El Comité Asesor sobre Prácticas de Inmunización de los CDC vota de...

El Comité Asesor sobre Prácticas de Inmunización de los CDC vota de manera unánime a favor de la recomendación de agregar una segunda dosis de rutina de la vacuna contra la varicela al cronograma de inmunización infantil

VARIVAX(R) y PROQUAD(R) de Merck son las únicas vacunas contra la varicela disponibles en los EE.UU.


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Untitled Document

Whitehouse Station, NJ–(HISPANIC
PR WIRE – BUSINESS WIRE)–30 de junio de 2006–Merck & Co., Inc. anunció
hoy que el Comité de Asesoría sobre Prácticas de Inmunización
(ACIP, por sus siglas en inglés) de los Centros para el Control y la
Prevención de Enfermedades (CDC) votó [de manera unánime]
a favor de recomendar que los niños entre los 4 y los 6 años de
edad reciban una segunda dosis de vacuna contra la varicela para prevenir tal
enfermedad. El comité también recomendó que niños,
adolescentes y adultos que recibieron únicamente una dosis de la vacuna
contra la varicela reciban una segunda dosis "complementaria", la
cual pueden recibir durante las consultas rutinarias como parte de su atención
médica y como requisito de inscripción escolar y universitaria.

VARIVAX(R) [vacuna viva
contra la varicela (Oka/Merck)] y PROQUAD(R) [vacuna viva contra el sarampión,
las paperas, la rubéola y la varicela (Oka/Merck)] de Merck, son las
únicas vacunas que pueden proteger contra la varicela en los Estados
Unidos. VARIVAX ha sido aprobada para vacunar contra la varicela a personas
mayores de 1 año, y PROQUAD ha sido aprobada para vacunar simultáneamente
contra el sarampión, las paperas, la rubéola y la varicela a niños
desde los 12 meses hasta los 12 años de edad. La varicela es muy contagiosa,
se propaga fácilmente, y algunas veces puede conllevar a complicaciones
serias, como infecciones de la piel, neumonía y encefalitis (inflamación
del cerebro) que puede resultar en la hospitalización o, en casos aislados,
la muerte.

"Si bien el uso de
un régimen de una dosis de la vacuna contra la varicela ha reducido significativamente
los casos de varicela, creemos que aún hay más por hacer",
manifestó el Dr. Keith Reisinger, MD, Director Médico de Primary
Physicians Research. "Porque los datos clínicos han demostrado que
un régimen de dos dosis potencialmente podría disminuir el riesgo
de infección en un mayor grado, la recomendación del ACIP de que
los niños reciban una segunda dosis de la vacuna contra la varicela aumenta
la posibilidad de que la mayoría de los niños norteamericanos
dispongan de una protección aún mayor contra esta enfermedad potencialmente
seria".

La varicela sigue siendo
una grave inquietud de salud

Antes de la introducción
de VARIVAX en 1995, una cantidad estimada de cuatro millones de personas resultaban
infectadas por el virus de la varicela al año, de las cuales 11,000 requirieron
hospitalización. En 1996, el ACIP y los CDC añadieron la vacuna
contra la varicela a la lista de vacunas infantiles recomendadas. PROQUAD obtuvo
una licencia en 2005 y ofrece la oportunidad de administrar una vacuna simultánea
contra el sarampión, las paperas, la rubéola y la varicela, reduciendo
así el número de inyecciones administradas a niños, incrementando
a la vez la cobertura de la vacuna contra la varicela al nivel nacional de aquellas
contra el sarampión, las paperas y la rubéola, la cual en la actualidad
se calcula es del 93 por ciento para niños de 19 a 35 meses de edad.
Las tasas de cobertura contra la varicela aún varían ampliamente
en los diferentes estados, de 70 a 90 por ciento en niños de 19 a 35
meses de edad; en el 2004, se estima que un 12.5 por ciento de los niños
no estaban vacunados. La vacunación con VARIVAX o PROQUAD podría
no resultar en la protección de todos los niños, adolescentes
y adultos sanos y propensos a la enfermedad.

"Merck está
orgullosa de que el uso de nuestras vacunas haya contribuido a la reducción
de la incidencia de la varicela en los últimos 11 años",
expresó Mark Feinberg, MD y PhD., Vicepresidente de Políticas,
Salud Pública y Asuntos Médicos en Merck Vaccines. "Con el
uso extendido de dos dosis de la vacuna contra la varicela, esperamos observar
menos brotes de varicela, especialmente en escuelas, y esperamos ver reducciones
adicionales en el número de niños propensos a padecer la enfermedad".

El ACIP votó adicionalmente
para recomendar la inclusión de una segunda dosis de varicela en el programa
Vacunas infantiles [Vaccines for Children (VFC)] de los CDC. Desde 1994, el
programa VFC ha proporcionado vacunas a niños elegibles para el seguro
Medicaid, no asegurados, infraasegurados o Indioamericanos. Los niños
elegibles pueden recibir las vacunas recomendadas por el VFC una vez que los
CDC obtengan un contrato para adquirir la vacuna.

Dos dosis de vacuna contra
la varicela disminuyen el riesgo de desarrollar varicela en estudios clínicos

En un estudio aleatorio
y controlado en 2,216 niños de 12 meses a 12 años de edad que
comparó una dosis de vacuna contra la varicela (VARIVAX) con dos dosis
durante un periodo de 10 años, la eficacia estimada de la vacuna fue
del 94.4 por ciento para una dosis y 98.3 por ciento para dos dosis. Durante
el periodo de observación de 10 años, esto se traduce en un riesgo
3.3 veces menor de desarrollar varicela más de 42 días después
de la vacunación en niños que recibieron dos dosis que en aquellos
que recibieron una dosis (2.2 por ciento comparado con 7.5 por ciento, respectivamente).
En este estudio, 99.6 de los niños de 12 meses a 12 años de edad
que recibieron dos dosis de la vacuna contra la varicela (VARIVAX) con una separación
de tres meses alcanzaron un nivel de anticuerpos de protección seis semanas
después de recibir la vacuna, en comparación con el 85.7 por ciento
de aquellos que recibieron sólo una dosis. Se desconoce la duración
de la protección de VARIVAX.

Entre 981 niños que
recibieron dos dosis de VARIVAX con tres meses de diferencia, el régimen
de dos dosis fue bien tolerado en términos generales, con un perfil de
seguridad comparable a modo general con el del régimen de una dosis.
La incidencia de quejas referentes al lugar de la inyección (principalmente
enrojecimiento e hinchazón) observadas en los primeros cuatro días
posteriores a la vacunación fue ligeramente más alta después
de la segunda dosis (incidencia general del 25.4%) que después de la
primera dosis (incidencia general del 21.7%), mientras que la incidencia de
las quejas sistémicas en el periodo de seguimiento de 42 días
fue inferior después de la segunda dosis (66.3%) que después de
la primera dosis (85.8%).

Desde 1964, el ACIP, un
panel compuesto por 15 expertos en inmunización, ha provisto guía
y consejo al Departamento de Salud y Servicios Humanos de los EE.UU. y a los
CDC sobre los medios más efectivos para prevenir las enfermedades que
se pueden prevenir con vacunas. El Comité escribe recomendaciones con
respecto al uso de las vacunas entre la población pediátrica,
así como cronogramas con respecto a la periodicidad apropiada, dosis
y contraindicaciones aplicables a las vacunas. Además de la varicela
y el virus del papiloma humano de acuerdo con las recomendaciones realizadas
previamente el día de hoy, el ACIP actualmente recomienda vacunas para
uso rutinario en niños con el fin de prevenir la difteria, influenza
hemófila tipo b, la hepatitis A, la hepatitis B, la influenza, el sarampión,
la enfermedad meningocócica, las paperas, la tos ferina, la enfermedad
pneumocócica, la polio, el rotavirus, la rubéola y el tétano.
Merck fabrica vacunas para ayudar a proteger contra 9 de estas 16 enfermedades.

Información importante
sobre VARIVAX

VARIVAX ha sido aprobada
para su uso en individuos a partir de los 12 meses de edad. La dosis inicial
para niños entre los 12 meses y los 12 años de edad debe ser de
0.5 ml y administrada subcutáneamente. Si se administra una segunda dosis
de 0.5 ml, debe hacerse un mínimo de tres meses después. Los adolescentes
y los adultos mayores de 13 años deben recibir una dosis de 0.5 ml administrada
subcutáneamente en la fecha seleccionada y una segunda dosis de 0.5 ml
de 4 a 8 semanas después.

VARIVAX está contraindicada
en ciertos individuos, incluidos aquellos con: historial de hipersensibilidad
a cualquier componente de la vacuna, incluyendo la gelatina; un historial de
reacción anafilactoide a la neomicina; discrasia de la sangre, leucemia,
linfomas de cualquier tipo, u otro neoplasma maligno que afecte la médula
espinal o el sistema linfático; una condición inmunodeficiente
o que esté recibiendo terapia inmunosupresora; tuberculosis activa y
sin tratamiento; enfermedad febril activa, o las mujeres embarazadas.

En niños, adolescentes
y adultos monitoreados por hasta 42 días después de la vacunación,
los efectos adversos reportados con más frecuencia fueron los siguientes:
fiebre, molestias en el lugar de la inyección, erupción similar
a la varicela (en el sitio de la inyección) y erupción similar
a la varicela (generalizada).

No existen datos suficientes
para evaluar la tasa de protección de VARIVAX contra las complicaciones
de la varicela (por ejemplo, encefalitis, hepatitis, neumonía) en niños.

En un estudio en el que
los niños recibieron dos dosis de VARIVAX con tres meses de diferencia
entre una y otra dosis, el régimen de dos dosis de VARIVAX fue bien tolerado
en términos generales, con un perfil de seguridad comparable al del régimen
de una dosis. Se desconoce la duración de la protección contra
la infección por varicela después de la vacunación con
VARIVAX; sin embargo, los estudios de eficacia a largo plazo han demostrado
una protección continua hasta por 10 años después de la
vacunación. La vacunación con VARIVAX podría no tener como
resultado la protección de todos los niños, adolescentes y adultos
saludables susceptibles.

