Fármacos, medicamentos, prospectos.
Prospecto y ficha técnica de BISOPROLOL NORMON
Ficha Técnica:
1. NOMBRE DEL MEDICAMENTO


Bisoprolol NORMON 2,5 mg comprimidos recubiertos con película

2. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA


Bisoprolol NORMON 2,5 mg comprimidos recubiertos con película:
Cada comprimido contiene: Bisoprolol NORMON hemifumarato: 2,5 mg
Excipientes: Almidón de maíz: 30 mg

Para consultar la lista completa de excipientes, ver sección 6.1

3. FORMA FARMACÉUTICA


Comprimidos recubiertos con película, de color blanco o casi blanco, redondos y ranurados.
4. DATOS CLÍNICOS


4.1 Indicaciones terapéuticas


Tratamiento de la insuficiencia cardiaca crónica estable, con función ventricular sistólica izquierda
reducida junto con inhibidores de la ECA y diuréticos, y de manera opcional con glucósidos cardiacos. (Para más información, ver la sección 5.1,)

4.2 Posología y forma de administración


El tratamiento estándar de la insuficiencia cardiaca congestiva consiste en un inhibidor de la ECA (o un
bloqueante del receptor de angiotensina en caso de intolerancia a los inhibidores de la ECA), un beta-
bloqueante, diuréticos y cuando sea adecuado glucósidos cardiacos. Los pacientes deben estar estables
(no haber sufrido crisis agudas) cuando se inicia el tratamiento con Bisoprolol NORMON.

Es recomendable experiencia previa del médico en el manejo de casos de insuficiencia cardiaca crónica.
Puede ocurrir un empeoramiento transitorio de la insuficiencia cardiaca, hipotensión, o bradicardia
durante el periodo de valoración y después del mismo.Fase de ajuste de la dosis

El tratamiento de la insuficiencia cardiaca crónica estable con Bisoprolol NORMON requiere una fase de
valoración.
El tratamiento con Bisoprolol NORMON debe ser iniciado con un aumento gradual de la dosis de
acuerdo con los siguientes pasos:

- 1,25 mg una vez al día durante una semana, si se tolera bien aumentar a

- 2,5 mg una vez al día durante una semana más, si se tolera bien aumentar a

- 3,75 mg una vez al día durante una semana más, si se tolera bien aumentar a

- 5 mg una vez al día durante las próximas 4 semanas, si se tolera bien aumentar a

- 7,5 mg una vez al día durante las próximas 4 semanas, si se tolera bien aumentar a

- 10 mg una vez al día para la terapia de mantenimiento.

La dosis máxima recomendada es de 10 mg una vez al día.
Se recomienda una vigilancia cercana de los signos vitales (frecuencia cardiaca, presión arterial) y de los
síntomas de empeoramiento de la insuficiencia cardiaca durante la fase de valoración. Los síntomas
pueden aparecer el mismo día de inicio del tratamiento.
Modificación del tratamiento

Si la dosis máxima recomendada no se tolera bien, se puede plantear una reducción gradual de la dosis.


En casos de empeoramiento pasajero de la insuficiencia cardiaca, hipotensión o bradicardia, se
recomienda una reconsideración de la dosificación de la medicación concomitante. También puede ser
necesario disminuir temporalmente la dosis de BISOPROLOL NORMON o plantear su interrupción.
La reintroducción y/o ajuste del BISOPROLOL NORMON se debe tener en cuenta siempre cuando el
paciente esté estable de nuevo.Si se plantea la interrupción, se recomienda una disminución gradual de la dosis, porque una retirada
brusca puede producir un deterioro agudo del estado del paciente.
El tratamiento de la insuficiencia cardiaca crónica con BISOPROLOL NORMON es, generalmente, un
tratamiento a largo plazo.
Administración

Los comprimidos de BISOPROLOL NORMON deben administrarse por la mañana y pueden ser
ingeridos con alimentos. Deben tragarse con líquido y no se deben masticar.
Poblaciones especiales

Disfunción renal o hepática

No se dispone de datos farmacocinéticos de BISOPROLOL NORMON en pacientes con insuficiencia
cardiaca crónica y con función hepática o renal deteriorada. Por lo tanto, los ajustes de posología
graduales en estos pacientes deben efectuarse con mayor precaución.

Ancianos

No se necesita ajustar la dosis.
Niños

No existe experiencia pediátrica con BISOPROLOL NORMON, por lo que no se recomienda su
utilización en niños.

4.3 Contraindicaciones

BISOPROLOL NORMON está contraindicado en pacientes con insuficiencia cardíaca crónica con:

- insuficiencia cardiaca aguda o durante los episodios de descompensación de la insuficiencia cardiaca

que requieran de tratamiento inotrópico intravenoso,
- shock cardiogénico,

- bloqueo AV de segundo o tercer grado (sin marcapasos),- síndrome del nodo sinusal,

- bloqueo atrioventricular,

- bradicardia inferior a 60 latidos por minuto previa al inicio del tratamiento,

- hipotensión (presión arterial sistólica inferior a 100 mmHg),

- asma bronquial o enfermedad pulmonar crónica obstructiva graves,

- oclusión arterial periférica avanzada y síndrome de Raynaud,

- feocromocitoma no tratado (Ver sección 4.4.),

- acidosis metabólica,

- hipersensibilidad al BISOPROLOL NORMON o a alguno de los excipientes.

4.4 Advertencias y precauciones especiales de empleo


BISOPROLOL NORMON se utilizará con precaución en:

- broncoespasmo (asma bronquial, enfermedades respiratorias obstructivas),

- diabetes mellitus con amplias fluctuaciones de la glucemia, ya que pueden enmascararse los síntomas

de hipoglucemia,
- ayuno prolongado,

- tratamientos de desensibilización en curso,

- bloqueo AV de primer grado,

- angina de Prinzmetal,

- enfermedad arterial periférica oclusiva (las molestias pueden verse acentuadas especialmente al inicio

de la terapia),
- anestesia general.

En pacientes sometidos a anestesia general, los beta-bloqueantes reducen la incidencia de aparición de
arritmias e isquemia miocárdica durante la inducción anestésica, la intubación y el periodo post-
operatorio. Actualmente se recomienda mantener el tratamiento con beta-bloqueantes durante el periodo
perioperatorio. El anestesista debe estar debidamente informado del tratamiento con beta-bloqueantes
debido a la posibilidad de interacción con otros fármacos que pudiera producir bradiarritmias,
disminución de la taquicardia refleja y disminución de la capacidad para compensar pérdidas de sangre. Cuando se considere necesario suspender el tratamiento beta-bloqueante antes de la cirugía, se realizará
de forma gradual y completa antes de las 48 horas previas a la anestesia.No existe experiencia terapéutica con BISOPROLOL NORMON en el tratamiento de la insuficiencia
cardiaca en pacientes con las siguientes condiciones y enfermedades:

- diabetes mellitus insulino-dependiente (Tipo I),

- deterioro grave de la función renal

- deterioro grave de la función hepática

- miocardiopatía restrictiva.
- cardiopatías congénitas.
- valvulopatías con afección hemodinámica significativa.
- infarto de miocardio en los últimos 3 meses.

En general, no se recomienda la combinación de BISOPROLOL NORMON con antagonistas del calcio
del tipo verapamil o diltiazem, con antiarrítmicos de Clase I y con antihipertensivos de acción central,
para detalles ver sección 4.5.

En el asma bronquial o en otras enfermedades pulmonares obstructivas crónicas que pueden causar
sintomatología, deben administrarse broncodilatadores concomitantemente. Ocasionalmente puede
producirse un incremento de la resistencia en las vías respiratorias en pacientes con asma, por lo que la
dosis de los estimulantes puede tener que aumentarse. ?
2

Como con otros beta-bloqueantes, BISOPROLOL NORMON puede aumentar tanto la sensibilidad frente
a los alergenos, como la gravedad de las reacciones anafilácticas. El tratamiento con adrenalina no
siempre da el resultado terapéutico esperado.

En pacientes con psoriasis o con antecedentes de psoriasis, la administración de beta-bloqueantes (ej. BISOPROLOL NORMON) se realizará tras evaluar cuidadosamente su relación riesgo-beneficio.
La administración de BISOPROLOL NORMON a pacientes con feocromocitoma no se realizará hasta
haber instaurado previamente tratamiento alfa-bloqueante.
Durante el tratamiento con BISOPROLOL NORMON, los síntomas de tireotoxicosis pueden quedar
enmascarados.El inicio del tratamiento con BISOPROLOL NORMON precisa de monitorización regularmente. Para
detalles sobre la posología y la forma de administración, véase la sección 4.2.
Salvo indicación explícita contraria, la interrupción del tratamiento con BISOPROLOL NORMON no se
debe realizar de forma brusca. Para más información, véase la sección 4.2.
Información importante para los deportistas:

Se advierte a los deportistas que este medicamento contiene un componente que puede establecer un
resultado analítico de control de dopaje como positivo.
4.5 Interacción con otros medicamentos y otras formas de interacción


Combinaciones no recomendadas

Antagonistas del calcio tipo verapamil y, en menor medida, del tipo diltiazem: efectos negativos sobre la
contractilidad y la conducción auriculoventricular. La administración intravenosa de verapamil en
pacientes en tratamiento con beta-bloqueantes puede provocar una profunda hipotensión y bloqueo
auriculoventricular.
Fármacos antiarrítmicos Clase I (ej. quinidina, disopiramida, lidocaína, fenitoína, flecainida,
propafenona): Pueden potenciar los efectos sobre el tiempo de conducción auriculoventricular y aumentar
el efecto inotrópico negativo.
Fármacos antihipertensivos de acción central como la clonidina y otros (ej. metildopa, moxonodina,
rilmenidina): El uso concomitante de fármacos antihipertensivos de acción central puede empeorar el
fallo cardiaco al disminuir el tono simpático central (disminución de la frecuencia cardiaca y del gasto
cardiaco, vasodilatación). Su retirada brusca, especialmente si se ha interrumpido previamente el
betabloqueante, puede aumentar el riesgo de \"hipertensión de rebote\".

