjects completed an overall 
evaluation of symptom relief on a daily basis and returned on treatment days 3 and 7, at which times 
the investigator assessed symptom severity. The investigator and subject each completed a global 
efficacy evaluation, and subjects were interviewed regarding adverse experiences. The primary 
efficacy variable was the physicians' global efficacy evaluation on day 3. Symptoms also were 
analyzed as summed severity scores for all symptoms and for the nasal symptom cluster of 
rhinorrhea, sneezing, and nasal blockage. At all post-baseline evaluations (days 3, 7, and averaged 
over the two days), brompheniramine was significantly better than loratadine and placebo for both 
sets of summed symptom scores and all three global assessments. Loratadine was significantly better 
than placebo for physician ratings of total symptom severity averaged over the two days and for the 
physician and subject ratings of the nasal cluster on day 3. Central nervous system-related symptoms 
were the most frequently reported adverse experiences; somnolence was reported most frequently 
by patients taking brompheniramine, and its occurrence was less frequent as treatment continued. A 
nonprescription, extended-release formulation of brompheniramine 12 mg twice daily provided 
significantly better relief of symptomatic allergic rhinitis than loratadine 10 mg once daily. 

============================================================= 
14.) Evaluation of the potential cardiotoxicity of the antihistamines terfenadine, astemizole, loratadine, 
and cetirizine in atopic children. 
============================================================= 
Ann Allergy Asthma Immunol 1998 Apr;80(4):333-7 

Comment in: 
Ann Allergy Asthma Immunol. 1999 Nov;83(5):422 

Delgado LF, Pferferman A, Sole D, Naspitz CK. 

Department of Pediatrics, Paulista School of Medicine, Federal University of Sao Paulo, SP, Brazil. 

BACKGROUND: Adverse cardiac effects have been related to the use of H1-receptor antagonists 
terfenadine and astemizole. OBJECTIVE: We have investigated the cardiac effects of the 
H1-receptor antagonists terfenadine, astemizole, loratadine and cetirizine, used in recommended 
doses, concomitantly or not with the antibiotic erythromycin. METHODS: A group of 80 children 
aged 5 to 12 years was studied. All children had been diagnosed with perennial allergic rhinitis based 
on symptoms, clinical signs and a positive immediate skin test to Dermatophagoides pteronyssinus. 
The children had no personal history of cardiac disease or hepatic dysfunction, and they had a 
normal electrocardiogram (ECG) at the beginning of the study. Forty children had allergic rhinitis and 
sinusitis, and were assigned to subgroups of ten children who received terfenadine, astemizole, 
loratadine, or cetirizine, concomitantly with erythromycin, for 14 days. Erythromycin was started to 
treat presumed bacterial infection in children with complete radiologic opacification of the maxillary 
sinus(es). The remaining 40 children had no sinusitis, and were assigned to subgroups of 10 children 
who received terfenadine, astemizole, loratadine, or cetirizine for 14 days. RESULTS: No significant 
changes in the QT interval and QTc (QT corrected by Bazzett's equation) were observed among 
children who received astemizole, loratadine or cetirizine, with or without erythromycin. Children 
who have received terfenadine and erythromycin showed significantly prolonged QT interval (mean 
pretreatment and posttreatment values 0.32s and 0.34s, respectively). Analysis of the QTc interval, 
however, showed no significant differences in the group treated with terfenadine and erythromycin 
(mean values 0.39s and 0.39s, respectively). CONCLUSIONS: Our results show that H1-receptor 
antagonists terfenadine, astemizole, loratadine and cetirizine, administered with or without 
erythromycin, to atopic children in recommended doses, do not induce adverse cardiac effects. 
Although the association between terfenadine and erythromycin has caused a statistically significant 
increase in QT interval measurements, the magnitude of these changes was below levels considered 
cardiotoxic or clinically relevant. 

============================================================= 
15.) Onset of action and efficacy of terfenadine, astemizole, cetirizine, and loratadine for the relief of 
symptoms of 
============================================================= 
allergic rhinitis. 

Ann Allergy Asthma Immunol 1997 Aug;79(2):163-72 

Day JH, Briscoe MP, Clark RH, Ellis AK, Gervais P. 

Division of Allergy and Immunology, Kingston General Hospital, Ontario, Canada. 