Información importante
sobre PROQUAD

PROQUAD es una vacuna de
virus vivo combinada que ha sido aprobada para su uso en niños entre
los 12 meses y los 12 años de edad que necesitan vacunarse contra los
virus del sarampión, las paperas, la rubéola y la varicela. No
hay datos clínicos disponibles con respecto a su inmunogenicidad y seguridad
en niños menores de 12 meses de edad. PROQUAD puede usarse en niños
de 12 meses a 12 años de edad si se requiere administrar una segunda
dosis contra el sarampión, las paperas y la rubéola.

Debe transcurrir al menos
un mes entre una dosis de la vacuna contra el sarampión, como la M-M-R(R)
II (vacuna viva contra virus de sarampión, paperas y rubéola)
y una dosis de PROQUAD. Si por alguna razón se requiere una segunda dosis
de vacuna contra la varicela, deben pasar por lo menos tres meses entre la administración
de ambas dosis.

PROQUAD no debe administrarse
a ciertos individuos, incluidos aquellos: con historial de reacciones anafiláticas
a la neomicina; historial de hipersensibilidad a la gelatina o a cualquier otro
componente de la vacuna; discrasias de la sangre, leucemia, linfomas de cualquier
tipo u otro neoplasma maligno que afecte la médula ósea o el sistema
linfático; que padezcan alguna enfermedad inmunodeficiente o que esté
recibiendo terapia inmunosupresora; tuberculosis activa sin tratamiento; enfermedad
febril activa (superior a 101.3 grados Fahrenheit); o mujeres embarazadas.

En ensayos clínicos
de PROQUAD con niños entre los 12 y 23 meses de edad, las experiencias
adversas en el sitio de la inyección reportadas con mayor frecuencia
(mayor que el 1% de los niños) fueron dolor/inflamación/sensibilidad,
eritema, hinchazón, equimoma y erupción. Las experiencias adversas
sistémicas relacionadas con la vacuna reportadas con mayor frecuencia
(mayor que el 1% de los niños) fueron fiebre (superior a 102 grados Fahrenheit),
irritabilidad, erupción parecida al sarampión, erupción
parecida a varicela, erupción (no especificado de otro modo), infección
de las vías respiratorias superiores, exantema viral y diarrea.

En un ensayo clínico
de 799 niños sanos de 4 a 6 años de edad que recibieron M-M-R
II y VARIVAX al menos un mes antes de su ingreso al ensayo, 399 recibieron PROQUAD
y placebo, mientras que 205 recibieron M-M-R II y placebo de manera concomitante
en sitios de inyección diferentes. Otros 195 niños sanos recibieron
M-M-R II y VARIVAX de manera concomitante en sitios de inyección diferentes.
En el ensayo clínico arriba descrito, las tasas de experiencias adversas
de reacciones en los sitios de la aplicación de la inyección,
nasofaringitis y tos, fueron generalmente similares entre los tres grupos del
tratamiento.

La vacunación con
PROQUAD puede no ofrecer un 100% de protección contra la infección
por sarampión, paperas, rubéola y varicela.

Se desconoce la duración
de la protección contra la infección por sarampión, paperas,
rubéola y varicela con PROQUAD.

Acerca de Merck

Merck & Co., Inc. es
una compañía farmacéutica que da prioridad por sobre todo
a los intereses del paciente. Fundada en 1891, Merck descubre, desarrolla, fabrica
y comercializa vacunas y medicinas en más de 20 categorías terapéuticas.
La compañía dedica grandes esfuerzos a aumentar el acceso a medicinas
a través de programas ambiciosos que no sólo donan medicinas de
Merck, sino que ayudan a llevarlas a las personas que las necesitan. Merck también
publica información de salud objetiva como un servicio sin fines de lucro.
Para obtener más información, visite http://www.merck.com.

Declaración a
futuro

Este comunicado de prensa
contiene "declaraciones a futuro", según dicho término
ha sido definido por la Private Securities Litigation Reform Act of 1995 (Ley
de Reforma de Litigio de Títulos Privados de 1995). Estas declaraciones
involucran riesgos e incertidumbres, los cuales pueden causar resultados que
difieran materialmente de aquéllos establecidos en estas declaraciones.
Las declaraciones a futuro pueden incluir declaraciones con respecto al desarrollo
de producto, el potencial de un producto o su rendimiento financiero. No se
pude garantizar ninguna declaración a futuro, y los resultados reales
pueden diferir materialmente de aquellos proyectados. Merck no asume obligación
alguna de actualizar públicamente ninguna declaración a futuro,
ya sea como resultado de información nueva, eventos futuros u otros.
Las declaraciones a futuro en este comunicado de prensa deben evaluarse conjuntamente
con las diversas incertidumbres que afectan el negocio de Merck, particularmente
aquellas mencionadas en la declaración de advertencia del punto 1 contenida
en el Formulario 10-K de Merck correspondiente al año finalizado del
31 de diciembre de 2004, y sus informes periódicos del Formulario 10-Q
y Formulario 8-K, los cuales la compañía incorpora a manera de
referencia.

Refiérase a la información
sobre prescripción adjunta para VARIVAX y PROQUAD.

PROQUAD(R) and VARIVAX(R)
are registered trademarks of Merck & Co., Inc., Whitehouse Station, N.J.,
U.S.A.

MMR(R) II is a registered
trademark of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.

ProQuad(R)
(Measles, Mumps, Rubella
and Varicella (Oka/Merck) Virus Vaccine Live)

DESCRIPTION

ProQuad*(C) is a combined
attenuated live virus vaccine containing measles, mumps, rubella, and varicella
viruses. ProQuad is a sterile lyophilized preparation of (1) the components
of M-M-R* II (Measles, Mumps and Rubella Virus Vaccine Live): Measles Virus
Vaccine Live, a more attenuated line of measles virus, derived from Enders’
attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps
Virus Vaccine Live, the Jeryl Lynn(TM) (B level) strain of mumps virus propagated
in chick embryo cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3
strain of live attenuated rubella virus propagated in WI-38 human diploid lung
fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck
strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus
pools, bovine serum, and human albumin used in manufacturing are all tested
to provide assurance that the final product is free of potential adventitious
agents.

ProQuad, when reconstituted
as directed, is a sterile preparation for subcutaneous administration. Each
0.5-mL dose contains not less than 3.00 log10 TCID50 (50% tissue culture infectious
dose) of measles virus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50
of rubella virus; and a minimum of 3.99 log10 PFU (plaque-forming units) of
Oka/Merck varicella virus.

Each 0.5-mL dose of the vaccine
contains no more than 21 mg of sucrose, 11 mg of hydrolyzed gelatin, 2.4 mg
of sodium chloride, 1.8 mg of sorbitol, 0.40 mg of monosodium L-glutamate, 0.34
mg of sodium phosphate dibasic, 0.31 mg of human albumin, 0.17 mg of sodium
bicarbonate, 72 mcg of potassium phosphate monobasic, 60 mcg of potassium chloride;
36 mcg of potassium phosphate dibasic; residual components of MRC-5 cells including
DNA and protein; <16 mcg of neomycin, bovine calf serum (0.5 mcg), and other
buffer and media ingredients. The product contains no preservative.

CLINICAL PHARMACOLOGY

Background

Measles, mumps, rubella, and
varicella are 4 common childhood diseases caused by measles virus, mumps virus,
rubella virus, and varicella virus, respectively. These diseases may be associated
with serious complications and/or death. For example, measles can be associated
with pneumonia and encephalitis; mumps can be associated with aseptic meningitis,
deafness, and orchitis; rubella occurring during pregnancy can cause congenital
rubella syndrome in the infants of infected mothers; and wild-type varicella
can be associated with bacterial superinfection, pneumonia, encephalitis, and
Reye’s syndrome.

Mechanism of action

In clinical efficacy studies,
seroconversion in response to vaccination against measles, mumps, and rubella
paralleled protection from these diseases. Also, in previous studies with varicella
vaccine, antibody responses against varicella virus (>=)5 units/mL in a glycoprotein
enzyme-linked immunosorbent assay (gpELISA) (not commercially available) similarly
correlated with long-term protection. Clinical studies with a single dose of
ProQuad have shown that vaccination elicited rates of antibody responses against
measles, mumps, and rubella that were similar to those observed after vaccination
with a single dose of M-M-RII (see CLINICAL STUDIES) and seroresponse rates
for varicella virus were similar to those observed after vaccination with a
single dose of VARIVAX (see CLINICAL STUDIES). The duration of protection from
measles, mumps, rubella, and varicella infections after vaccination with ProQuad
is unknown.

* Registered trademark of
Merck & Co., Inc.
Copyright 2005 Merck
& Co., Inc.
All rights reserved

Persistence of Antibody Responses
after Vaccination

The persistence of antibody
at 1 year after vaccination was evaluated in a subset of 2107 children enrolled
in the clinical trials. Antibody was detected in 98.9% (1722/1741) for measles,
96.7% (1676/1733) for mumps, 99.6% (1796/1804) for rubella, and 97.5% (1512/1550)
for varicella (=>5 gpELISA units/mL) of vaccinees following a single dose
of ProQuad.

Experience with M-M-RII demonstrates
that antibodies to measles, mumps, and rubella viruses are still detectable
in most individuals 11 to 13 years after primary vaccination.1 Varicella antibodies
were present for up to ten years post-vaccination in most of the individuals
tested who received 1 dose of VARIVAX.

CLINICAL STUDIES

Formal studies to evaluate
the clinical efficacy of ProQuad have not been performed.

Efficacy of the measles, mumps,
rubella and varicella components of ProQuad was previously established in a
series of clinical studies with the monovalent vaccines. A high degree of protection
from infection was demonstrated in these studies.2-9

Immunogenicity

Immunogenicity was studied
in 5835 healthy children 12 months to 6 years of age with a negative clinical
history of measles, mumps, rubella, and varicella who participated in 5 randomized
clinical trials. The immunogenicity of ProQuad was similar to that of its individual
component vaccines (M-M-RII and VARIVAX), which are currently used in routine
immunization.

The presence of detectable
antibody was assessed by an appropriately sensitive enzyme-linked immunosorbent
assay (ELISA) for measles, mumps (wild type and vaccine type strains), and rubella,
and by gpELISA for varicella. For evaluation of vaccine response rates, a positive
result in the measles ELISA corresponded to measles antibody concentrations
of =>255 mIU/mL when compared to the WHO II (66/202) Reference Immunoglobulin
for Measles.