Combinaciones a usar con precaución

Antagonistas del calcio del tipo dihidropiridina como felodipino y amlodipino: no puede descartarse que
su utilización concomitante en pacientes con insuficiencia cardiaca pueda aumentar el riesgo de
hipotensión y de un posterior deterioro de la función de bomba ventricular.Antiarrítmicos de clase III (ej. amiodarona): Puede potenciarse el efecto sobre el tiempo de conducción
auriculoventricular.
Beta-bloqueantes tópicos (ej. gotas oculares para el tratamiento del glaucoma) pueden sumarse a los
efectos sistémicos de BISOPROLOL NORMON.
Parasimpaticomiméticos: su utilización concomitante puede aumentar el tiempo de conducción
auriculoventricular y el riesgo de bradicardia.
Insulina y antidiabéticos orales: Intensificación del efecto hipoglucemiante. El bloqueo de los receptores
beta-adrenérgicos puede enmascarar síntomas de hipoglucemia.
Agentes anestésicos: atenuación de la taquicardia refleja e incremento del riesgo de hipotensión (para más
información sobre anestesia general ver también la sección 4.4.).
Glucósidos digitálicos: disminución de la frecuencia cardiaca, aumento del tiempo de conducción
auriculoventricular.
Fármacos antiinflamatorios no esteroideos (AINES): los AINES pueden reducir los efectos hipotensores
del BISOPROLOL NORMON.
Agentes ß-simpaticomiméticos (ej. Isoprenalina, dobutamina): Combinados con BISOPROLOL
NORMON, pueden reducir el efecto de las dos sustancias.

Simpaticomiméticos con efecto estimulante sobre receptores - y - adrenérgicos (ej. noradrenalina,
?
?
adrenalina): En combinación con BISOPROLOL NORMON pueden desenmascarar los efectos
vasoconstrictores mediados por receptores alfa-adrenérgicos producidos por estos fármacos con un
aumento de la presión arterial y exacerbación de la claudicación intermitente. Esta interacción es más
probable cuando se utilizan beta-bloqueantes no selectivos.

El uso concomitante con fármacos antihipertensivos y con fármacos con potencial efecto hipotensor (ej. antidepresivos tricíclicos, barbitúricos, fenotiazinas) puede aumentar el riesgo de hipotensión.

Combinaciones cuyo uso debe evaluarseMefloquina: riesgo incrementado de bradicardia.
Inhibidores de la monoaminooxidasa IMAO (excepto los inhibidores de la MAO B): aumento del efecto
hipotensor de los beta-bloqueantes pero también del riesgo de crisis hipertensivas.
4.6 Embarazo y lactancia


Embarazo

BISOPROLOL NORMON tiene ciertas acciones farmacológicas que pueden causar efectos perjudiciales
en el embarazo y/o feto/recién nacido. En general, los bloqueantes beta-adrenérgicos disminuyen la
perfusión placentaria, lo que se ha asociado con retraso en el crecimiento, muerte intrauterina, y aborto o
parto prematuro. En alguna ocasión pueden aparecer reacciones adversas (ej. hipoglucemia y bradicardia)
en el feto o en el recién nacido. Si el tratamiento con bloqueantes beta-adrenérgicos es indispensable,
entonces es preferible que sean bloqueantes adrenérgicos beta selectivos. 1
BISOPROLOL NORMON no debe administrarse durante el embarazo a no ser que sea estrictamente
necesario. Si se considera imprescindible seguir el tratamiento con BISOPROLOL NORMON, deberá
monitorizarse el flujo sanguíneo úteroplacental y el crecimiento fetal. Si se producen efectos perjudiciales
durante el embarazo o en el feto, debe considerarse la posibilidad de seguir un tratamiento alternativo. El
recién nacido deberá estar estrechamente monitorizado. Generalmente son de esperar síntomas de
hipoglucemia y bradicardia durante los primeros 3 días.
Lactancia

Se desconoce si este fármaco se excreta por la leche humana. Por ello, no se recomienda la lactancia
mientras se sigue tratamiento con BISOPROLOL NORMON.
4.7 Efectos sobre la capacidad para conducir y utilizar máquinas


En un estudio con BISOPROLOL NORMON en pacientes con enfermedad coronaria no se observaron
efectos negativos sobre la capacidad de conducción. No obstante, debido a la variedad de reacciones
individuales al fármaco, la capacidad para conducir o utilizar maquinaria puede verse afectada. Esto debe
tenerse en cuenta especialmente al inicio del tratamiento, y en los cambios de medicación, así como en
asociación con alcohol.4.8 Reacciones adversas


Las siguientes definiciones se aplican a la terminología de frecuencias utilizada a continuación:

Muy frecuentes ( 1/10)
?

Frecuentes ( 1/100, < 1/10)
?

Poco frecuentes ( 1/1,000, < 1/100)
?

Raras ( 1/10,000, < 1/1,000)
?

Muy raras (< 1/10,000)




Trastornos cardiacos:
Muy frecuentes: bradicardia,
Frecuentes: empeoramiento de la insuficiencia cardiaca. Poco frecuentes: alteraciones de la conducción AV.
Exploraciones complementarias:
Raras: Aumento de triglicéridos, aumento de enzimas hepáticas (ALAT, ASAT)

Trastornos del sistema nervioso:
Frecuentes: mareos, cefalea. Raros: síncope.
Trastornos oculares:
Raros: disminución de la producción de lágrimas (a tener en cuenta si el paciente utiliza lentes de
contacto). Muy raros: conjuntivitis.
Trastornos del oído y del laberinto:
Raros: deterioro de la audición.
Trastornos respiratorios, torácicos y mediastínicos:Poco frecuentes: broncoespasmo en pacientes con asma bronquial o historia de obstrucción de vías aéreas. Raros: rinitis alérgica.
Trastornos gastrointestinales:
Frecuentes: molestias gastrointestinales tales como nauseas, vómitos, diarrea, estreñimiento.
Trastornos de la piel y del tejido subcutáneo:
Raros: reacciones de hipersensibilidad (prurito, rubefacción, erupción cutánea). Muy raros: los beta-bloqueantes pueden causar o empeorar la psoriasis, o inducir reacciones similares a la
psoriasis, alopecia.
Trastornos musculoesqueléticos y del tejido conectivo:
Poco frecuentes: debilidad muscular y calambres.
Trastornos vasculares:
Frecuentes: sensación de frío o entumecimiento en las extremidades, hipotensión
Poco frecuentes: hipotensión ortostática.
Trastornos generales:
Frecuentes: astenia, fatiga

Trastornos hepatobiliares:
Raros: hepatitis.
Trastornos del aparato reproductor y de la mama:
Raros: trastornos de la potencia sexual.
Trastornos psiquiátricos:
Poco frecuentes: alteraciones del sueño, depresión
Raros: pesadillas, alucinaciones

4.9 SobredosisEn casos de sobredosis (ej. dosis diarias de 15 mg en lugar de 7,5 mg) se ha comunicado bloqueo AV de
tercer grado, bradicardia y mareo. En general, los síntomas esperados con mayor frecuencia en la
sobredosificación de beta-bloqueantes son bradicardia, hipotensión, broncoespasmo, insuficiencia
cardiaca aguda e hipoglucemia. Hasta la fecha se han comunicado únicamente algunos casos de
sobredosis (máximo 2000 mg) con BISOPROLOL NORMON en pacientes que sufren hipertensión y/o
enfermedad coronaria, apareciendo bradicardia y/o hipotensión, recuperándose todos los pacientes. Después de la administración de una dosis única elevada de BISOPROLOL NORMON, existe una gran
variabilidad interindividual y parece ser que los pacientes con insuficiencia cardíaca son probablemente
muy sensibles. Por lo tanto, es condición indispensable iniciar el tratamiento de estos pacientes de forma
gradual, de acuerdo con el esquema de la sección 4.2. Si se diera una sobredosis, se debería interrumpir el tratamiento con BISOPROLOL NORMON e
instaurar tratamiento sintomático y de apoyo. Los pocos datos disponibles indican que BISOPROLOL
NORMON es prácticamente no dializable. En base a los efectos farmacológicos esperados y a las
recomendaciones para otros beta-bloqueantes, se tomarán las siguientes medidas cuando se justifique
clínicamente

Bradicardia: administración intravenosa de atropina. Si la respuesta es inapropiada podrá utilizarse con
precaución isoprenalina o cualquier otro fármaco con actividad cronotrópica positiva. En algunos casos
puede ser necesaria la colocación de un marcapasos transvenoso.
Hipotensión: se administrarán líquidos intravenosos y vasopresores. Puede ser útil la administración de
glucagón intravenoso.
Bloqueo AV (segundo o tercer grado): Los pacientes deberán ser cuidadosamente monitorizados,
administrándoles isoprenalina en perfusión o mediante la colocación de un marcapaso transvenoso.
Empeoramiento agudo de la insuficiencia cardiaca: administración intravenosa de diuréticos, fármacos
inotrópicos y vasodilatadores.
Broncoespasmo: administrar tratamiento broncodilatador como isoprenalina, simpaticomiméticos y/o
?
2
aminofilina.
Hipoglucemia: administración de glucosa intravenosa.5. PROPIEDADES FARMACOLÓGICAS