BACKGROUND: Terfenadine, astemizole, cetirizine, and loratadine are compared in their abilities 
to produce relief of symptoms of allergic rhinitis. OBJECTIVE: The aim of this study was to 
compare the onset of action and efficacy of the study medications. METHODS: 111 
ragweed-sensitive subjects were primed with pollen in the Environmental Exposure Unit. Study entry 
required adequate symptoms over a 3 hour exposure to 5000 +/- 300 grains/m3 of ragweed pollen. 
On the test day, subjects were given a single dose of either terfenadine 60 mg (22), astemizole 10 
mg (22), cetirizine 10 mg (23), loratadine 10 mg (22), or placebo (22) when sufficiently symptomatic 
after a 60-minute exposure. Allergen levels were maintained and symptoms recorded every 30 
minutes. RESULTS: Proportions of subjects with clinically important relief were cetirizine, 69.6%; 
terfenadine, 54.5%; loratadine, 50.0%; astemizole, 40.9%; and placebo, 31.8% but differences 
weren't significant between treatment groups (P = .119). Survival curves for times to onset of 
clinically important relief for the four treatment groups were not different (P = .119). Subjects 
realizing definitive relief were cetirizine, 65.2%; terfenadine, 45.5%; loratadine, 31.8%; placebo, 
27.3%; and astemizole, 22.7% (P = .023). Survival analysis of onset time for definitive relief found 
significant differences (P = .010). The ranking was cetirizine --> terfenadine --> loratadine --> 
astemizole (quickest to slowest). Global evaluation based on subject willingness to take the 
medication again yielded percentages: cetirizine, 82.6%; terfenadine, 66.7%; astemizole, 63.6%; 
loratadine, 40.9%; and placebo, 36.4% (P = .036). CONCLUSION: Cetirizine and terfenadine 
continuously ranked higher in terms of onset of action and efficacy, while loratadine and astemizole 
ranked lower. Significance was detected in definitive relief and relative efficacy. 

============================================================= 
16.) Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine, 
loratadine, and placebo for seasonal allergic rhinitis. 
============================================================= 
J Allergy Clin Immunol 1996 Feb;97(2):617-26 

Meltzer EO, Weiler JM, Widlitz MD. 

Allergy and Asthma Medical Group and Research Center, San Diego, CA 92123, USA. 

BACKGROUND: Cetirizine, a new once-daily highly specific H1-antagonist, has been shown in 
conventional studies to be efficacious in the treatment of seasonal and perennial allergic rhinitis and 
chronic idiopathic urticaria. OBJECTIVE: The efficacy, duration and onset of action, and safety of 
cetirizine, 10 mg once daily, was compared with that of loratadine, 10 mg once daily, and placebo in 
a field study of patients with seasonal allergic rhinitis. METHODS: This was a randomized, 
double-blind, parallel, double-dummy study conducted over 2 days in spring allergy season at 
outdoor parks in San Diego and Iowa City. Study medication was administered at 10:00 AM on 
both days. After screening, eligible patients completed rhinitis symptom diaries in the park hourly 
from 7:30 to 9:30 AM (baseline); at 10:30 AM and hourly from 11:00 AM to 4:00 PM (period I); 
at 6:00, 8:00, and 10:00 PM at home (period II); and the next day in the park hourly from 8:00 to 
10:00 AM (period III), and from 11:00 AM to 4:00 PM (period IV). Major and total symptom 
complex scores, global efficacy and overall satisfaction, and adverse events were assessed. 
RESULTS: Of the 279 patients (140 men and 139 women; mean age, 29 years) randomized to 
treatment, 278 were included in the efficacy analysis. Cetirizine produced significantly greater mean 
reductions than loratadine or placebo in major symptom complex severity scores at all periods (p < 
or = 0.05), except period I for placebo. Cetirizine also produced mean reductions in total symptom 
complex severity scores that were superior to loratadine at every evaluation period (p < 0.05) and 
were statistically different from placebo at period II (p < 0.01). A rapid onset of action was 
observed with cetirizine, as was a better response pattern in the patient global assessment of efficacy 
compared with loratadine. Study medications were well tolerated; no patient stopped treatment 
because of side effects. The incidence of somnolence with cetirizine was 13% versus 2% with 
placebo (p < 0.05); headache occurred more frequently with loratadine (23%) than with cetirizine 
(11%, p = 0.03). CONCLUSIONS: Cetirizine relieved rhinitis symptoms more effectively and 
quickly than loratadine and placebo in this field study of seasonal allergic rhinitis. Both active agents 
were generally well tolerated. 