Children were positive for
mumps antibody if the antibody level was =>10 ELISA units/mL. A positive
result in the rubella ELISA corresponded to concentrations of =>10 IU rubella
antibody/mL when compared to the WHO International Reference Serum for Rubella;
children with varicella antibody levels =>5 gpELISA units/mL were considered
to be seropositive since a response rate based on =>5 gpELISA units/mL has
been shown to be highly correlated with long-term protection.

Children who received a single
dose of ProQuad at 12-23 months of age

In 4 randomized clinical trials,
5446 healthy children 12 to 23 months of age were administered ProQuad, and
2038 children were vaccinated with M-M-RII and VARIVAX given concomitantly at
separate injection sites. Subjects enrolled in each of these trials had a negative
clinical history, no known recent exposure and no vaccination history for varicella,
measles, mumps, and rubella. Children were excluded from study participation
if they had an immune impairment or had a history of allergy to components of
the vaccine(s). Except for in 1 trial (see Studies With Other Vaccines), no
concomitant vaccines were permitted during study participation. Following a
single dose of ProQuad, the vaccine response rates were 97.4% (95% CI: 96.9,
97.9) for measles, 95.8 (95% CI: 95.1, 96.4) to 98.8% (95% CI: 97.9, 99.4) for
mumps, and 98.5% (95% CI: 98.1, 98.8) for rubella. The vaccine response rate
was 91.2% (95% CI: 90.3, 92.0) for varicella. These results were similar to
the immune response rates induced by concomitant administration of single doses
of M-M-RII and VARIVAX at separate injection sites. Fever and measles-like rashes
were the only adverse experiences that occurred more frequently in recipients
of a single dose of ProQuad compared with recipients of single doses of M-M-RII
and VARIVAX (see ADVERSE REACTIONS).

Children Who Received a Second
Dose of ProQuad

In 2 of the 4 randomized clinical
trials described above, a subgroup (N=1035) of the 5446 children administered
a single dose of ProQuad were administered a second dose of ProQuad approximately
3 months after the first dose. Children were excluded from receiving a second
dose of ProQuad if they were recently exposed to or developed varicella, measles,
mumps, and/or rubella prior to receipt of the second dose. No concomitant vaccines
were administered to these children. The proportion of initially seronegative
vaccinees with positive serological responses following two doses were 99.4%
(95% CI: 98.6, 99.8) for measles, 99.9% (95% CI: 99.4, 100) for mumps, 98.3%
(95% CI: 97.2, 99.0) for rubella, and 99.4% (95% CI: 98.7, 99.8) for varicella
(=>5 gpELISA units/mL). The geometric mean titers (GMTs) following the second
dose of ProQuad increased approximately 2-fold each for measles, mumps, and
rubella, and approximately 41-fold for varicella.

In these trials, the rates
of adverse experiences after the second dose of ProQuad were generally similar
to, or lower than, those seen with the first dose. The fever rate was lower
after the second dose than after the first dose.

Children Who Received ProQuad
at 4 to 6 Years of Age After Primary Vaccination With M-M-RII and VARIVAX

In a clinical trial involving
799 healthy 4- to 6-year-old children who had received M-M-RII and VARIVAX at
least 1 month prior to study entry, 399 received ProQuad and placebo while 205
received M-M-RII and placebo concomitantly at separate injection sites. Another
195 healthy children were administered M-M-RII and VARIVAX concomitantly at
separate injection sites. Children were eligible if they were previously administered
primary doses of M-M-RII and VARIVAX, either concomitantly or non-concomitantly,
at 12 months of age or older. Children were excluded if they were recently exposed
to measles, mumps, rubella, and/or varicella, had an immune impairment, or had
a history of allergy to components of the vaccine(s). No concomitant vaccines
were permitted during study participation.

Following the dose of ProQuad,
seropositivity rates were 99.2% (95% CI: 97.6, 99.8) for measles, 99.5% (95%
CI: 98.0, 99.9) for mumps, 100% (95% CI: 99.0, 100) for rubella, and 98.9% (95%
CI: 97.2, 99.7) for varicella (=>5 gpELISA units/mL). Approximate geometric
mean fold-rises in antibody titers (pre-vaccination to post-vaccination) for
measles, mumps, rubella, and varicella were 1.2, 2.4, 3.0 and 12, respectively.
Post-vaccination GMTs for recipients of ProQuad were similar to those following
a second dose of M-M-RII and VARIVAX administered concomitantly at separate
injection sites. Additionally, GMTs for measles, mumps, and rubella were similar
to those following a second dose of M-M-RII given concomitantly with placebo.
The rates of adverse experiences, including the most commonly reported adverse
experiences of injection site reactions, nasopharyngitis and cough were generally
similar among the 3 treatment groups.

Studies With Other Vaccines

In a clinical trial involving
1913 healthy children 12 to 15 months of age, 949 received ProQuad plus Diphtheria
and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus
Influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis
B (Recombinant) Vaccine concomitantly at separate injection sites. Another 485
healthy children received ProQuad at the initial visit followed by DTaP and
Haemophilus b Conjugate and Hepatitis B (Recombinant) Vaccine given concomitantly
6 weeks later while 479 children were immunized with M-M-RII and VARIVAX given
concomitantly at separate injection sites at the first visit. Seroconversion
rates and antibody titers for measles, mumps, rubella, varicella, anti-PRP and
hepatitis B were comparable between the 2 groups at approximately 6 weeks post-vaccination
indicating the ProQuad and Haemophilus b Conjugate (Meningococcal Protein Conjugate)
and Hepatitis B (Recombinant) Vaccine may be administered concomitantly at separate
injection sites. There are insufficient data to support concomitant immunization
with diphtheria, tetanus and acellular pertussis vaccine. No clinically significant
differences in adverse experiences were reported between treatment groups.

Herpes Zoster

2 cases of herpes zoster were
reported in 2108 healthy subjects 12 to 23 months of age who were vaccinated
with ProQuad in clinical trials and followed for 1 year. Both cases were unremarkable
and no sequelae were reported (see ADVERSE REACTIONS, Other).

Reye’s Syndrome

Reye’s syndrome following
wild-type varicella infection has occurred in children and adolescents, the
majority of whom had received salicylates. In clinical studies of ProQuad or
VARIVAX, the recommendation was made to avoid the use of salicylates for 6 weeks
after vaccination. There were no reports of Reye’s syndrome in recipients of
ProQuad or VARIVAX during these studies.

INDICATIONS AND USAGE

ProQuad is indicated for simultaneous
vaccination against measles, mumps, rubella, and varicella in children 12 months
to 12 years of age.

ProQuad may be used in children
12 months to 12 years of age if a second dose of measles, mumps and rubella
vaccine is to be administered.

CONTRAINDICATIONS

ProQuad should not be administered:

— to individuals with a history
of anaphylactic reactions to neomycin. If vaccination with ProQuad is medically
necessary for such individuals, they are advised to consult an allergist or
immunologist and should receive ProQuad only in settings where anaphylactic
reactions can be appropriately managed.
— to individuals with
a history of hypersensitivity to gelatin or any other component of the vaccine
(see WARNINGS for exceptions).
— to individuals with
blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms
affecting the bone marrow or lymphatic system.
— to individuals on
immunosuppressive therapy (including high-dose systemic corticosteroids); ProQuad
may be used by individuals who are receiving topical corticosteroids or low-dose
corticosteroids, as are commonly used for asthma prophylaxis or in patients
who are receiving corticosteroids as replacement therapy, e.g., for Addison’s
disease.
— to individuals with
primary and acquired immunodeficiency states, including AIDS or other clinical
manifestations of infection with human immunodeficiency viruses; cellular immune
deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. Measles
inclusion body encephalitis, pneumonitis, and death as a direct consequence
of disseminated measles vaccine virus infection have been reported in severely
immunocompromised individuals inadvertently vaccinated with measles-containing
vaccine.
— to individuals with
a family history of congenital or hereditary immunodeficiency, unless the immune
competence of the potential vaccine recipient is demonstrated.
— to individuals with
active untreated tuberculosis.
— to individuals with
an active febrile illness with fever >101.3(degree)F (>38.5(degree)C).
— to individuals who
are pregnant; the possible effects of the vaccine on fetal development are unknown
at this time (see PRECAUTIONS, Pregnancy).

WARNINGS

Caution should be exercised
in administering ProQuad to persons with a history of cerebral injury, individual
or family history of convulsions, or any other condition in which stress due
to fever should be avoided. The physician should be alert to the temperature
elevations that may occur following vaccination (see ADVERSE REACTIONS). Vaccination
with a live attenuated vaccine, such as varicella, can result in a more extensive
vaccine-associated rash or disseminated disease in individuals on immunosuppressive
drugs.

Hypersensitivity to Eggs

Live measles vaccine and live
mumps vaccine are produced in chick embryo cell culture. Persons with a history
of anaphylactic or other immediate hypersensitivity reactions (e.g., hives,
swelling of the mouth and throat, difficulty breathing, hypotension, or shock)
subsequent to egg ingestion may be at an enhanced risk of immediate-type hypersensitivity
reactions after receiving vaccines containing traces of chick embryo antigen.
The potential risk-to-benefit ratio should be carefully evaluated before considering
vaccination in such cases. Such individuals may be vaccinated with extreme caution;
adequate treatment should be readily available should a reaction occur (see
PRECAUTIONS).10

Children with egg allergy
are at low risk for anaphylactic reactions to measles-containing vaccines (including
MMR), and skin testing of children allergic to eggs is not predictive of reactions
to MMR vaccine. Persons with allergies to chickens or feathers are not at increased
risk of reaction to the vaccine.10

Hypersensitivity to Neomycin

Most often, neomycin allergy
manifests as a contact dermatitis, which is not a contraindication to receiving
measles, mumps, rubella or varicella containing vaccine.