5.1 Propiedades farmacodinámicas


Grupo farmacoterapéutico: agentes beta-bloqueantes selectivos. Clasificación ATC: C07AB07.
BISOPROLOL es un bloqueante de los receptores beta 1 adrenérgicos altamente selectivo, desprovisto de
actividad estimuladora y de efecto estabilizador de membrana relevante. Presenta una escasa afinidad por
los receptores beta 2 de la musculatura lisa bronquial y vascular, así como por los receptores beta 2
implicados en la regulación metabólica. Por ello no es de esperar que BISOPROLOL NORMON afecte a
las resistencias aéreas ni a los efectos metabólicos mediados por receptores beta 2. La selectividad beta 1
del BISOPROLOL NORMON se mantiene a dosis superiores de las terapéuticamente recomendadas.
En el estudio CIBIS II se incluyeron 2647 pacientes en total. El 83% (n=2202) pertenecían a la clase III
de la NYHA y un 17% (n=445) a la clase IV de la NYHA. Todos ellos sufrían insuficiencia cardiaca
sistólica estable y sintomática (fracción de eyección 35%, valorada mediante ecocardiografía). La
?
mortalidad total se redujo del 17,3% al 11,8% (reducción relativa 34%). Se observó una disminución en la
incidencia de muerte súbita (3,6 vs 6,3%, reducción relativa del 44%) y un número menor de episodios de
insuficiencia cardiaca que precisaron hospitalización (12% vs 17,6%, reducción relativa del 36%). Finalmente, se ha demostrado una mejora significativa del status funcional de acuerdo con la clasificación
NYHA. Durante el inicio y ajuste de dosificación del tratamiento con BISOPROLOL NORMON, se
observaron hospitalizaciones debido a bradicardia (0,53%), hipotensión (0,23%) y descompensación
aguda (4,97%) pero que no fueron más frecuentes que en el grupo placebo (0%, 0,3% y 6,74%). Durante
todo el estudio, el número de accidentes vasculares fatales e incapacitantes fue de 20 en el grupo tratado
con BISOPROLOL NORMON y 15 en el grupo placebo.
El estudio CIBIS III investigó a 1010 pacientes con edad 65 años y con insuficiencia cardiaca crónica
?
de leve a moderada (ICC; clasificación NYHA II o III) y fracción de eyección del ventrículo izquierdo
?
35%, que no habían sido tratados previamente con inhibidores ECA, beta-bloqueantes, o bloqueantes del
receptor de angiotensina. Los pacientes fueron tratados con una combinación de BISOPROLOL
NORMON y enalapril durante un periodo de 6 a 24 meses tras un tratamiento inicial de 6 meses con
BISOPROLOL NORMON o enalapril.Hubo una tendencia hacia una frecuencia más elevada de empeoramiento de la insuficiencia cardíaca
crónica cuando se utilizaba BISOPROLOL NORMON en el tratamiento inicial de 6 meses. La no
inferioridad de BISOPROLOL NORMON en primer lugar frente a enalapril en primer lugar no se
demostró en los análisis por protocolos, aunque las dos estrategias para el inicio del tratamiento de la
insuficiencia cardiaca congestiva mostraron un índice similar del punto final primario de muerte y
hospitalización combinadas al final del estudio (32,4% en el grupo de BISOPROLOL NORMON en
primer lugar frente a 33,1% en el grupo de enalaprilo en primer lugar). El estudio muestra que
BISOPROLOL NORMON puede utilizarse también en pacientes ancianos con insuficiencia cardiaca
crónica con enfermedad de leve a moderada.
BISOPROLOL NORMON se utiliza también para el tratamiento de la hipertensión y de la angina de
pecho.
Tras administración aguda en pacientes con enfermedad coronaria sin insuficiencia cardiaca crónica,
BISOPROLOL NORMON reduce la frecuencia cardiaca y el volumen latido, y por tanto el gasto
cardíaco y el consumo de oxígeno. En la administración crónica disminuyen las resistencias vasculares
periféricas que se ven aumentadas al inicio.
5.2 Propiedades farmacocinéticas


BISOPROLOL NORMON se absorbe y tiene una biodisponibilidad de un 90% tras administración oral. Aproximadamente un 30% de BISOPROLOL NORMON se halla unido a proteínas plasmáticas. El
volumen de distribución es de 3,5 l/kg. El aclaramiento total es de aproximadamente 15 l/h. La vida
media plasmática es de 10-12 horas, lo que proporciona un efecto de 24 horas tras dosis única diaria.
Bisoprolol NORMON se elimina por dos vías. El 50% se metaboliza en el hígado dando lugar a
metabolitos inactivos que serán eliminados por los riñones. El otro 50% se elimina por los riñones de
forma inalterada. Dado que la eliminación tiene lugar en la misma proporción en hígado y riñones, no se
requiere un ajuste de dosificación en pacientes con insuficiencia renal o función hepática deteriorada. No
se ha estudiado la farmacocinética en pacientes con insuficiencia cardiaca crónica estable y con función
hepática o renal deteriorada.
La cinética del Bisoprolol NORMON es lineal e independiente de la edad.Los niveles plasmáticos de Bisoprolol NORMON en pacientes con insuficiencia cardíaca crónica (NYHA
grado III) son mayores y la vida media se prolonga en comparación con los valores de los voluntarios
sanos. La concentración plasmática máxima en estado de equilibrio es de 64 ± 21 ng/ml a una dosis diaria
de 10 mg y la vida media de 17 ± 5 horas.
5.3 Datos preclínicos sobre seguridad


Los datos preclínicos muestran que no existe un peligro especial en humanos y se basan en los estudios
convencionales de seguridad, farmacología, toxicidad a dosis repetida, genotoxicidad o carcinogénesis. Al
igual que otros beta-bloqueantes, Bisoprolol NORMON administrado a altas dosis causó toxicidad
maternal (disminución de la ingesta de comida y reducción del peso corporal) y toxicidad embrio-fetal
(incidencia elevada de resorciones, peso al nacer disminuido, desarrollo físico retardado), pero no fue
teratogénico.
6. DATOS FARMACÉUTICOS


6.1 Lista de excipientes


Bisoprolol NORMON 2,5 mg comprimidos recubiertos con película
Núcleo: Celulosa microcristalina, almidón de maíz, croscarmelosa de sodio, sílice coloidal, hipromelosa,
estearato de magnesio y fosfato disódico anhidro. Recubrimiento: Hipromelosa, dióxido de titanio (E
171), macrogol 6000.
6.2 Incompatibilidades

No procede.
6.3 Periodo de validez

2 años.
6.4 Precauciones especiales de conservación

No conservar a temperatura superior a 25 °C.
6.5 Naturaleza y contenido del envase

Blister de PVC y aluminio. Bisoprolol NORMON 2,5 mg Comprimidos recubiertos con película se presenta en envases
conteniendo 28 y 100 (envase clínico) comprimidos.
6.6 Precauciones especiales de eliminaciónNinguna especial. La eliminación del medicamento no utilizado y de todos los materiales que hayan estado en contacto con
él, se realizará de acuerdo con la normativa local.
7. TITULAR DE LA AUTORIZACIÓN DE COMERCIALIZACIÓN

LABORATORIOS NORMON S.A. Ronda de Valdecarrizo, 6 ? 28760 Tres Cantos ? Madrid (ESPAÑA)


8. NÚMERO(S) DE AUTORIZACIÓN DE COMERCIALIZACIÓN


9. FECHA DE LA PRIMERA AUTORIZACIÓN/RENOVACIÓN DE LA AUTORIZACIÓN


Abril 2010
10. FECHA DE LA REVISIÓN DEL TEXTO
Prospecto:
SUMMARY OF PRODUCT CHARACTERISTICS1. NAME OF THE MEDICINAL PRODUCT

4 MG CHEWABLE TABLETS




2. QUALITATIVE AND QUANTITATIVE COMPOSITION

ONE CHEWABLE TABLET CONTAINS MONTELUKAST SODIUM, WHICH IS EQUIVALENT TO
4 MG MONTELUKAST. EXCIPIENT
: ASPARTAME (E 951) 1.2 MG PER TABLET. FOR A FULL LIST OF EXCIPIENTS, SEE SECTION 6.1.

3.
PHARMACEUTICAL FORM

CHEWABLE TABLET.
Pink, oval, bi-convex-shaped, engraved on one side and MSD 711 on the other.

4.
CLINICAL PARTICULARS

4.1
Therapeutic indications

is indicated in the treatment of asthma as add-on therapy in those 2 to 5 year old
patients with mild to moderate persistent asthma who are inadequately controlled on inhaled
corticosteroids and in whom ?as-needed? short acting -agonists provide inadequate clinical control of
?
asthma.
may also be an alternative treatment option to low-dose inhaled corticosteroids for 2 to
5 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks
that required oral corticosteroid use, and who have demonstrated that they are not capable of using
inhaled corticosteroids (see section 4.2).
is also indicated in the prophylaxis of asthma from 2 years of age and older in which
the predominant component is exercise-induced bronchoconstriction.
4.2
Posology and method of administration

This medicinal product is to be given to a child under adult supervision. For children who have problems
consuming a chewable tablet, a granule formulation is available (see 4 mg granule
SPC). The dosage for paediatric patients 2-5 years of age is one 4 mg chewable tablet daily to be taken in
the evening. If taken in connection with food, should be taken 1 hour before or 2 hours
after food. No dosage adjustment within this age group is necessary. The 4 mg
chewable tablet formulation is not recommended below 2 years of age.General recommendations. The therapeutic effect of on parameters of asthma control
occurs within one day. Patients should be advised to continue taking even if their
asthma is under control, as well as during periods of worsening asthma.
No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic
impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for
both male and female patients.
as an alternative treatment option to low-dose inhaled corticosteroids for mild,
persistent asthma
:
Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of
montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild
persistent asthma should only be considered for patients who do not have a recent history of serious
asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable
of using inhaled corticosteroids (see section 4.1). Mild persistent asthma is defined as asthma symptoms
more than once a week but less that once a day, nocturnal symptoms more than twice a month but less
than once a week, normal lung function between episodes. If satisfactory control of asthma is not
achieved at follow-up (usually within one month), the need for an additional or different anti-
inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should
be periodically evaluated for their asthma control.
as prophylaxis of asthma for 2 to 5 year old patients in whom the predominant
component is exercise-induced bronchoconstriction:
In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant manifestation of
persistent asthma that requires treatment with inhaled corticosteroids. Patients should be evaluated after 2
to 4 weeks of treatment with montelukast. If satisfactory response is not achieved, an additional or
different therapy should be considered.
Therapy with in relation to other treatments for asthma. When treatment with is used as add-on therapy to inhaled corticosteroids,
should not be abruptly substituted for inhaled corticosteroids (see section 4.4).
10 mg film-coated tablets are available for adults 15 years of age and older. 5 mg chewable tablets are available for paediatric patients 6 to 14 years of age. 4 mg granules are available for paediatric patients 6 months to 5 years of age.
4.3
Contraindications

Hypersensitivity to the active substance or to any of the excipients.


4.4
Special warnings and precautions for use

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their
usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-
acting inhaled -agonist should be used. Patients should seek their doctors? advice as soon as possible if
?
they need more inhalations of short-acting -agonists than usual. ?

Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given
concomitantly.
In rare cases, patients on therapy with anti-asthma agents including montelukast may present with
systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-
Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases
usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid
therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of
Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to
eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy
presenting in their patients. Patients who develop these symptoms should be reassessed and their
treatment regimens evaluated.
contains aspartame, a source of phenylalanine. Patients with phenylketonuria should
take into account that each 4 mg chewable tablet contains phenylalanine in an amount equivalent to
0.674 mg phenylalanine per dose.
4.5
Interactions with other medicinal products and other forms of interaction

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic
treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not
have clinically important effects on the pharmacokinetics of the following medicinal products:
theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1),
terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40%
in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4,
caution should be exercised, particularly in children, when montelukast is coadministered with inducers
of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.
In vitro
studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a
clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate
representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that montelukast
does not inhibit CYP 2C8
in vivo.
Therefore, montelukast is not anticipated to markedly alter the
metabolism of medicinal products metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and
repaglinide.)

4.6
Pregnancy and lactation

Use during pregnancy

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal
development.