============================================================= 
17.) [Severe adverse effect of the anti-allergy drug loratadine--warning against prolonged use of 
non-prescription drugs]. 
============================================================= 
Lakartidningen 1992 Jun 17;89(25):2281 

[Article in Swedish] 

Nyman K, Bergman U. 

Lisebergs vardcentral, Alvsjo. 
============================================================= 
============================================================= 
18.) Loratadine (SCH29851) 40 mg once daily versus terfenadine 60 mg twice daily in the treatment 
of seasonal allergic rhinitis. 
============================================================= 
J Int Med Res 1987 Mar-Apr;15(2):63-70 

Bruttmann G, Pedrali P. 

Seventy patients received loratadine 40 mg once daily, terfenadine 60 mg twice daily, or placebo in 
a 14-day, double-blind, randomized study. Four nasal and four non-nasal symptoms associated with 
allergic rhinitis were evaluated. At the endpoint (the last evaluable visit), the mean total scores of 
combined nasal and non-nasal symptoms decreased (improved) from the baseline by 51.8% and 
55.7% with loratadine and terfenadine, respectively, but increased (worsened) by 6.1% with 
placebo. There was a significant difference between both the loratadine and terfenadine treatment 
groups and the placebo group (P = 0.001) but not between the active medication groups (P = 
0.608). Overall therapeutic response was good or excellent in 14 of the 23 patients given loratadine, 
in 18 of the 24 given terfenadine and in none of the 23 given placebo. The difference between each 
active medication group and the placebo group was significant (P less than or equal to 0.01) but 
there was no significant difference between the two active treatment groups (P greater than 0.35). 
No loratadine patient had any adverse side-effects. Sedating effects occurred in one terfenadine 
patient, headache in one placebo patient and two terfenadine patients (one terfenadine patient with 
severe headache discontinued treatment), and dyspepsia in two placebo patients. No anti-cholinergic 
effects occurred in this study. Loratadine 40 mg once daily was effective and safe in the relief of 
symptoms of allergic rhinitis. 

============================================================= 
19.) Suppression of histamine-induced wheal response by loratadine SCH 29851) over 28 days in 
man. 
============================================================= 
Ann Allergy 1986 Oct;57(4):253-6 

Roman IJ, Kassem N, Gural RP, Herron J. 

Five groups of 12 healthy volunteers each received in double-blind, randomized fashion oral b.i.d. 
doses of 10, 20, or 40 mg loratadine, 12 mg chlorpheniramine maleate (CTM), or placebo for 28 
days. Histamine and saline were injected intradermally into opposite arms at baseline and at specified 
times following treatment on days 1, 3, 7, 14, 21, and 28. Notable suppression of adjusted wheal 
formation (histamine-induced minus saline-induced) occurred within two hours after the first dose of 
each active treatment on day 1. In general, throughout the treatment period, suppression of adjusted 
wheal formation by all doses of loratadine was significantly greater than by placebo. Suppression by 
10 mg loratadine was comparable to CTM, and 20 and 40 mg loratadine were significantly greater 
than CTM. Suppression of wheal formation by loratadine during the treatment period and during five 
days posttreatment were dose related. The continued effectiveness of loratadine throughout the 28 
days suggests that tolerance to loratadine did not develop in this study. Sedation occurred in 8 of 12 
subjects receiving CTM, 1 of 12 receiving 10 mg loratadine, and 1 of 12 receiving placebo. 

============================================================= 
19.) FEXOFENADINE, FDA SUMMARY REPORT 
============================================================= 
Source: The FDA 

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

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

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

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

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

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

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

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

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

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

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

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

============================================================= 
CETIRIZINE, FDA SUMMARY REPORT 
============================================================= 
Source: The FDA 

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

There are two approved formulations of cetirizine: 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

============================================================= 
21.) Loratadine in childrens with skin alergic diseases 
============================================================= 
Der Kinderarzt 20/12, 1818-1821(1989) 

Sitzmann, F.C, Neumann Y 
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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(107)  27/09/2.001 DR. JOSE LAPENTA R. 
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