Thrombocytopenia

No clinical data are available
regarding the development or worsening of thrombocytopenia in individuals vaccinated
with ProQuad. Cases of thrombocytopenia have been reported after use of measles
vaccine, measles, mumps and rubella vaccine and after varicella vaccination.
Post-marketing experience with live measles, mumps, and rubella vaccine indicates
that individuals with current thrombocytopenia may develop more severe thrombocytopenia
following vaccination. In addition, individuals who experienced thrombocytopenia
following the first dose of a live measles, mumps, and rubella vaccine may develop
thrombocytopenia with repeat doses. Serologic testing for antibody to measles,
mumps or rubella should be considered in order to determine if additional doses
of vaccine are needed. The potential risk-to-benefit ratio should be carefully
evaluated before considering vaccination with ProQuad in such cases.

Theoretical Risk of Transmission
of Creutzfeld-Jakob Disease

This product contains albumin,
a derivative of human blood. Based on effective donor screening and product
manufacturing processes, it carries an extremely remote risk for transmission
of viral diseases. Although there is a theoretical risk for transmission of
Creutzfeld-Jakob disease (CJD), no cases of transmission of CJD or viral disease
have ever been identified that were associated with the use of albumin.

PRECAUTIONS

General

Prior to administering the
vaccine, obtain the prospective vaccinee’s vaccination history and determine
whether the individual had any previous reactions to any vaccine including ProQuad,
VARIVAX or any measles, mumps or rubella containing vaccines.

Adequate treatment provisions,
including epinephrine injection (1:1000), should be available for immediate
use should an anaphylactic reaction occur.

Vaccination with a live attenuated
vaccine, such as varicella, can result in a more extensive vaccine-associated
rash or disseminated disease in individuals on immunosuppressive doses of corticosteroids.

The safety and efficacy of
ProQuad for use after exposure to measles, mumps, rubella or varicella have
not been established.

The safety and efficacy of
ProQuad for use in children and young adults who are known to be infected with
human immunodeficiency viruses have not been established (see CONTRAINDICATIONS).

Transmission

Excretion of small amounts
of the live attenuated rubella virus from the nose or throat has occurred in
the majority of susceptible individuals 7 to 28 days after vaccination. There
is no confirmed evidence to indicate that such virus is transmitted to susceptible
persons who are in contact with the vaccinated individuals. Consequently, transmission
through close personal contact, while accepted as a theoretical possibility,
is not regarded as a significant risk. However, transmission of the rubella
vaccine virus to infants via breast milk has been documented (see PRECAUTIONS,
Nursing Mothers).

There are no reports of transmission
of the more attenuated Ender’s Edmonston strain of measles virus or the Jeryl
Lynn(TM) strain of mumps virus from vaccine recipients to susceptible contacts.

Post-licensing experience
with VARIVAX suggests that transmission of varicella vaccine virus may occur
rarely between healthy vaccine recipients who develop a varicella-like rash
and contacts susceptible to varicella, as well as high-risk individuals susceptible
to varicella.

High-risk individuals susceptible
to varicella include:

— Immunocompromised individuals;
— Pregnant women without
documented positive history of varicella (chickenpox) or laboratory evidence
of prior infection;
— Newborn infants of
mothers without documented positive history of varicella or laboratory evidence
of prior infection.

Vaccine recipients should
attempt to avoid, to the extent possible, close association with high-risk individuals
susceptible to varicella for up to 6 weeks following vaccination. In circumstances
where contact with high-risk individuals susceptible to varicella is unavoidable,
the potential risk of transmission of the varicella vaccine virus should be
weighed against the risk of acquiring and transmitting wild-type varicella virus.

Information for Patients

The health care provider should
provide the required vaccine information to the patient, parent, or guardian.

The health care provider should
inform the patient, parent, or guardian of the benefits and risks associated
with vaccination.

The health care provider should
tell the vaccine recipient or his or her parent or guardian that the vaccine
recipient should avoid use of salicylates for 6 weeks after vaccination with
ProQuad (see DRUG INTERACTIONS).

Female vaccine recipients
of childbearing age should be told to avoid pregnancy for 3 months following
vaccination.

Patients, parents, or guardians
should be told that vaccination with ProQuad may not offer 100% protection from
measles, mumps, rubella, and varicella infection.

Patients, parents, or guardians
should be instructed to report any adverse reactions to their health care provider.
The U.S. Department of Health and Human Services has established a Vaccine Adverse
Event Reporting System (VAERS) to accept all reports of suspected adverse events
after the administration of any vaccine, including but not limited to the reporting
of events required by the National Childhood Vaccine Injury Act of 1986. The
VAERS toll-free number for VAERS forms and information is 1-800-822-7967 or
information may be submitted electronically via http://www.fda.gov/cber/vaers/vaers.htm

Drug Interactions

Immune Globulins and Transfusions

Immune globulins administered
concomitantly with ProQuad may interfere with the expected immune response.
Vaccination should be deferred for at least 3 months following blood or plasma
transfusions, or administration of immune globulins (IG).

The appropriate suggested
interval between transfusion or IG administration and vaccination will vary
with the type of transfusion or indication for, and dose of, IG (e.g., 5 months
for Varicella Zoster Immune Globulin (VZIG)).10 Following administration of
ProQuad, any immune globulin (IG) including VZIG should not be given for 1 month
thereafter unless its use outweighs the benefits of vaccination.10

Salicylates

Reye’s syndrome has been reported
following the use of salicylates during wild-type varicella infection. Vaccine
recipients should avoid use of salicylates for 6 weeks after vaccination with
ProQuad.

Corticosteroids and Immunosuppressive
Drugs

ProQuad may be used in individuals
who are receiving topical corticosteroids or low-dose corticosteroids for asthma
prophylaxis or replacement therapy, e.g., for Addison’s disease. ProQuad should
not be given to individuals receiving immunosuppressive doses of corticosteroids
or other immunosuppressive drugs.

Drug/Laboratory Test Interactions

Live attenuated measles, mumps,
and rubella virus vaccines given individually may result in a temporary depression
of tuberculin skin sensitivity. Therefore, if a tuberculin test is to be done,
it should be administered either any time before, simultaneously with, or at
least 4 to 6 weeks after ProQuad.

Use with Other Vaccines

At least 1 month should elapse
between a dose of a measles-containing vaccine such as M-M-RII, and a dose of
ProQuad. If for any reason a second dose of varicella-containing vaccine is
required, at least 3 months should elapse between administration of the 2 doses.

ProQuad may be administered
concomitantly with Haemophilus influenzae type b conjugate (meningococcal protein
conjugate) and hepatitis B (recombinant) vaccine.

There are no data regarding
the administration of ProQuad with inactivated poliovirus vaccine or pneumococcal
conjugate vaccine.

There are insufficient data
to support concomitant vaccination with diphtheria, tetanus and acellular pertussis
vaccine (see CLINICAL STUDIES, Studies with Other Vaccines).

Children under treatment for
tuberculosis have not experienced exacerbation of the disease when vaccinated
with live measles virus vaccine; no studies have been reported to date of the
effect of measles virus vaccines on children with untreated tuberculosis.

Carcinogenesis, Mutagenesis,
Teratogenicity, Impairment of Fertility

ProQuad has not been evaluated
for its carcinogenic, mutagenic or teratogenic potential, or its potential to
impair fertility.

Pregnancy

Pregnancy Category C: Animal
reproduction studies have not been conducted with ProQuad.

It is also not known whether
ProQuad can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Therefore, ProQuad should not be administered to pregnant
females. If vaccination of post-pubertal females is undertaken, pregnancy should
be avoided for 3 months following vaccination (see CONTRAINDICATIONS).

In counseling women who are
inadvertently vaccinated when pregnant or who become pregnant within 3 months
of vaccination, the physician should be aware of the following: (1) Reports
have indicated that contracting wild-type measles during pregnancy enhances
fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital
defects and prematurity have been observed subsequent to natural measles during
pregnancy. There are no adequate studies of the attenuated (vaccine) strain
of measles virus in pregnancy. However, it would be prudent to assume that the
vaccine strain of virus is also capable of inducing adverse fetal effects; (2)
Mumps infection during the first trimester of pregnancy may increase the rate
of spontaneous abortion. Although mumps vaccine virus has been shown to infect
the placenta and fetus, there is no evidence that it causes congenital malformations
in humans;11 and (3) In a 10-year survey involving over 700 pregnant women who
received rubella vaccine within 3 months before or after conception (of whom
189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities
compatible with congenital rubella syndrome;12 (4) Wild-type varicella can sometimes
cause congenital varicella infection.

Merck & Co., Inc. maintains
a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to
varicella-containing vaccine (Oka/Merck). In the first 9 years of the Pregnancy
Registry for varicella vaccine (Oka/Merck), of 129 seronegative women and 423
women of unknown serostatus who received varicella vaccine during pregnancy
or within 3 months before pregnancy, none had newborns with abnormalities compatible
with congenital varicella syndrome.

Patients and health care providers
are encouraged to report any exposure to varicella-containing vaccine (Oka/Merck)
during pregnancy by calling (800) 986-8999.

Nursing Mothers

The secretion of viruses in
human milk has not been studied in measles and mumps vaccine viruses. Studies
have shown that lactating postpartum women vaccinated with live rubella vaccine
may secrete the virus in breast milk and transmit it to breast-fed infants.
Limited evidence in the literature suggests that virus, viral DNA, or viral
antigen could not be detected in the breast milk of women who were vaccinated
postpartum with the vaccine strain of varicella virus.13-14 For additional information
on transmission of vaccine virus from vaccine recipients to susceptible infants
see Transmission. ProQuad should not be administered to nursing women.

Pediatric Use

No clinical data are available
on the safety, immunogenicity, and efficacy of ProQuad in children less than
12 months of age.

Geriatric Use

ProQuad is not indicated for
use in the geriatric population ((>=)age 65).