Limited data from available pregnancy databases do not suggest a causal relationship between
and malformations (i.e. limb defects) that have been rarely reported in worldwide post
marketing experience.

may be used during pregnancy only if it is considered to be clearly essential.Use during lactation

Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is not known if
montelukast is excreted in human milk.
may be used in breast-feeding mothers only if it is considered to be clearly essential.
4.7
Effects on ability to drive and use machines

Montelukast is not expected to affect a patient?s ability to drive a car or operate machinery. However, in
very rare cases, individuals have reported drowsiness or dizziness.
4.8
Undesirable effects

Montelukast has been evaluated in clinical studies as follows:
ƒ

10 mg film-coated tablets in approximately 4000 adult patients 15 years of age and older
ƒ

5 mg chewable tablets in approximately 1750 paediatric patients 6 to 14 years of age, and
ƒ

4 mg chewable tablets in 851 paediatric patients 2 to 5 years of age.
The following drug-related adverse reactions in clinical studies were reported commonly ( 1/100 to
?
<1/10) in patients treated with montelukast and at a greater incidence than in patients treated with
placebo:

Body System Class

Adult Patients
15 years and older
(two 12-week studies;
n=795)

Paediatric Patients
6 to 14 years old
(one 8-week study;
n=201)
(two 56 week studies;
n=615)

Paediatric Patients
2 to 5 years old
(one 12-week study;
n=461)
(one 48-week study;
n=278)
Nervous system
disorders
Headache
headache
Gastrointestinal
disorders
abdominal pain

abdominal pain
General disorders and
administration site
conditions
thirst

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults,
and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change. Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least
3 months, 338 for 6 months or longer, and 534 patients for 12 months or longer. With prolonged
treatment, the safety profile did not change in these patients either.
The following adverse reactions have been reported in post-marketing use:
Blood and lymphatic system disorders:
increased bleeding tendency.Immune system disorders:
hypersensitivity reactions including anaphylaxis, hepatic eosinophilic
infiltration. Psychiatric disorders:
dream abnormalities including nightmares, hallucinations, insomnia, irritability,
anxiety, restlessness, agitation including aggressive behaviour, tremor, depression, suicidal thinking and
behaviour (suicidality) in very rare cases. Nervous system disorders:
dizziness drowsiness, paraesthesia/hypoesthesia, seizure. Cardiac disorders:
palpitations. Respiratory, thoracic and mediastinal disorders:
epistaxis. Gastrointestinal disorders:
diarrhoea, dry mouth, dyspepsia, nausea, vomiting.
Hepatobiliary disorders:
elevated levels of serum transaminases (ALT, AST), cholestatic hepatitis. Skin and subcutaneous tissue disorders:
angiooedema, bruising, urticaria, pruritus, rash, erythema
nodosum. Musculoskeletal and connective tissue disorders:
arthralgia, myalgia including muscle cramps. General disorders and administration site conditions:
asthenia/fatigue, malaise, oedema, pyrexia. Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in
asthmatic patients (see section 4.4).
4.9
Overdose

No specific information is available on the treatment of overdose with montelukast. In chronic asthma
studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and
in short term studies, up to 900 mg/day to patients for approximately one week without clinically
important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with
montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately
61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the
safety profile in adults and paediatric patients. There were no adverse experiences in the majority of
overdose reports. The most frequently occurring adverse experiences were consistent with the safety
profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and
psychomotor hyperactivity.
It is not known whether montelukast is dialyzable by peritoneal- or hemo-dialysis.

5.
PHARMACOLOGICAL PROPERTIES

5.1
Pharmacodynamic properties

Pharmacotherapeutic group:
Leukotriene receptor antagonist
ATC-code:
R03D C03

The cysteinyl leukotrienes (LTC , LTD , LTE ) are potent inflammatory eicosanoids released from
4
4
4
various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to
cysteinyl leukotriene receptors (CysLT) found in the human airway and cause airway actions, including
bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.

Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT
1
receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD at doses as low
4as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect
caused by a -agonist was additive to that caused by montelukast. Treatment with montelukast inhibited
?
both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with
placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study,
treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum). In
adult and paediatric patients 2 to 14 years of age, montelukast, compared with placebo, decreased
peripheral blood eosinophils while improving clinical asthma control.
In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant
improvements in morning FEV (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate
1
(PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total -agonist use
?
(-26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma
symptoms scores was significantly better than placebo.
Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled
corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclomethasone,
respectively for FEV : 5.43% vs 1.04%; -agonist use: -8.70% vs 2.64%). Compared with inhaled
1
?
beclomethasone (200 g twice daily with a spacer device), montelukast demonstrated a more rapid initial
?
response, although over the 12-week study, beclomethasone provided a greater average treatment effect
(% change from baseline for montelukast vs beclomethasone, respectively for FEV : 7.49% vs 13.3%;
1
?
-agonist use: -28.28% vs -43.89%). However, compared with beclomethasone, a high percentage of
patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with
beclomethasone achieved an improvement in FEV of approximately 11% or more over baseline while
1
approximately 42% of patients treated with montelukast achieved the same response).
In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once
daily improved parameters of asthma control compared with placebo irrespective of concomitant
controller therapy (inhaled/nebulized corticosteroids or inhaled/nebulized sodium cromoglycate). Sixty
percent of patients were not on any other controller therapy. Montelukast improved daytime symptoms
(including coughing, wheezing, trouble breathing and activity limitation) and nighttime symptoms
compared with placebo. Montelukast also decreased \"as-needed\" -agonist use and corticosteroid rescue
?
for worsening asthma compared with placebo. Patients receiving montelukast had more days without
asthma than those receiving placebo. A treatment effect was achieved after the first dose.
In a 12-month, placebo-controlled study in paediatric patients 2 to 5 years of age with mild asthma and
episodic exacerbations, montelukast 4 mg once daily significantly (p 0.001) reduced the yearly rate of
?
asthma exacerbation episodes (EE) compared with placebo (1.60 EE vs. 2.34 EE, respectively), [EE
defined as 3 consecutive days with daytime symptoms requiring -agonist use, or corticosteroids (oral or
?
?
inhaled), or hospitalization for asthma]. The percentage reduction in yearly EE rate was 31.9%, with a
95% CI of 16.9, 44.1.
In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared
with placebo, significantly improved respiratory function (FEV 8.71% vs 4.16% change from baseline;
1
AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased \"as-needed\" -agonist use
?
(-11.7% vs +8.2% change from baseline).
In a 12-month study comparing the efficacy of montelukast to inhaled fluticasone on asthma control in
paediatric patients 6 to 14 years of age with mild persistent asthma, montelukast was non-inferior to
fluticasone in increasing the percentage of asthma rescue-free days (RFDs), the primary endpoint.
Averaged over the 12-month treatment period, the percentage of asthma RFDs increased from 61.6 to
84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The between groupdifference in LS mean increase in the percentage of asthma RFDs was statistically significant (-2.8 with a
95% CI of -4.7, -0.9), but within the limit pre-defined to be clinically not inferior. Both montelukast and fluticasone also improved asthma control on secondary variables assessed over the
12 month treatment period:
FEV increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the
1
fluticasone group. The between-group difference in LS mean increase in FEV was -0.02 L with a 95% CI
1
of -0.06, 0.02. The mean increase from baseline in % predicted FEV was 0.6% in the montelukast
1
treatment group, and 2.7% in the fluticasone treatment group. The difference in LS means for the change
from baseline in the % predicted FEV was significant: -2.2% with a 95% CI of -3.6, -0.7.
1
The percentage of days with -agonist use decreased from 38.0 to 15.4 in the montelukast group, and
?
from 38.5 to 12.8 in the fluticasone group. The between group difference in LS means for the percentage
of days with -agonist use was significant: 2.7 with a 95% CI of 0.9, 4.5.
?
The percentage of patients with an asthma attack (an asthma attack being defined as a period of
worsening asthma that required treatment with oral steroids, an unscheduled visit to the doctor?s office, an
emergency room visit, or hospitalization) was 32.2 in the montelukast group and 25.6 in the fluticasone
group; the odds ratio (95% CI) being significant: equal to 1.38 (1.04, 1.84). The percentage of patients with systemic (mainly oral) corticosteroid use during the study period was
17.8% in the montelukast group and 10.5% in the fluticasone group. The between group difference in
LS means was significant: 7.3% with a 95%CI of 2.9; 11.7.
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week
study in adults (maximal fall in FEV 22.33% for montelukast vs 32.40% for placebo; time to recovery to
1
within 5% of baseline FEV 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week
1
study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients 6 to
14 years of age (maximal fall in FEV 18.27% vs 26.11%; time to recovery to within 5% of baseline
1
FEV 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily
1
dosing interval.
In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment
with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV
1
8.55% vs -1.74% change from baseline and decrease in total -agonist use -27.78% vs 2.09% change
?
from baseline).
5.2
Pharmacokinetic properties

Absorption. Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated
tablet, the mean peak plasma concentration (C
max
) is achieved 3 hours (T
max
) after administration in adults
in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C
max
are not
influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg
film-coated tablet was administered without regard to the timing of food ingestion.

For the 5 mg chewable tablet, the C
max
is achieved in 2 hours after administration in adults in the fasted
state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted
state, C
max
is achieved 2 hours after administration. The mean C
max
is 66% higher while mean C is
min
lower than in adults receiving a 10 mg tablet.
Distribution. Montelukast is more than 99% bound to plasma proteins. The steady-state volume of
distribution of montelukast averages 8-11 liters. Studies in rats with radiolabeled montelukast indicateminimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at
24 hours post-dose were minimal in all other tissues.
Biotransformation. Montelukast is extensively metabolized. In studies with therapeutic doses, plasma
concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
In vitro
studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are
involved in the metabolism of montelukast. Based on further
in vitro
results in human liver microsomes,
therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6,
2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination. The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an
oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections
and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this
indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in Patients. No dosage adjustment is necessary for the elderly or mild to moderate hepatic
insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast
and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in
patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with
severe hepatic insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma
theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg
once daily.
5.3
Preclinical safety data

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and
triglycerides were observed which were transient in nature. The signs of toxicity in animals were
increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred
at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the
adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the
clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at
systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in
pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical
systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with
concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at
the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental
barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses up to
5,000 mg/kg in mice and rats (15,000 mg/m and 30,000 mg/m in mice and rats, respectively), the
2
2
maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose
(based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses
up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).
Montelukast was neither mutagenic in
in vitro
and
in vivo
tests nor tumorigenic in rodent species.6.
PHARMACEUTICAL PARTICULARS

6.1
List of excipients

Mannitol
Microcrystalline cellulose
Hyprolose (E 463)
Red ferric oxide (E 172)
Croscarmellose sodium
Cherry flavour
Aspartame (E 951)
Magnesium stearate

6.2
Incompatibilities

Not applicable.
6.3
Shelf-life

2 years.
6.4
Special precautions for storage

Store in the original package in order to protect from light and moisture.
6.5
Nature and contents of container

Packaged in polyamide/PVC/aluminum blister package in:
. Blisters in packages of: 7, 10, 14, 20, 28, 30, 50, 56, 98, 100, 140 and 200 tablets. Blisters (unit doses), in packages of: 49, 50 and 56 tablets. Not all pack sizes may be marketed.
6.6
Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7.
MARKETING AUTHORIZATION HOLDER

[TO BE COMPLETED NATIONALLY]



8.
MARKETING AUTHORIZATION NUMBER

[TO BE COMPLETED NATIONALLY]9. DATE OF first AUTHORIZATION/RENEWAL OF the AUTHORIZATION

[TO BE COMPLETED NATIONALLY]


10. DATE OF REVISION OF THE TEXT

{MM/YYYY}1. NAME OF THE MEDICINAL PRODUCT

4 MG GRANULES



2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One sachet of granules contains montelukast sodium, which is equivalent to 4 mg montelukast. For a full list of excipients, see section 6.1.