ADVERSE REACTIONS

Children 12 to 23 Months of
Age

ProQuad was administered to
4497 children 12 to 23 months of age in clinical trials without concomitant
administration with other vaccines. The safety of ProQuad was compared with
the safety of M-M-RII and VARIVAX given concomitantly at separate injection
sites. The safety profile for ProQuad was similar to the component vaccines.
Children in these studies were monitored for up to 42 days post-vaccination.
The only systemic vaccine-related adverse experiences that were reported at
a significantly greater rate in individuals who received ProQuad than in individuals
who received M-M-RII and VARIVAX concomitantly at separate injection sites were
fever (=>102(degree)F (=>38.9(degree)C) oral equivalent or abnormal) (21.5%
versus 14.9%, respectively, and measles-like rash (3.0% versus 2.1%, respectively).
Both fever and measles-like rash usually occurred within 5 to 12 days following
the vaccination, were of short duration, and resolved with no long-term sequelae.
Pain/tenderness/soreness at the injection site was reported at a statistically
lower rate in individuals who received ProQuad than in individuals who received
M-M-RII and VARIVAX concomitantly at separate injection sites (22.0% versus
26.7%, respectively). The only vaccine-related injection-site adverse experience
that was more frequent among recipients of ProQuad than recipients of M-M-RII
and VARIVAX was rash at the injection site (2.3% versus 1.5%, respectively).
Table 1 summarizes the frequencies of injection-site and systemic adverse experiences
that were reported as vaccine related by the investigator among =>1% of children
in these clinical trials.

                               
Table 1

    Vaccine-Related Injection-Site and Systemic Adverse Experiences
    Reported
in =>1% of Children Who Received 1 Dose of ProQuad or
            
M-M-RII and VARIVAX at 12 to 23 Months of Age
                     
(0-42 Days Postvaccination)

Adverse Experiences                                     
M-M-RII
                                          
ProQuad      and VARIVAX
                                         
(N = 4497)     (N = 2038)
                                             
%              
%
———————————————————————-
Injection Site+
  Pain/tenderness/soreness++                
22.0            26.7
  Erythema++                                
14.4            15.8
  Swelling++                                 
8.4            
9.8
  Ecchymosis        
                         1.5            
2.3
  Rash                                       
2.3            
1.5
———————————————————————-
Systemic
  Fever =>102(degree)F
   (=>38.9(degree)C)++ss.               
    21.5           
14.9
  Irritability                               
6.7            
6.7
  Measles-like
rash++                        
3.0            
2.1
  Varicella-like
rash++                      
2.1            
2.2
  Rash (not otherwise
specified)              1.6            
1.4
  Upper respiratory
infection                
1.3            
1.1
  Viral exanthema                            
1.2            
1.1
  Diarrhea                                   
1.2            
1.3
———————————————————————-

+ Injection-site adverse experiences
for M-M-RII and VARIVAX are based
  on occurrence
with either of the vaccines administered.

++ Designates a solicited
adverse experience. Injection-site adverse
   experiences
were solicited only from Days 0-4 postvaccination.

ss. Temperature reported as
oral equivalent or abnormal.

The following additional vaccine-related
clinical adverse experiences (incidence =>0.2% but <1%) were observed
in individuals following a single dose of ProQuad. Solicited adverse experiences
are designated with the symbol (++).

— Infections and infestations:
otitis, otitis media, pharyngitis, viral infection.
— Metabolism and nutrition
disorders: anorexia.
— Psychiatric disorders:
crying, insomnia, sleep disorder.
— Nervous system disorders:
somnolence.
— Respiratory, thoracic,
and mediastinal disorders: cough, nasal congestion, respiratory congestion,
rhinorrhea.
— Gastrointestinal
disorders: vomiting.
— Skin and subcutaneous
tissue disorders: miliaria rubra, rubella-like rash++.
— General disorders
and administration site conditions: malaise.

Adverse Experiences after
vaccination with M-M-RII or VARIVAX

Other adverse experiences
have been reported in clinical studies and with marketed use of either M-M-RII,
the monovalent component vaccines of M-M-RII, or VARIVAX. These adverse effects
are listed below without regard to causality or frequency.

Infections and infestations
— Atypical measles,
candidiasis, cellulitis, herpes zoster, infection, influenza, measles, orchitis,
parotitis, respiratory infection, skin infection.
— Blood and the lymphatic
system disorders
— Lymphadenitis, regional
lymphadenopathy, thrombocytopenia.

Immune system disorders
— Anaphylactoid reaction,
anaphylaxis and related phenomenon such as angioneurotic edema, facial edema,
and peripheral edema, anaphylaxis in individuals with or without an allergic
history.

Psychiatric disorders
— Agitation, apathy,
nervousness.

Nervous system disorders
— Afebrile convulsions
or seizures, aseptic meningitis (see below), Bell’s palsy, cerebrovascular accident,
dizziness, dream abnormality,encephalitis (see below), encephalopathy (see below),
Guillain-Barre syndrome, headache, hypersomnia, measles inclusion body encephalitis
(see CONTRAINDICATIONS), ocular palsies, paraesthesia, polyneuritis, polyneuropathy,
subacute sclerosing panencephalitis (see below), syncope, transverse myelitis,
tremor.

Eye disorders
— Edema of the eyelid,
irritation, optic neuritis, retinitis, retrobulbar neuritis.

Ear and labyrinth disorders
— Ear pain, nerve deafness.

Vascular disorders
— Extravasation.

Respiratory, thoracic and
mediastinal disorders

— Bronchial spasm, bronchitis,
epistaxis, pneumonitis (see CONTRAINDICATIONS), pneumonia, pulmonary congestion,
rhinitis, sinusitis, sneezing, sore throat, wheezing.

Gastrointestinal disorders
— Abdominal pain, flatulence,
hematochezia, mouth ulcer.

Skin and subcutaneous tissue
disorders
— Erythema multiforme,
Henoch-Schonlein purpura, herpes simplex, impetigo, panniculitis, pruritus,
purpura, skin induration, Stevens-Johnson syndrome, sunburn.

Musculoskeletal, connective
tissue and bone disorders
— Arthritis and/or
arthralgia (usually transient and rarely chronic (see below)), musculoskeletal
pain, myalgia, pain of the hip, leg, or neck, swelling.

General disorders and administration
site conditions
— Injection-site complaints
(burning and/or stinging of short duration, eczema, edema/swelling, hive-like
rash, discoloration, hematoma, induration, lump, vesicles, wheal and flare),
inflammation, lip abnormality, papillitis, roughness/dryness, stiffness, trauma,
varicella-like rash, venipuncture site hemorrhage, warm sensation, warm to touch.

Post-marketing surveillance

The discussion that follows
describes adverse reactions which have been identified post approval for the
monovalent components of ProQuad. Because these reactions are described in the
literature or reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship.

Death from various, and in
some cases unknown, causes has been reported rarely following vaccination with
measles, mumps, and rubella vaccines; however, a causal relationship has not
been established in healthy individuals. Death as a direct consequence of disseminated
measles vaccine virus infection has been reported in severely immunocompromised
individuals in whom a measles containing vaccine is contraindicated and who
were inadvertently vaccinated. However, there were no deaths or permanent sequelae
reported in a published post-marketing surveillance study in Finland involving
1.5 million children and adults who were vaccinated with M-M-RII during 1982
to 1993.15

Encephalitis and encephalopathy
have been reported approximately once for every 3 million doses of the combination
of measles, mumps, and rubella vaccine contained in M-M-RII. Post-marketing
surveillance of the more than 400 million doses that have been distributed worldwide
(1978 to 2003) indicates that serious adverse events such as encephalitis and
encephalopathy continue to be rarely reported. In no case has it been shown
conclusively that reactions were actually caused by the vaccine; however, the
data suggest the possibility that some of these cases may have been caused by
measles vaccines. The risk of such serious neurological disorders following
live measles virus vaccine administration remains far less than that for encephalitis
and encephalopathy with wild-type measles (1 per 2000 reported cases).

Arthralgia and/or arthritis
(usually transient and rarely chronic), and polyneuritis are features of infection
with wild-type rubella and vary in frequency and severity with age and gender,
being greatest in adult females and least in prepubertal children. Following
vaccination in children, reactions in joints are generally uncommon (0 to 3%)
and of brief duration. In women, incidence rates for arthritis and arthralgia
are generally higher than those seen in children (12 to 26%), and the reactions
tend to be more marked and of longer duration. Symptoms may persist for a matter
of months or on rare occasions for years. In adolescent girls, the reactions
appear to be intermediate in incidence between those seen in children and adult
women. In women 35 to 45 years old these reactions are generally well tolerated
and rarely interfere with normal activities.

Chronic arthritis has been
associated with wild-type rubella infection and has been related to persistent
virus and/or viral antigen isolated from body tissues. Only rarely have vaccine
recipients developed chronic joint symptoms.

There have been reports of
subacute sclerosing panencephalitis (SSPE) in children who did not have a history
of infection with wild-type measles but did receive measles vaccine. Some of
these cases may have resulted from unrecognized measles in the first year of
life or possibly from the measles vaccination. Based on estimated measles vaccine
distribution in the United States (US), the association of SSPE cases to measles
vaccination is about one case per million vaccine doses distributed. This is
far less than the association with infection with wild-type measles, 6 to 22
cases of SSPE per million cases of measles. The results of a retrospective case-controlled
study suggest that the overall effect of measles vaccine has been to protect
against SSPE by preventing measles with its inherent higher risk of SSPE.

Cases of aseptic meningitis
have been reported to VAERS following measles, mumps, and rubella vaccination.
Although a causal relationship between other strains of mumps vaccine and aseptic
meningitis has been shown, there is no evidence to link Jeryl Lynn(TM) mumps
vaccine to aseptic meningitis.

The reported rate of zoster
in recipients of VARIVAX appears not to exceed that previously determined in
a population-based study of healthy children who had experienced wild-type varicella.16
In clinical trials, 8 cases of herpes zoster were reported in 9454 vaccinated
individuals 12 months to 12 years of age during 42,556 person-years of follow-up.
This resulted in a calculated incidence of at least 18.8 cases per 100,000 person-years.
All 8 cases reported after VARIVAX were mild and no sequelae were reported.
The long-term effect of VARIVAX on the incidence of herpes zoster is unknown
at present.

DOSAGE AND ADMINISTRATION

Dosage

When reconstituted, each vial
of ProQuad contains a single 0.5-mL dose. Individuals 12 months through 12 years
of age should receive a single 0.5-mL dose of ProQuad administered subcutaneously.
At least 1 month should elapse between a dose of a measles-containing vaccine
such as M-M-RII, and a dose of ProQuad. If for any reason a second dose of varicella-containing
vaccine is required, at least 3 months should elapse between administration
of the 2 doses.