3.
PHARMACEUTICAL FORM

GRANULES.
White granules


4.
CLINICAL PARTICULARS

4.1
Therapeutic indications

is indicated in the treatment of asthma as add-on therapy in those 6 months to 5 year
old patients with mild to moderate persistent asthma who are inadequately controlled on inhaled
corticosteroids and in whom ?as-needed? short acting -agonists provide inadequate clinical control of
?
asthma.
may also be an alternative treatment option to low-dose inhaled corticosteroids for 2 to
5 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks
that required oral corticosteroid use, and who have demonstrated that they are not capable of using
inhaled corticosteroids (see section 4.2).
is also indicated in the prophylaxis of asthma from 2 years of age and older in which
the predominant component is exercise-induced bronchoconstriction.
4.2
Posology and method of administration

This medicinal product is to be given to a child under adult supervision. The dosage for paediatric
patients 6 months to 5 years of age is one sachet of 4 mg granules daily to be taken in the evening. No
dosage adjustment within this age group is necessary. Efficacy data from clinical trials in paediatric
patients 6 months to 2 years of age with persistent asthma are limited. Patients should be evaluated after 2
to 4 weeks for response to montelukast treatment. Treatment should be discontinued if a lack of response
is observed. The 4 mg granules formulation is not recommended below 6 months of
age.

Administration of granules:
granules can be administered either directly in the mouth, or mixed with a spoonful of
cold or room temperature soft food (e.g., applesauce, ice cream, carrots and rice). The sachet should notbe opened until ready to use. After opening the sachet, the full dose of granules must
be administered immediately (within 15 minutes). If mixed with food, granules must
not be stored for future use. granules are not intended to be dissolved in liquid for
administration. However, liquids may be taken subsequent to administration. granules
can be administered without regard to the timing of food ingestion.
General recommendations. The therapeutic effect of on parameters of asthma control
occurs within one day. Patients should be advised to continue taking even if their
asthma is under control, as well as during periods of worsening asthma.
No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic
impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for
both male and female patients.
as an alternative treatment option to low-dose inhaled corticosteroids for mild,
persistent asthma
:
Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of
montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children 2 to 5
years old with mild persistent asthma should only be considered for patients who do not have a recent
history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that
they are not capable of using inhaled corticosteroids (see section 4.1). Mild persistent asthma is defined as
asthma symptoms more than once a week but less that once a day, nocturnal symptoms more than twice a
month but less than once a week, normal lung function between episodes. If satisfactory control of asthma
is not achieved at follow-up (usually within one month), the need for an additional or different anti-
inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should
be periodically evaluated for their asthma control.
as prophylaxis of asthma for 2 to 5 year old patients in whom the predominant
component is exercise-induced bronchoconstriction:
In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant manifestation of
persistent asthma that requires treatment with inhaled corticosteroids. Patients should be evaluated after 2
to 4 weeks of treatment with montelukast. If satisfactory response is not achieved, an additional or
different therapy should be considered.
Therapy with in relation to other treatments for asthma. When treatment with is used as add-on therapy to inhaled corticosteroids,
should not be abruptly substituted for inhaled corticosteroids (see section 4.4).
10 mg film-coated tablets are available for adults 15 years of age and older. 5 mg chewable tablets are available for paediatric patients 6 to 14 years of age. 4 mg chewable tablets are available as an alternative formulation for paediatric patients 2 to 5 years of
age.
4.3
Contraindications

Hypersensitivity to the active substance or to any of the excipients.


4.4
Special warnings and precautions for use

The diagnosis of persistent asthma in very young children (6 months ? 2 years) should be established by a
paediatrician or pulmonologist.Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their
usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-
acting inhaled -agonist should be used. Patients should seek their doctors? advice as soon as possible if
?
they need more inhalations of short-acting -agonists than usual. ?

Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given
concomitantly.
In rare cases, patients on therapy with anti-asthma agents including montelukast may present with
systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-
Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases
usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid
therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of
Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to
eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy
presenting in their patients. Patients who develop these symptoms should be reassessed and their
treatment regimens evaluated.

4.5
Interactions with other medicinal products and other forms of interaction

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic
treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not
have clinically important effects on the pharmacokinetics of the following medicinal products:
theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1),
terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40%
in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4,
caution should be exercised, particularly in children, when montelukast is coadministered with inducers
of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.
In vitro
studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a
clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate
representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that montelukast
does not inhibit CYP 2C8
in vivo.
Therefore, montelukast is not anticipated to markedly alter the
metabolism of medicinal products metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and
repaglinide.)

4.6
Pregnancy and lactation

Use during pregnancy

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal
development.Limited data from available pregnancy databases do not suggest a causal relationship between
and malformations (i.e. limb defects) that have been rarely reported in worldwide post
marketing experience.

may be used during pregnancy only if it is considered to be clearly essential.
Use during lactation

Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is not known if
montelukast is excreted in human milk.
may be used in breast-feeding mothers only if it is considered to be clearly essential.
4.7
Effects on ability to drive and use machines

Montelukast is not expected to affect a patient?s ability to drive a car or operate machinery. However, in
very rare cases, individuals have reported drowsiness or dizziness.
4.8
Undesirable effects

Montelukast has been evaluated in clinical studies as follows:
ƒ

10 mg film-coated tablets in approximately 4000 adult patients 15 years of age and older
ƒ

5 mg chewable tablets in approximately 1750 paediatric patients 6 to 14 years of age
ƒ

4 mg chewable tablets in 851 paediatric patients 2 to 5 years of age, and
ƒ

4 mg granules in 175 paediatric patients 6 months to 2 years of age.
The following drug-related adverse reactions in clinical studies were reported commonly ( 1/100 to
?
<1/10) in patients treated with montelukast and at a greater incidence than in patients treated with
placebo:


Body System
Class
Adult Patients
15 years and
older
(two 12-week
studies; n=795)
Paediatric
Patients
6 to 14 years
old
(one 8-week
study; n=201)
(two 56-week
studies; n=615)
Paediatric
Patients
2 to 5 years old
(one 12-week
study; n=461)
(one 48-week
study; n=278)
Paediatric
Patients
6 months up to
2 years old
(one 6-week
study; n=175)
Nervous system
disorders
headache
headache
hyperkinesia
Respiratory,
thoracic, and
mediastinal
disorders
asthma
Gastrointestinal
disorders
abdominal
pain
abdominal pain
diarrhoeaSkin and
subcutaneous
tissue disorders
dermatitis,
eczematous
rash
General disorders
and
administration
site conditions
thirst

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults,
and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change. Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least
3 months, 338 for 6 months or longer, and 534 patients for 12 months or longer. With prolonged
treatment, the safety profile did not change in these patients either. The safety profile in paediatric patients 6 months to 2 years of age did not change with treatment up to
3 months.
The following adverse reactions have been reported in post-marketing use:
Blood and lymphatic system disorders:
increased bleeding tendency. Immune system disorders:
hypersensitivity reactions including anaphylaxis, hepatic eosinophilic
infiltration. Psychiatric disorders:
dream abnormalities including nightmares, hallucinations, insomnia, irritability,
anxiety, restlessness, agitation including aggressive behaviour, tremor, depression, suicidal thinking and
behaviour (suicidality) in very rare cases. Nervous system disorders:
dizziness drowsiness, paraesthesia/hypoesthesia, seizure. Cardiac disorders:
palpitations. Respiratory, thoracic and mediastinal disorders:
epistaxis. Gastrointestinal disorders:
diarrhoea, dry mouth, dyspepsia, nausea, vomiting. Hepatobiliary disorders:
elevated levels of serum transaminases (ALT, AST), cholestatic hepatitis. Skin and subcutaneous tissue disorders:
angiooedema, bruising, urticaria, pruritus, rash, erythema
nodosum. Musculoskeletal and connective tissue disorders:
arthralgia, myalgia including muscle cramps. General disorders and administration site conditions:
asthenia/fatigue, malaise, oedema, pyrexia. Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in
asthmatic patients (see section 4.4).

4.9
Overdose

No specific information is available on the treatment of overdose with montelukast. In chronic asthma
studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and
in short term studies, up to 900 mg/day to patients for approximately one week without clinically
important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with
montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately
61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the
safety profile in adults and paediatric patients. There were no adverse experiences in the majority of
overdose reports. The most frequently occurring adverse experiences were consistent with the safety
profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and
psychomotor hyperactivity.It is not known whether montelukast is dialyzable by peritoneal- or hemo-dialysis.

5.
PHARMACOLOGICAL PROPERTIES

5.1
Pharmacodynamic properties

Pharmacotherapeutic group:
Leukotriene receptor antagonist
ATC-code:
R03D C03

The cysteinyl leukotrienes (LTC , LTD , LTE ) are potent inflammatory eicosanoids released from
4
4
4
various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to
cysteinyl leukotriene receptors (CysLT) found in the human airway and cause airway actions, including
bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT
1
receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD at doses as low
4
as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect
caused by a -agonist was additive to that caused by montelukast. Treatment with montelukast inhibited
?
both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with
placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study,
treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum). In
adult and paediatric patients 2 to 14 years of age, montelukast, compared with placebo, decreased
peripheral blood eosinophils while improving clinical asthma control.
In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant
improvements in morning FEV (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate
1
(PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total -agonist use
?
(-26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma
symptoms scores was significantly better than placebo.
Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled
corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclomethasone,
respectively for FEV : 5.43% vs 1.04%; -agonist use: -8.70% vs 2.64%). Compared with inhaled
1
?
beclomethasone (200 g twice daily with a spacer device), montelukast demonstrated a more rapid initial
?
response, although over the 12-week study, beclomethasone provided a greater average treatment effect
(% change from baseline for montelukast vs beclomethasone, respectively for FEV : 7.49% vs 13.3%;
1
?
-agonist use: -28.28% vs -43.89%). However, compared with beclomethasone, a high percentage of
patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with
beclomethasone achieved an improvement in FEV of approximately 11% or more over baseline while
1
approximately 42% of patients treated with montelukast achieved the same response).
In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared
with placebo, significantly improved respiratory function (FEV 8.71% vs 4.16% change from baseline;
1
AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased \"as-needed\" -agonist use
?
(-11.7% vs +8.2% change from baseline).
In a 12-month study comparing the efficacy of montelukast to inhaled fluticasone on asthma control in
paediatric patients 6 to 14 years of age with mild persistent asthma, montelukast was non-inferior tofluticasone in increasing the percentage of asthma rescue-free days (RFDs), the primary endpoint. Averaged over the 12-month treatment period, the percentage of asthma RFDs increased from 61.6 to
84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The between group
difference in LS mean increase in the percentage of asthma RFDs was statistically significant (-2.8 with a
95% CI of -4.7, -0.9), but within the limit pre-defined to be clinically not inferior. Both montelukast and fluticasone also improved asthma control on secondary variables assessed over the
12 month treatment period:
FEV increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the
1
fluticasone group. The between-group difference in LS mean increase in FEV was -0.02 L with a 95% CI
1
of -0.06, 0.02. The mean increase from baseline in % predicted FEV was 0.6% in the montelukast
1
treatment group, and 2.7% in the fluticasone treatment group. The difference in LS means for the change
from baseline in the % predicted FEV was significant: -2.2% with a 95% CI of -3.6, -0.7.
1
The percentage of days with -agonist use decreased from 38.0 to 15.4 in the montelukast group, and
?
from 38.5 to 12.8 in the fluticasone group. The between group difference in LS means for the percentage
of days with -agonist use was significant: 2.7 with a 95% CI of 0.9, 4.5.
?
The percentage of patients with an asthma attack (an asthma attack being defined as a period of
worsening asthma that required treatment with oral steroids, an unscheduled visit to the doctor?s office, an
emergency room visit, or hospitalization) was 32.2 in the montelukast group and 25.6 in the fluticasone
group; the odds ratio (95% CI) being significant: equal to 1.38 (1.04, 1.84). The percentage of patients with systemic (mainly oral) corticosteroid use during the study period was
17.8% in the montelukast group and 10.5% in the fluticasone group. The between group difference in
LS means was significant: 7.3% with a 95%CI of 2.9; 11.7.
In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once
daily improved parameters of asthma control compared with placebo irrespective of concomitant
controller therapy (inhaled/nebulized corticosteroids or inhaled/nebulized sodium cromoglycate). Sixty
percent of patients were not on any other controller therapy. Montelukast improved daytime symptoms
(including coughing, wheezing, trouble breathing and activity limitation) and nighttime symptoms
compared with placebo. Montelukast also decreased \"as-needed\" -agonist use and corticosteroid rescue
?
for worsening asthma compared with placebo. Patients receiving montelukast had more days without
asthma than those receiving placebo. A treatment effect was achieved after the first dose.
In a 12-month, placebo-controlled study in paediatric patients 2 to 5 years of age with mild asthma and
episodic exacerbations, montelukast 4 mg once daily significantly (p 0.001) reduced the yearly rate of
?
asthma exacerbation episodes (EE) compared with placebo (1.60 EE vs. 2.34 EE, respectively),
[EE defined as 3 consecutive days with daytime symptoms requiring -agonist use, or corticosteroids
?
?
(oral or inhaled), or hospitalization for asthma]. The percentage reduction in yearly EE rate was
31.9%, with a 95% CI of 16.9, 44.1.
Efficacy of montelukast is supported in paediatric patients 6 months to 2 years of age by extrapolation
from the demonstrated efficacy in patients 2 years of age and older with asthma, and is based on similar
pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the
medicinal products?s effect are substantially similar among these populations.
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week
study in adults (maximal fall in FEV 22.33% for montelukast vs 32.40% for placebo; time to recovery to
1
within 5% of baseline FEV 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week
1
study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients 6 to
14 years of age (maximal fall in FEV 18.27% vs 26.11%; time to recovery to within 5% of baseline
1
FEV 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily
1
dosing interval.In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment
with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV
1
8.55% vs -1.74% change from baseline and decrease in total -agonist use -27.78% vs 2.09% change
?
from baseline).
5.2
Pharmacokinetic properties

Absorption. Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated
tablet, the mean peak plasma concentration (C
max
) is achieved 3 hours (T
max
) after administration in adults
in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C
max
are not
influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg
film-coated tablet was administered without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the C
max
is achieved in 2 hours after administration in adults in the fasted
state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted
state, C
max
is achieved 2 hours after administration. The mean C
max
is 66% higher while mean C is
min
lower than in adults receiving a 10 mg tablet.
The 4 mg granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in
the fasted state. In paediatric patients 6 months to 2 years of age, C
max
is achieved 2 hours after
administration of the 4 mg granules formulation. C
max
is nearly 2-fold greater than in adults receiving a
10 mg tablet. The co-administration of applesauce or a high-fat standard meal with the granule
formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as
determined by AUC (1225.7 vs 1223.1 ng hr/mL with and without applesauce, respectively, and

.
1191.8 vs 1148.5 ng hr/mL with and without a high-fat standard meal, respectively). . Distribution. Montelukast is more than 99% bound to plasma proteins. The steady-state volume of
distribution of montelukast averages 8-11 liters. Studies in rats with radiolabeled montelukast indicate
minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at
24 hours post-dose were minimal in all other tissues.
Biotransformation. Montelukast is extensively metabolized. In studies with therapeutic doses, plasma
concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
In vitro
studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are
involved in the metabolism of montelukast. Based on further
in vitro
results in human liver microsomes,
therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6,
2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination. The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an
oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections
and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this
indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in Patients. No dosage adjustment is necessary for the elderly or mild to moderate hepatic
insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast
and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary inpatients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with
severe hepatic insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma
theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg
once daily.
5.3
Preclinical safety data

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and
triglycerides were observed which were transient in nature. The signs of toxicity in animals were
increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred
at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the
adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the
clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at
systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in
pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical
systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with
concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at
the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental
barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses up to
5,000 mg/kg in mice and rats (15,000 mg/m and 30,000 mg/m in mice and rats, respectively), the
2
2
maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose
(based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses
up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).
Montelukast was neither mutagenic in
in vitro
and
in vivo
tests nor tumorigenic in rodent species.

6.
PHARMACEUTICAL PARTICULARS

6.1
List of excipients

Mannitol
Hyprolose (E 463)
Magnesium stearate

6.2
Incompatibilities


Not applicable.
6.3
Shelf-life

2 years.6.4
Special precautions for storage

Store in the original package in order to protect from light and moisture.
6.5
Nature and contents of container

Packaged in polyethylene/aluminum/polyester sachet in:
Cartons of 7, 20, 28 and 30 sachets. Not all pack sizes may be marketed.
6.6
Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7.
MARKETING AUTHORIZATION HOLDER


[To be completed nationally.]


8.
MARKETING AUTHORIZATION NUMBER

[TO BE COMPLETED NATIONALLY.]


9. DATE OF first AUTHORIZATION/RENEWAL OF the AUTHORIZATION

[To be completed nationally.]


10. DATE OF REVISION OF THE TEXT

{MM/YYYY}LABELLING AND PACKAGE LEAFLETLABELLINGPARTICULARS TO APPEAR ON THE OUTER PACKAGING

4 mg Tablets ? Outer Carton


1. NAME OF THE MEDICINAL PRODUCT


4 mg chewable tablets
montelukast
For children 2 to 5 years of age

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One chewable tablet contains montelukast sodium, which is equivalent to 4 mg montelukast.

3. LIST OF EXCIPIENTS


Contains aspartame (E 951). See the leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS


7, 10, 14, 20, 28, 30, 49, 50, 56, 98, 100, 140, 200 chewable tablets.

5. METHOD AND ROUTE(S) OF ADMINISTRATION


Oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN


Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



8.
EXPIRY DATE


EXP


9. SPECIAL STORAGE CONDITIONSStore in the original package in order to protect from light and moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE


11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

[To be completed nationally]


12.
MARKETING AUTHORISATION NUMBER(S)


[To be completed nationally]


13.
BATCH NUMBER


Batch


14. GENERAL CLASSIFICATION FOR SUPPLY


[To be completed nationally]


15. INSTRUCTIONS ON USE


[To be completed nationally]


16.
INFORMATION IN BRAILLE


4 mgMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

4 mg tablets - Blister


1. NAME OF THE MEDICINAL PRODUCT

4 mg chewable tablet
montelukast


2. NAME OF THE MARKETING AUTHORISATION HOLDER

[To be completed nationally]


3.
EXPIRY DATE

EXP


4.
BATCH NUMBER

Batch


5.
OTHERPARTICULARS TO APPEAR ON THE OUTER PACKAGING

4 mg Granules? Outer Carton


1. NAME OF THE MEDICINAL PRODUCT


4 mg granules
montelukast
For children 6 months to 5 years of age


2. STATEMENT OF ACTIVE SUBSTANCE(S)

One sachet of granules contains montelukast sodium, which is equivalent to 4 mg montelukast.

3. LIST OF EXCIPIENTS




4. PHARMACEUTICAL FORM AND CONTENTS


Granules
7 x 1 sachet
20 x 1 sachet
28 x 1 sachet
30 x 1 sachet


5. METHOD AND ROUTE(S) OF ADMINISTRATION


Oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN


Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



8.
EXPIRY DATE


EXP9. SPECIAL STORAGE CONDITIONS


Store in the original package in order to protect from light and moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE


11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

[To be completed nationally]


12.
MARKETING AUTHORISATION NUMBER(S)


[To be completed nationally]


13.
BATCH NUMBER


Batch


14. GENERAL CLASSIFICATION FOR SUPPLY


[To be completed nationally]


15. INSTRUCTIONS ON USE


[To be completed nationally]


16.
INFORMATION IN BRAILLE


4 mg granulesMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

4 mg Granules - Sachet


1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

4 mg granules
montelukast


2.
METHOD OF ADMINISTRATION

Oral use.