Preparation

CAUTION: Preservatives, antiseptics,
detergents, and other anti-viral substances may inactivate the vaccine. Use
only sterile syringes that are free of preservatives, antiseptics, detergents
and other anti-viral substances for reconstitution and injection of ProQuad.

Withdraw the entire volume
of the supplied diluent into a syringe. Use only the diluent supplied with the
vaccine since it is free of preservatives or other anti-viral substances.

Inject the entire content
of the syringe into the vial containing the powder. Gently agitate to dissolve
completely.

Visually inspect the vaccine
before and after reconstitution for particulate matter and discoloration prior
to administration. Before reconstitution, the lyophilized vaccine is a white
to pale yellow compact crystalline plug. ProQuad, when reconstituted, is a clear
pale yellow to light pink liquid.

Withdraw the entire amount
of the reconstituted vaccine from the vial into the same syringe and inject
the entire volume.

TO MINIMIZE LOSS OF POTENCY,
THE VACCINE SHOULD BE ADMINISTERED IMMEDIATELY AFTER RECONSTITUTION. DISCARD
RECONSTITUTED VACCINE IF IT IS NOT USED WITHIN 30 MINUTES.

Method of Administration

FOR SUBCUTANEOUS ADMINISTRATION
DO NOT INJECT INTRAVASCULARLY

Use a separate sterile syringe
and needle for each patient to prevent transmission of infectious agents from
one individual to another.

The vaccine is to be injected
subcutaneously in the outer aspect of the deltoid region of the upper arm or
in the higher anterolateral area of the thigh.

Properly dispose of all needles
and syringes. Do not recap needles.

Use With Other Vaccines

If another vaccine is administered
concomitantly, a different injection site should be used.

See PRECAUTIONS, Drug Interactions,
Use With Other Vaccines.

HOW SUPPLIED

No. 4984 — ProQuad is supplied
as follows: (1) a single-dose vial of lyophilized vaccine, NDC 0006-4984-00
(package A); and (2) a separate package of 10 vials of sterile water diluent
(package B).

No. 4999 — ProQuad is supplied
as follows: (1) a package of 10 single-dose vials of lyophilized vaccine, NDC
0006-4999-00 (package A); and (2) a separate package of 10 vials of sterile
water diluent (package B).

Storage

During shipment, to ensure
that there is no loss of potency, the vaccine must be maintained at a temperature
of -4(degree)F (-20(degree)C) or colder.

Before reconstitution, store
the lyophilized vaccine continuously in a freezer (e.g., chest, frost-free)
for up to 18 months, at an average temperature of 5(degree)F (-15(degree)C)
or colder. Any freezer that reliably maintains an average temperature of 5(degree)F
or colder and has a separate sealed freezer door is acceptable for storing ProQuad.

DO NOT STORE LYOPHILIZED VACCINE
IN THE REFRIGERATOR.

IF LYOPHILIZED VACCINE IS
INADVERTENTLY STORED IN THE REFRIGERATOR, IT SHOULD BE DISCARDED.

Protect the vaccine from light
at all times since such exposure may inactivate the vaccine viruses.

DISCARD RECONSTITUTED VACCINE
IF IT IS NOT USED WITHIN 30 MINUTES.

DO NOT FREEZE RECONSTITUTED
VACCINE.

Diluent should be stored separately
at room temperature (68 to 77(degree)F, 20 to 25(degree)C), or in a refrigerator
(36 to 46(degree)F, 2 to 8(degree)C).

REFERENCES

1. Weibel RE, et al. Clinical
and laboratory studies of combined live measles, mumps, and rubella vaccines
using the RA 27/3 rubella virus. Proc Soc Exp Biol Med. 165(2):323-326, 1980.
2. Hilleman MR, Stokes
J, Jr., Buynak EB, Weibel R, Halenda R, Goldner H. Studies of live attenuated
measles virus vaccine in man: II. appraisal of efficacy. Am J Public Health.
52(2):44-56, 1962.
3. Krugman S, Giles
JP, Jacobs AM. Studies on an attenuated measles-virus vaccine: VI. clinical,
antigenic and prophylactic effects of vaccine in institutionalized children.
N Engl J Med. 263(4):174-7, 1960.
4. Hilleman MR, Weibel
RE, Buynak EB, Stokes J, Jr., Whitman JE, Jr. Live, attenuated mumps-virus vaccine.
4. Protective efficacy as measured in a field evaluation. N Engl J Med. 276(5):252-8,
1967.
5. Sugg WC, Finger JA,
Levine RH, Pagano JS. Field evaluation of live virus mumps vaccine. J Pediatr.
72(4):461-6, 1968.
6. The Benevento and
Compobasso Pediatricians Network for the Control of Vaccine-Preventable Diseases,
D’Argenio P, Citarella A, Selvaggi MTM. Field evaluation of the clinical effectiveness
of vaccines against pertussis, measles, rubella and mumps. Vaccine. 16(8):818-22,
1998.
7. Furukawa T, Miyata
T, Kondo K, Kuno K, Isomura S, Takekoshi T. Rubella vaccination during an epidemic.
JAMA. 213(6):987-90, 1970.
8. Vazquez M, et al.
The effectiveness of the varicella vaccine in clinical practice. N Engl J Med.
344(13):955-960, 2001.
9. Kuter B, et al. Ten
year follow-up of healthy children who received one or two injections of varicella
vaccine. Pediatr Infect Dis J. 23(2):132-137, 2004.
10. Committee on Infectious
Diseases, American Academy of Pediatrics. In: Pickering LK, Baker CJ, Overturf
GD, et al., eds. Red Book: 2003 Report of the Committee on Infectious Diseases.
26th ed. Elk Grove Village, IL: American Academy of Pediatrics. 419-29, 2003.
11. Recommendations
of the Immunization Practices Advisory Committee (ACIP), Mumps Prevention. MMWR.
38(22):388-392, 397-400, 1989.
12. Rubella vaccination
during pregnancy–United States, 1971-1986. MMWR Morb Mortal Wkly Rep. 36(28):457-61,
1987.
13. Bohlke K, Galil
K, Jackson LA, et al. Postpartum varicella vaccination: Is the vaccine virus
excreted in breast milk? Obstetrics and Gynecology. 102(5): 970-977, 2003.
14. Dolbear GL, Moffat
J, Falkner C and Wojtowycz M. A Pilot Study: Is attenuated varicella virus present
in breast milk after postpartum immunization? Obstetrics and Gynecology. 101(4
Suppl.): 47S-47S, 2003.
15. Peltola H, et al.
The elimination of indigenous measles, mumps, and rubella from Finland by a
12-year, two-dose vaccination program. N Engl J Med. 331(21):1397-1402, 1994.
16. Guess HA, et al.
Population-based studies of varicella complications. Pediatrics. 78(4 Pt 2):723-727,
1986.

Issued August 2005
Printed in USA

                        
                                      7999915

VARIVAX(R)
(Varicella Virus Vaccine Live (Oka/Merck))

DESCRIPTION

VARIVAX* (Varicella Virus
Vaccine Live (Oka/Merck)) is a preparation of the Oka/Merck strain of live,
attenuated varicella virus. The virus was initially obtained from a child with
natural varicella, then introduced into human embryonic lung cell cultures,
adapted to and propagated in embryonic guinea pig cell cultures and finally
propagated in human diploid cell cultures (WI-38). Further passage of the virus
for varicella vaccine was performed at Merck Research Laboratories (MRL) in
human diploid cell cultures (MRC-5) that were free of adventitious agents. This
live, attenuated varicella vaccine is a lyophilized preparation containing sucrose,
phosphate, glutamate, and processed gelatin as stabilizers.

VARIVAX, when reconstituted
as directed, is a sterile preparation for subcutaneous administration. Each
0.5 mL dose contains the following: a minimum of 1350 PFU (plaque forming units)
of Oka/Merck varicella virus when reconstituted and stored at room temperature
for 30 minutes, approximately 25 mg of sucrose, 12.5 mg hydrolyzed gelatin,
3.2 mg sodium chloride, 0.5 mg monosodium L-glutamate, 0.45 mg of sodium phosphate
dibasic, 0.08 mg of potassium phosphate monobasic, 0.08 mg of potassium chloride;
residual components of MRC-5 cells including DNA and protein; and trace quantities
of sodium phosphate monobasic, EDTA, neomycin, and fetal bovine serum. The product
contains no preservative.

To maintain potency, the lyophilized
vaccine must be kept frozen at an average temperature of – 15(degree)C (+5(degree)F)
or colder and must be used before the expiration date (see HOW SUPPLIED, Stability
and Storage). Storage in any freezer (e.g., chest, frost-free) that reliably
maintains an average temperature of – 15(degree)C (+5(degree)F) or colder and
has a separate sealed freezer door is acceptable.

CLINICAL PHARMACOLOGY

Varicella is a highly communicable
disease in children, adolescents, and adults caused by the varicella-zoster
virus (VZV). The disease usually consists of 300 to 500 maculopapular and/or
vesicular lesions accompanied by a fever (oral temperature >=100(degree)F)
in up to 70% of individuals.1,2 Approximately 3.5 million cases of varicella
occurred annually from 1980-1994 in the United States with the peak incidence
occurring in children five to nine years of age.3 The incidence rate of chickenpox
in the total population was 8.3-9.1% per year in children 1-9 years of age before
licensure of VARIVAX.4,6 The attack rate of natural varicella following household
exposure among healthy susceptible children was shown to be 87% in unvaccinated
populations.2 Although it is generally a benign, self-limiting disease, varicella
may be associated with serious complications (e.g., bacterial superinfection,
pneumonia, encephalitis, Reye’s Syndrome), and/or death. Evaluation of Clinical
Efficacy Afforded by VARIVAX

The following section presents
clinical efficacy data on a 1-dose regimen and a 2-dose regimen in children,
and a 2-dose regimen in adolescents and adults. Clinical Data in Children One-Dose
Regimen in Children

In combined clinical trials5
of VARIVAX at doses ranging from 1000-17,000 PFU, the majority of subjects who
received VARIVAX and were exposed to wild-type virus were either completely
protected from chickenpox or developed a milder form (for clinical description
see below) of the disease. The protective efficacy of VARIVAX was evaluated
in three different ways: 1) by comparing chickenpox rates in vaccinees versus
historical controls, 2) by assessment of protection from disease following household
exposure, and 3) by a placebo-controlled, double-blind clinical trial.