3.
EXPIRY DATE

EXP


4.
BATCH NUMBER

Batch


5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 sachet


6.
OTHER

{Name of the Marketing Authorisation Holder}
[To be completed nationally]PACKAGE LEAFLETPACKAGE LEAFLETPACKAGE LEAFLET: INFORMATION FOR THE USER


4 mg chewable tablets
montelukast

Read all of this leaflet carefully before your child starts taking this medicine. ?

Keep this leaflet. You may need to read it again. ?

If you have any further questions, please ask your doctor or pharmacist. ?

This medicine has been prescribed for your child. Do not pass it on to others. It may harm them,
even if their symptoms are the same as your child?s.
?

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What is and what it is used for
2. Before is taken
3. How to take
4. Possible side effects
5. How to store
6.
Further information


1. WHAT IS AND WHAT IT IS USED FOR

is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause narrowing and swelling of airways in the lungs. By blocking leukotrienes,
improves asthma symptoms and helps control asthma.
Your doctor has prescribed to treat your child?s asthma, preventing asthma symptoms
during the day and night.
?

is used for the treatment of 2 to 5 year old patients who are not adequately
controlled on their medication and need additional therapy. ?

may also be used as an alternative treatment to inhaled corticosteroids for 2 to 5
year old patients who have not recently taken oral corticosteroids for their asthma and have shown
that they are unable to use inhaled corticosteroids.
?

also helps prevent the narrowing of airways triggered by exercise for patients 2
years of age and older.
Your doctor will determine how should be used depending on the symptoms and
severity of your child's asthma.
What is asthma?
Asthma is a long-term disease. Asthma includes:

?

difficulty breathing because of narrowed airways. This narrowing of airways
worsens and improves in response to various conditions. ?

sensitive airways that react to many things, such as cigarette smoke, pollen, cold
air, or exercise.?

swelling (inflammation) in the lining of the airways. Symptoms of asthma include: Coughing, wheezing, and chest tightness.


2. BEFORE IS TAKEN


Tell your doctor about any medical problems or allergies your child has now or has had.
Do not give to your child if he/she
?

is allergic (hypersensitive) to montelukast or any of the other ingredients of
(see 6. FURTHER INFORMATION).
Take special care with
?

If your child?s asthma or breathing gets worse, tell your doctor immediately. ?

Oral is not meant to treat acute asthma attacks. If an attack occurs, follow the
instructions your doctor has given you for your child. Always have your child?s inhaled rescue
medicine for asthma attacks with you. ?

It is important that your child take all asthma medications prescribed by your doctor. should not be used instead of other asthma medications your doctor has
prescribed for your child. ?

If your child is on anti-asthma medicines, be aware that if he/she develops a combination of
symptoms such as flu-like illness, pins and needles or numbness of arms or legs, worsening of
pulmonary symptoms, and/or rash, you should consult your doctor. ?

Your child should not take acetyl-salicylic acid (aspirin) or anti-inflammatory medicines (also
known as non-steroidal anti-inflammatory drugs or NSAIDs) if they make his/her asthma worse.
Taking other medicines

Some medicines may affect how works, or may affect how your
child?s other medicines work.
Please tell your doctor or pharmacist if your child is taking or has recently taken other medicines,
including those obtained without a prescription.
Tell your doctor if your child is taking the following medicines before starting :
?

phenobarbital (used for treatment of epilepsy)
?

phenytoin (used for treatment of epilepsy)
?

rifampicin (used to treat tuberculosis and some other infections)

Taking with food and drink
4 mg chewable tablets should not be taken immediately with food; they should be
taken at least 1 hour before or 2 hours after food.
Pregnancy and breast-feeding
This subsection is not applicable for the 4 mg chewable tablets since they are intended
for use in children 2 to 5 years of age, however the following information is relevant to the active
ingredient, montelukast.
Use in pregnancy
Women who are pregnant or intend to become pregnant should consult their doctor before taking
. Your doctor will assess whether you can take during this time.Use in breast-feeding
It is not known if appears in breast milk. You should consult your doctor before taking
if you are breast-feeding or intend to breast-feed.
Driving and using machines

This subsection is not applicable for the 4 mg chewable tablets since they are intended
for use in children 2 to 5 years of age, however the following information is relevant to the active
ingredient, montelukast.
is not expected to affect your ability to drive a car or operate machinery. However,
individual responses to medication may vary. Certain side effects (such as dizziness and drowsiness) that
have been reported very rarely with may affect some patients? ability to drive or
operate machinery.
Important information about some of the ingredients of
chewable tablets contain aspartame, a source of phenylalanine. If your child has
phenylketonuria (a rare, hereditary disorder of the metabolism) you should take into account that each 4-
mg chewable tablet contains phenylalanine (equivalent to 0.674 mg phenylalanine per 4 mg chewable
tablet).

3. HOW TO TAKE

?

This medicine is to be given to a child under adult supervision. For children who have problems
consuming a chewable tablet, an oral granule formulation is available. ?

Your child should take only one tablet of once a day as prescribed by your
doctor. ?

It should be taken even when your child has no symptoms or if he/she has an acute asthma attack. ?

Always have your child take as your doctor has told you. You should check
with your child?s doctor or pharmacist if you are not sure. ?

To be taken by mouth

For children 2 to 5 years of age:
One 4 mg chewable tablet daily to be taken in the evening. 4 mg chewable tablets
should not be taken immediately with food; it should be taken at least 1 hour before or 2 hours after food. If your child is taking , be sure that he/she does not take any other medicines that
contain the same active ingredient, montelukast.
For children 2 to 5 years old, 4 mg chewable tablets and 4 mg granules are available. For children 6 to 14 years old, 5 mg chewable tablets are available. The
4 mg chewable tablet is not recommended below 2 years of age.
If your child takes more than he/she should
Contact your child?s doctor immediately for advice.
There were no side effects reported in the majority of overdose reports. The most frequently occurring
symptoms reported with overdose in adults and children included abdominal pain, sleepiness, thirst,
headache, vomiting, and hyperactivity.
If you forget to give to your child
Try to give as prescribed. However, if your child misses a dose, just resume the usual
schedule of one tablet once daily.Do not give a double dose to make up for a forgotten dose.
If your child stops taking
can treat your child?s asthma only if he/she continues taking it. It is important for your child to continue taking for as long as your doctor prescribes. It
will help control your child?s asthma. If you have any further questions on the use of this product, ask your child?s doctor or pharmacist.

4.
POSSIBLE SIDE EFFECTS


Like all medicines, can cause side effects, although not everybody gets them.
In clinical studies with 4 mg chewable tablets, the most commonly reported side
effects (occurring in at least 1 of 100 patients and less than 1 of 10 paediatric patients treated) thought to
be related to were:
?

abdominal pain
?

thirst
Additionally, the following side effect was reported in clinical studies with 10 mg
film-coated tablets and 5 mg chewable tablets:
?

headache
These were usually mild and occurred at a greater frequency in patients treated with
than placebo (a pill containing no medication).
Additionally, while the medicine has been on the market, the following have been reported:
?

increased bleeding tendency
?

allergic reactions including rash, swelling of the face, lips, tongue, and/or throat which may cause
difficulty in breathing or swallowing
?

behaviour and mood related changes [dream abnormalities, including nightmares, hallucinations,
irritability, feeling anxious, restlessness, agitation including aggressive behaviour, tremor,
depression, trouble sleeping, suicidal thoughts and actions (in very rare cases)]
?

dizziness, drowsiness, pins and needles/numbness, seizure
?

palpitations
?

nosebleed
?

diarrhea, dry mouth, indigestion, nausea, vomiting
?

hepatitis
?

bruising, itching, hives, tender red lumps under the skin most commonly on your shins (erythema
nodosum),
?

joint or muscle pain, muscle cramps
?

tiredness, feeling unwell, swelling, fever

In asthmatic patients treated with montelukast, very rare cases of a combination of symptoms such as flu-
like illness, pins and needles or numbness of arms and legs, worsening of pulmonary symptoms and/or
rash (Churg-Strauss syndrome) have been reported. You must tell your doctor right away if your child
gets one or more of these symptoms.
Ask your doctor or pharmacist for more information about side effects. If any of the side effects gets
serious, or if you notice any side effects not listed in this leaflet, please tell your child?s doctor or
pharmacist.5. HOW TO STORE

?

Keep out of the reach and sight of children. ?

Do not use this medicine after the date shown by the six numbers following EXP on the blister. The
first two numbers indicate the month; the last four numbers indicate the year. This medicine expires
at the end of the month shown. ?

Store in the original package in order to protect from light and moisture. ?

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how
to dispose of medicines no longer required. These measures will help to protect the environment.

6.
FURTHER INFORMATION


What contains
?

The active substance is montelukast. Each tablet contains montelukast sodium which corresponds
to 4 mg of montelukast. ?

The other ingredients are:
Mannitol, microcrystalline cellulose, hyprolose (E 463), red ferric oxide (E 172), croscarmellose
sodium, cherry flavour, aspartame (E951), and magnesium stearate.
What looks like and contents of the pack
4 mg chewable tablets are pink, oval, biconvex with engraved on
one side and MSD 711 on the other. Blisters in packages of: 7, 10, 14, 20, 28, 30, 50, 56, 98, 100, 140 and 200 tablets. Blisters (unit doses), in packages of: 49, 50 and 56 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer

Marketing Authorization Holder and Manufacturer
Information is given by
{To be completed nationally}
{To be completed nationally}

This medicinal product is authorized in the Member States of the EEA under the following names:

Austria, Germany, Hungary, Netherlands, Romania,

AIRATHON

Belgium, Finland, Luxemburg, Portugal, Poland, Spain

TRADENAME and Montelukast MSD

CZECH Republic

MONTES and MONAIR

SLOVAKIA

AIRAMON and MontelairThis leaflet was last approved in {DD.MM.YYYY.}PACKAGE LEAFLET: INFORMATION FOR THE USER

4 mg Granules
montelukast

Read all of this leaflet carefully before your child starts taking this medicine. ?

Keep this leaflet. You may need to read it again. ?

If you have any further questions, please ask your doctor or pharmacist. ?

This medicine has been prescribed for your child. Do not pass it on to others. It may harm them,
even if their symptoms are the same as your child?s.
?