In early clinical trials,5
a total of 4240 children 1 to 12 years of age received 1000-1625 PFU of attenuated
virus per dose of VARIVAX and have been followed for up to nine years post single-dose
vaccination. In this group there was considerable variation in chickenpox rates
among studies and study sites, and much of the reported data was acquired by
passive follow-up. It was observed that 0.3%-3.8% of

* Registered trademark of
MERCK & CO., Inc.
COPYRIGHT (C) 1995,
1999, 2001 MERCK & CO. Inc.
All rights reserved

vaccinees per year reported
chickenpox (called breakthrough cases). This represents an approximate 83% (95%
confidence interval (CI), 82%, 84%) decrease from the age-adjusted expected
incidence rates in susceptible subjects over this same period.19 In those who
developed breakthrough chickenpox postvaccination, the majority experienced
mild disease (median of the maximum number of lesions <50). In one study,
a total of 47% (27/58) of breakthrough cases had <50 lesions compared with
8% (7/92) in unvaccinated individuals, and 7% (4/58) of breakthrough cases had
>300 lesions compared with 50% (46/92) in unvaccinated individuals.7

Among a subset of vaccinees
who were actively followed in these early trials for up to nine years postvaccination,
179 individuals had household exposure to chickenpox. There were no reports
of breakthrough chickenpox in 84% (150/179) of exposed children, while 16% (29/179)
reported a mild form of chickenpox (38% (11/29) of the cases with a maximum
total number of <50 lesions; no individuals with >300 lesions). This represents
an 81% reduction in the expected number of varicella cases utilizing the historical
attack rate of 87% following household exposure to chickenpox in unvaccinated
individuals in the calculation of efficacy.

In later clinical trials5
with the current vaccine, a total of 1114 children 1 to 12 years of age received
2900-9000 PFU of attenuated virus per dose of VARIVAX and have been actively
followed for up to 10 years post single-dose vaccination. It was observed that
0.2%-2.3% of vaccinees per year reported breakthrough chickenpox for up to 10
years post single-dose vaccination. This represents an estimated efficacy of
94% (95% CI, 93%, 96%), compared with the age-adjusted expected incidence rates
in susceptible subjects over the same period.4,6,19 In those who developed breakthrough
chickenpox postvaccination, the majority experienced mild disease, with the
median of the maximum total number of lesions <50. The severity of reported
breakthrough chickenpox, as measured by number of lesions and maximum temperature,
appeared not to increase with time since vaccination.

Among a subset of vaccinees
who were actively followed in these later trials for up to 10 years postvaccination,
95 individuals were exposed to an unvaccinated individual with wild-type chickenpox
in a household setting. There were no reports of breakthrough chickenpox in
92% (87/95) of exposed children, while 8% (8/95) reported a mild form of chickenpox
(maximum total number of lesions <50; observed range, 10 to 34). This represents
an estimated efficacy of 90% (95% CI, 82%, 96%) based on the historical attack
rate of 87% following household exposure to chickenpox in unvaccinated individuals
in the calculation of efficacy.

Although no placebo-controlled
trial was carried out with VARIVAX using the current vaccine, a placebo-controlled
trial was conducted using a formulation containing 17,000 PFU per dose.4,8 In
this trial, a single dose of VARIVAX protected 96-100% of children against chickenpox
over a two-year period. The study enrolled healthy individuals 1 to 14 years
of age (n=491 vaccine, n=465 placebo). In the first year, 8.5% of placebo recipients
contracted chickenpox, while no vaccine recipient did, for a calculated protection
rate of 100% during the first varicella season. In the second year, when only
a subset of individuals agreed to remain in the blinded study (n=163 vaccine,
n=161 placebo), 96% protective efficacy was calculated for the vaccine group
as compared to placebo.

There are insufficient data
to assess the rate of protection against the complications of chickenpox (e.g.,
encephalitis, hepatitis, pneumonia) in children. Two-Dose Regimen in Children

In a clinical trial, a total
of 2216 children 12 months to 12 years of age with a negative history of varicella
were randomized to receive either 1 dose of VARIVAX (n=1114) or 2 doses of VARIVAX
(n=1102) given 3 months apart. Subjects were actively followed for varicella,
any varicella-like illness, or herpes zoster and any exposures to varicella
or herpes zoster on an annual basis for 10 years after vaccination. Persistence
of VZV antibody was measured annually for 9 years. Most cases of varicella reported
in recipients of 1 dose or 2 doses of vaccine were mild.26 The estimated vaccine
efficacy for the 10-year observation period was 94% for 1 dose and 98% for 2
doses (p<0.001). This translates to a 3.4-fold lower risk of developing varicella
>42 days postvaccination during the 10-year observation period in children
who received 2 doses than in those who received 1 dose (2.2% vs. 7.5%, respectively).
Clinical Data in Adolescents and Adults Two-Dose Regimen in Adolescents and
Adults

In early clinical trials,
a total of 796 adolescents and adults received 905-1230 PFU of attenuated virus
per dose of VARIVAX and have been followed for up to six years following 2-dose
vaccination. A total of 50 clinical varicella cases were reported >42 days
following 2-dose vaccination. Based on passive followup, the annual chickenpox
breakthrough event rate ranged from <0.1% to 1.9%. The median of the maximum
total number of lesions ranged from 15 to 42 per year.

Although no placebo-controlled
trial was carried out in adolescents and adults, the protective efficacy of
VARIVAX was determined by evaluation of protection when vaccinees received 2
doses of VARIVAX 4 or 8 weeks apart and were subsequently exposed to chickenpox
in a household setting.5 Among the subset of vaccinees who were actively followed
in these early trials for up to six years, 76 individuals had household exposure
to chickenpox. There were no reports of breakthrough chickenpox in 83% (63/76)
of exposed vaccinees, while 17% (13/76) reported a mild form of chickenpox.
Among 13 vaccinated individuals who developed breakthrough chickenpox after
a household exposure, 62% (8/13) of the cases reported maximum total number
of lesions <50, while no individual reported >75 lesions. The attack rate
of unvaccinated adults exposed to a single contact in a household has not been
previously studied. Utilizing the previously reported historical attack rate
of 87% for natural varicella following household exposure to chickenpox among
unvaccinated children in the calculation of efficacy, this represents an approximate
80% reduction in the expected number of cases in the household setting.

In later clinical trials,
a total of 220 adolescents and adults received 3315-9000 PFU of attenuated virus
per dose of VARIVAX and have been actively followed for up to six years following
2-dose vaccination. A total of 3 clinical varicella cases were reported >42
days following 2-dose vaccination. Two cases reported <50 lesions and none
reported >75. The annual chickenpox breakthrough event rate ranged from 0%
to 1.2%. Among the subset of vaccinees who were actively followed in these later
trials for up to five years, 16 individuals were exposed to an unvaccinated
individual with wild-type chickenpox in a household setting. There were no reports
of breakthrough chickenpox among the exposed vaccinees.

There are insufficient data
to assess the rate of protection of VARIVAX against the serious complications
of chickenpox in adults (e.g., encephalitis, hepatitis, pneumonitis) and during
pregnancy (congenital varicella syndrome). Immunogenicity of VARIVAX

The following section presents
immunogenicity data on a 1-dose regimen and a 2-dose regimen in children, and
a 2-dose regimen in adolescents and adults. One-Dose Regimen in Children

Clinical trials with several
formulations of the vaccine containing attenuated virus ranging from 1000 to
17,000 PFU per dose have demonstrated that VARIVAX induces detectable immune
responses in a high proportion of individuals and is generally well tolerated
in healthy individuals ranging from 12 months to 55 years of age.4,5,9-15

Seroconversion is defined
by the acquisition of any detectable VZV antibodies, based on an optical density
(OD) cutoff, corresponding approximately to a lower limit of 0.6 glycoprotein
enzyme-linked immunosorbent assay (gpELISA) units/mL.

The gpELISA is a highly sensitive
assay that is not commercially available. Seroconversion was observed in 97%
of vaccinees at approximately 4-6 weeks postvaccination in 6889 susceptible
children 12 months to 12 years of age. Rates of breakthrough disease were significantly
lower among children with VZV antibody titers >=5 gpELISA units/mL compared
with children with titers <5 gpELISA units/mL. Titers >=5 gpELISA units/mL
were induced in approximately 76% of children vaccinated with a single dose
of vaccine at 1000-17,000 PFU per dose.

VARIVAX also induces cell-mediated
immune responses in vaccinees. The relative contributions of humoral immunity
and cell-mediated immunity to protection from chickenpox are unknown. Two-Dose
Regimen in Children

In a multicenter study, healthy
children 12 months to 12 years of age received either 1 dose of VARIVAX or 2
doses administered 3 months apart. The immunogenicity results are shown in the
following table.