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What is and what it is used for
2. Before is taken
3. How to take
4. Possible side effects
5. How to store
6.
Further information


1. WHAT IS AND WHAT IT IS USED FOR

is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause narrowing and swelling of airways in the lungs. By blocking leukotrienes,
improves asthma symptoms and helps control asthma.
Your doctor has prescribed to treat your child?s asthma, preventing asthma symptoms
during the day and night.
?

is used for the treatment of 6 months to 5 year old patients who are not
adequately controlled on their medication and need additional therapy. ?

may also be used as an alternative treatment to inhaled corticosteroids for 2 to
5 year old patients who have not recently taken oral corticosteroids for their asthma and have
shown that they are unable to use inhaled corticosteroids. ?

also helps prevent the narrowing of airways triggered by exercise for patients
2 years of age and older.
Your doctor will determine how should be used depending on the symptoms and
severity of your child's asthma.
What is asthma?
Asthma is a long-term disease. Asthma includes:
?

difficulty breathing because of narrowed airways. This narrowing of airways
worsens and improves in response to various conditions. ?

sensitive airways that react to many things, such as cigarette smoke, pollen,
cold air, or exercise. ?

swelling (inflammation) in the lining of the airways.Symptoms of asthma include: Coughing, wheezing, and chest tightness.


2. BEFORE IS TAKEN

Tell your doctor about any medical problems or allergies your child has now or has had.
Do not give to your child if he/she
?

is allergic (hypersensitive) to montelukast or any of the other ingredients of
(see 6. FURTHER INFORMATION).
Take special care with
?

If your child?s asthma or breathing gets worse, tell your doctor immediately. ?

Oral is not meant to treat acute asthma attacks. If an attack occurs, follow the
instructions your doctor has given you for your child. Always have your child?s inhaled rescue
medicine for asthma attacks with you. ?

It is important that your child take all asthma medications prescribed by your doctor. should not be used instead of other asthma medications your doctor has
prescribed for your child. ?

If your child is on anti-asthma medicines, be aware that if the he/she develops a combination of
symptoms such as flu-like illness, pins and needles or numbness of arms or legs, worsening of
pulmonary symptoms, and/or rash, you should consult your doctor. ?

Your child should not take acetyl-salicylic acid (aspirin) or anti-inflammatory medicines (also
known as non-steroidal anti-inflammatory drugs or NSAIDs) if they make his/her asthma worse.
Taking other medicines
Some medicines may affect how works, or may affect how your
child's other medicines work. Please tell your doctor or pharmacist if your child is taking or has recently taken other medicines,
including those obtained without a prescription. Tell your doctor if your child is taking the following medicines before starting :
?

phenobarbital (used for treatment of epilepsy)
?

phenytoin (used for treatment of epilepsy)
?

rifampicin (used to treat tuberculosis and some other infections)

Taking with food and drink
granules can be taken without regard to the timing of food intake.
Pregnancy and breast-feeding
This subsection is not applicable for the 4 mg granules since they are intended for use
in children 6 months to 5 years of age, however the following information is relevant to the active
ingredient, montelukast.
Use in pregnancy
Women who are pregnant or intend to become pregnant should consult their doctor before taking
. Your doctor will assess whether you can take during this time.
Use in breast-feeding
It is not known if appears in breast milk. You should consult your doctor before taking
if you are breast-feeding or intend to breast-feed.Driving and using machines

This subsection is not applicable for the 4 mg granules since they are intended for use
in children 6 months to 5 years of age, however the following information is relevant to the active
ingredient, montelukast.
is not expected to affect your ability to drive a car or operate machinery. However,
individual responses to medication may vary. Certain side effects (such as dizziness and drowsiness) that
have been reported very rarely with may affect some patients? ability to drive or
operate machinery.

3. HOW TO TAKE


?

This medicine is to be given to a child under adult supervision. Your child should take
every evening. ?

It should be taken even when your child has no symptoms or if he/she has an acute asthma attack. ?

Always have your child take as your doctor has told you. You should check
with your child?s doctor or pharmacist if you are not sure. ?

To be taken by mouth

For children 6 months to 5 years of age:

One sachet of 4 mg granules to be taken by mouth each evening.
If your child is taking , be sure that your child does not take any other products that
contain the same active ingredient, montelukast.
For children 6 months to 2 years old, 4 mg granules are available. For children 2 to 5 years old, 4 mg chewable tablets and 4 mg
granules are available. The 4 mg granules formulation is not recommended below 6
months of age.
How should I give granules to my child?
?

Do not open the sachet until ready to use. ?

granules can be given either:
- directly in the mouth;

- OR mixed with a spoonful of cold or room temperature soft food (for example, applesauce, ice

cream, carrots and rice). ?

Mix all of the contents of the granules into a spoonful of cold or room
temperature soft food, taking care to see that the entire dose is mixed with the food. ?

Be sure the child is given the entire spoonful of the granule/food mixture immediately (within 15
minutes). IMPORTANT: Never store any granule/food mixture for use at a later time. ?

granules are not intended to be dissolved in liquid. However, your child may
take liquids after swallowing the granules. ?

granules can be taken without regard to the timing of food intake.
If your child takes more than he/she should
Contact your child?s doctor immediately for advice. There were no side effects reported in the majority of overdose reports. The most frequently occurring
symptoms reported with overdose in adults and children included abdominal pain, sleepiness, thirst,
headache, vomiting, and hyperactivity.If you forget to give to your child
Try to give as prescribed. However, if your child misses a dose, just resume the usual
schedule of one sachet once daily.
Do not give a double dose to make up for a forgotten dose.
If your child stops taking
can treat your child's asthma only if he/she continues taking it. It is important for your child to continue taking for as long as your doctor prescribes. It
will help control your child?s asthma.

If you have any further questions on the use of this product, ask your child?s doctor or pharmacist.

4.
POSSIBLE SIDE EFFECTS


Like all medicines, can cause side effects, although not everybody gets them.
In clinical studies with 4 mg granules, the most commonly reported side effects
(occurring in at least 1 of 100 patients and less than 1 of 10 paediatric patients treated) thought to be
related to were:
?

diarrhoea
?

hyperactivity
?

asthma
?

scaly and itchy skin
?

rash
Additionally, the following side effects were reported in clinical studies with either
10 mg film-coated tablets, 5 mg or 4 mg chewable tablets:
?

abdominal pain
?

headache
?

thirst
These were usually mild and occurred at a greater frequency in patients treated with
than placebo (a pill containing no medication).

Additionally, while the medicine has been on the market, the following have been reported:
?

increased bleeding tendency
?

allergic reactions including rash, swelling of the face, lips, tongue, and/or throat which may cause
difficulty in breathing or swallowing
?

behaviour and mood related changes [dream abnormalities, including nightmares, hallucinations,
irritability, feeling anxious, restlessness, agitation including aggressive behaviour, tremor,
depression, trouble sleeping, suicidal thoughts and actions (in very rare cases)]
?

dizziness, drowsiness, pins and needles/numbness, seizure
?

palpitations
?

nosebleed
?

diarrhea, dry mouth, indigestion, nausea, vomiting
?

hepatitis
?

bruising, itching, hives, tender red lumps under the skin most commonly on your shins (erythema
nodosum),
?

joint or muscle pain, muscle cramps
?

tiredness, feeling unwell, swelling, feverIn asthmatic patients treated with montelukast, very rare cases of a combination of symptoms such as flu-
like illness, pins and needles or numbness of arms and legs, worsening of pulmonary symptoms and/or
rash (Churg-Strauss syndrome) have been reported. You must tell your doctor right away if your child
gets one or more of these symptoms.
Ask your doctor or pharmacist for more information about side effects. If any of the side effects gets
serious, or if you notice any side effects not listed in this leaflet, please tell your child?s doctor or
pharmacist.

5. HOW TO STORE


?

Keep out of the reach and sight of children. ?

Do not use this medicine after the date shown by the six numbers following EXP on the sachet. The
first two numbers indicate the month; the last four numbers indicate the year. This medicine expires
at the end of the month shown. ?

Store in the original package in order to protect from light and moisture. ?

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how
to dispose of medicines no longer required. These measures will help to protect the environment.

6.
FURTHER INFORMATION


What contains
?

The active substance is montelukast. Each sachet of granules contains montelukast sodium which
corresponds to 4 mg of montelukast. ?

The other ingredients are: Mannitol, hyprolose (E 463), and magnesium stearate.
What looks like and contents of the pack
4 mg granules are white granules.

Cartons of 7, 20, 28 and 30 sachets. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer

Marketing Authorization Holder and Manufacturer
Information is given by
{To be completed nationally}
{To be completed nationally}

This medicinal product is authorized in the Member States of the EEA under the following names:

Austria, Germany, Hungary, Netherlands, Romania,

AIRATHON

Belgium, Finland, Luxemburg, Portugal, Poland, Spain

AIRATHON and Montelukast MSD

CZECH RepublicMONTES and MONAIR

SLOVAKIA

AIRAMON and Montelair

This leaflet was last approved in {DD.MM.YYYY.}

Presentaciones:

BISOPROLOL NORMON 2,5MG 28 COMPRIMIDOS RECUBIERTOS PELICULA EFG

Envase:

COMPRIMIDO

Forma farmaceut.:

COMPRIMIDOS RECUBIERTOS CON PELICULA - FORMA ORAL LIBERACION INMEDIATA - Per Os (oral) - Comprimidos - Ingerir

Grupo:

COMPRIMIDOS

Unid. posológicas:28
Unid. contenido:C201
Precio:2,4 EUR
Precio referencia:3,12 EUR
Precio comercial:2,4 EUR
Situación:EFG -TRATAMIENTO LARGA DURACIÓN (TLD)
Composición:2,5MILIGRAMOS (MG) de BISOPROLOL HEMIFUMARATO

BISOPROLOL NORMON 2,5MG 100 COMPRIMIDOS RECUBIERTOS PELICULA EFG

Envase:

COMPRIMIDO

Forma farmaceut.:

COMPRIMIDOS RECUBIERTOS CON PELICULA - FORMA ORAL LIBERACION INMEDIATA - Per Os (oral) - Comprimidos - Ingerir

Grupo:

COMPRIMIDOS

Unid. posológicas:100
Unid. contenido:C201
Precio:5,55 EUR
Precio referencia:0 EUR
Precio comercial:5,55 EUR
Situación:ALTA GENERAL SIN CLASIFICAR
Composición:2,5MILIGRAMOS (MG) de BISOPROLOL HEMIFUMARATO