———————————————————————-
                     
VARIVAX 1-Dose    VARIVAX 2-Dose Regimen (N =
                       
Regimen (N =               
1102)
                           
1114)
———————————————————————-
                         
6 Weeks    6 Weeks Postdose 6 Weeks Postdose
                     
Postvaccination       1          
     2

———————————————————————-
Seroconversion Rate  
98.9% (882/892) 99.5% (847/851)  99.9% (768/769)
———————————————————————-
Percent with VZV
 Antibody Titer
>=5
 gpELISA units/mL    
84.9% (757/892) 87.3% (743/851)  99.5% (765/769)
———————————————————————-
Geometric mean titers     
12.0            12.8            
141.5|
———————————————————————-

  ——————————————————————–
   (gpELISA
units/mL)
  ——————————————————————–

The results from this study
and other studies in which a second dose of vaccine was administered 3 to 6
years after the initial dose demonstrate significant boosting of the VZV antibody
response with a second dose. VZV antibody levels after 2 doses given 3 to 6
years apart are comparable to those obtained when the 2 doses are given 3 months
apart. Two-Dose Regimen in Adolescents and Adults

In a multicenter study involving
susceptible adolescents and adults 13 years of age and older, 2 doses of VARIVAX
administered 4 to 8 weeks apart induced a seroconversion rate of approximately
75% in 539 individuals 4 weeks after the first dose and of 99% in 479 individuals
4 weeks after the second dose. The average antibody response in vaccinees who
received the second dose 8 weeks after the first dose was higher than that in
vaccinees who received the second dose 4 weeks after the first dose. In another
multicenter study involving adolescents and adults, 2 doses of VARIVAX administered
8 weeks apart induced a seroconversion rate of 94% in 142 individuals 6 weeks
after the first dose and 99% in 122 individuals 6 weeks after the second dose.
Persistence of Immune Response

The following section presents
immune persistence data on a 1-dose regimen and a 2-dose regimen in children,
and a 2-dose regimen in adolescents and adults. One-Dose Regimen in Children

In clinical studies involving
healthy children who received 1 dose of vaccine, detectable VZV antibodies were
present in 99.0% (3886/3926) at 1 year, 99.3% (1555/1566) at 2 years, 98.6%
(1106/1122) at 3 years, and 99.4% (1168/1175) at 4 years, 99.2% (737/743) at
5 years, 100% (142/142) at 6 years, 97.4% (38/39) at 7 years, 100% (34/34) at
8 years, and 100% (16/16) at 10 years postvaccination. Two-Dose Regimen in Children

In recipients of 1 dose of
VARIVAX over 9 years of follow-up, the geometric mean titer (GMT) and the percent
of subjects with VZV antibody titers >=5 gpELISA units/mL generally increased.
The GMTs and percent of subjects with VZV antibody titers >=5 gpELISA units/mL
in the 2-dose recipients were higher than those in the 1-dose recipients for
the first year of follow-up and generally comparable thereafter. The cumulative
rate of VZV antibody persistence with both regimens remained very high at year
9 (99.0% for the 1-dose group and 98.8% for the 2-dose group). Two-Dose Regimen
in Adolescents and Adults

In clinical studies involving
healthy adolescents and adults who received 2 doses of vaccine, detectable VZV
antibodies were present in 97.9% (568/580) at 1 year, 97.1% (34/35) at 2 years,
100% (144/144) at 3 years, 97.0% (98/101) at 4 years, 97.4% (76/78) at 5 years,
and 100% (34/34) at 6 years postvaccination.

A boost in antibody levels
has been observed in vaccinees following exposure to natural varicella which
could account for the apparent long-term persistence of antibody levels after
vaccination in these studies. The duration of protection from varicella obtained
using VARIVAX in the absence of wild-type boosting is unknown. VARIVAX also
induces cell-mediated immune responses in vaccinees. The relative contributions
of humoral immunity and cell-mediated immunity to protection from chickenpox
are unknown. Transmission

In the placebo-controlled
trial, transmission of vaccine virus was assessed in household settings (during
the 8-week postvaccination period) in 416 susceptible placebo recipients who
were household contacts of 445 vaccine recipients. Of the 416 placebo recipients,
three developed chickenpox and seroconverted, nine reported a varicella-like
rash and did not seroconvert, and six had no rash but seroconverted. If vaccine
virus transmission occurred, it did so at a very low rate and possibly without
recognizable clinical disease in contacts. These cases may represent either
natural varicella from community contacts or a low incidence of transmission
of vaccine virus from vaccinated contacts (see PRECAUTIONS, Transmission).4,16
Post-marketing experience suggests that transmission of vaccine virus may occur
rarely between healthy vaccinees who develop a varicella-like rash and healthy
susceptible contacts. Transmission of vaccine virus from vaccinees without a
varicella-like rash has been reported but has not been confirmed. Herpes Zoster

Overall, 9454 healthy children
(12 months to 12 years of age) and 1648 adolescents and adults (13 years of
age and older) have been vaccinated with Oka/Merck live attenuated varicella
vaccine in clinical trials. Eight cases of herpes zoster have been reported
in children during 42,556 person years of follow-up in clinical trials, resulting
in a calculated incidence of at least 18.8 cases per 100,000 person years. The
completeness of this reporting has not been determined. One case of herpes zoster
has been reported in the adolescent and adult age group during 5410 person years
of follow-up in clinical trials resulting in a calculated incidence of 18.5
cases per 100,000 person years.5

All nine cases were mild and
without sequelae. Two cultures (one child and one adult) obtained from vesicles
were positive for wild-type VZV as confirmed by restriction endonuclease analysis.5,17
The long-term effect of VARIVAX on the incidence of herpes zoster, particularly
in those vaccinees exposed to natural varicella, is unknown at present.

In children, the reported
rate of herpes zoster in vaccine recipients appears not to exceed that previously
determined in a population-based study of healthy children who had experienced
natural varicella.5,18,19 The incidence of herpes zoster in adults who have
had natural varicella infection is higher than that in children.20 Reye’s Syndrome

Reye’s Syndrome has occurred
in children and adolescents following natural varicella infection, the majority
of whom had received salicylates.21 In clinical studies in healthy children
and adolescents in the United States, physicians advised varicella vaccine recipients
not to use salicylates for six weeks after vaccination. There were no reports
of Reye’s Syndrome in varicella vaccine recipients during these studies. Studies
with Other Vaccines

In combined clinical studies
involving 1080 children 12 to 36 months of age, 653 received VARIVAX and M-M-R*
II (Measles, Mumps, and Rubella Virus Vaccine Live) concomitantly at separate
sites and 427 received the vaccines six weeks apart. Seroconversion rates and
antibody levels were comparable between the two groups at approximately six
weeks post-vaccination to each of the virus vaccine components. No differences
were noted in adverse reactions reported in those who received VARIVAX concomitantly
with M-M-R II at separate sites and those who received VARIVAX and M-M-R II
at different times (see PRECAUTIONS, Drug Interactions, Use with Other Vaccines).5

In a clinical study involving
318 children 12 months to 42 months of age, 160 received an investigational
vaccine (a formulation combining measles, mumps, rubella, and varicella in one
syringe) concomitantly with booster doses of DTaP (diphtheria, tetanus, acellular
pertussis) and OPV (oral poliovirus vaccine) while 144 received M-M-R II concomitantly
with booster doses of DTaP and OPV followed by VARIVAX 6 weeks later. At six
weeks postvaccination, seroconversion rates for measles, mumps, rubella, and
VZV and the percentage of vaccinees whose titers were boosted for diphtheria,
tetanus, pertussis, and polio were comparable between the two groups, but anti-VZV
levels were decreased when the investigational vaccine containing varicella
was administered concomitantly with DTaP. No clinically significant differences
were noted in adverse reactions between the two groups.5

In another clinical study
involving 307 children 12 to 18 months of age, 150 received an investigational
vaccine (a formulation combining measles, mumps, rubella, and varicella in one
syringe) concomitantly with a booster dose of PedvaxHIB* (Haemophilus b Conjugate
Vaccine (Meningococcal Protein Conjugate)) while 130 received M-M-R II concomitantly
with a booster dose of PedvaxHIB followed by VARIVAX 6 weeks later. At six weeks
postvaccination, seroconversion rates for measles, mumps, rubella, and VZV,
and geometric mean titers for PedvaxHIB were comparable between the two groups,
but anti-VZV levels were decreased when the investigational vaccine containing
varicella was administered concomitantly with PedvaxHIB. No clinically significant
differences in adverse reactions were seen between the two groups.5

In a clinical study involving
609 children 12 to 23 months of age, 305 received VARIVAX, M-M-R II, and

**

TETRAMUNE (Haemophilus influenzae
type b, diphtheria, tetanus, and pertussis vaccines) concomitantly at separate
sites, and 304 received M-M-R II and TETRAMUNE concomitantly at separate sites,
followed by VARIVAX 6 weeks later. At six weeks postvaccination, seroconversion
rates for measles, mumps, rubella and VZV were similar between the two groups.
Postvaccination GMTs for all antigens were similar in both treatment groups
except for VZV, which was lower when VARIVAX was administered concomitantly
with M-M-R II and TETRAMUNE, but within the range of GMTs seen in previous clinical
experience when VARIVAX was administered alone. At 1 year postvaccination, GMTs
for measles, mumps, rubella, VZV and Haemophilus influenzae type b were similar
between the two groups. All three vaccines were well tolerated regardless of
whether they were administered concomitantly at separate sites

** Registered trademark of
Lederle Laboratories or 6 weeks apart. There were no clinically important differences
in reaction rates when the three vaccines were administered concomitantly versus
6 weeks apart.

In a clinical study involving
822 children 12 to 15 months of age, 410 received COMVAX* (Haemophilus b Conjugate
(Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) vaccine), M-M-R
II, and VARIVAX concomitantly at separate sites, and 412 received COMVAX followed
by M-M-R II and VARIVAX given concomitantly at separate sites, 6 weeks later.
At six weeks postvaccination, the immune responses for the subjects who received
the concomitant doses of COMVAX, M-M-R II, and VARIVAX were similar to those
of the subjects who received COMVAX followed 6 weeks later by M-M-R II and VARIVAX
with respect to all antigens administered. All three vaccines were generally
well tolerated regardless of whether they were administered concomitantly at
separate sites or 6 weeks apart. There were no clinically important differences
in reaction rates when the three vaccines were administered concomitantly versus
6 weeks apart.

VARIVAX is recommended for
subcutaneous administration. However, during clinical trials, some children
received VARIVAX intramuscularly resulting in seroconversion rates similar to
those in children who received the vaccine by the subcutaneous route.22 Persistence
of antibody and efficacy in those receiving intramuscular doses have not been
defined.

INDICATIONS AND USAGE

VARIVAX is indicated for vaccination
against varicella in individuals 12 months of age and older.

The duration of protection
of VARIVAX is unknown; however, long-term efficacy studies have demonstrated
continued protection up to 10 years after vaccination.26 In addition, a boost
in antibody levels has been observed in vaccinees following exposure to natural
varicella as well as following a second dose of VARIVAX.5

In a highly vaccinated population,
immunity for some individuals may wane due to lack of exposure to natural varicella
as a result of shifting epidemiology. Post-marketing surveillance studies are
ongoing to evaluate the need and timing for booster vaccination.

Vaccination with VARIVAX may
not result in protection of all healthy, susceptible children, adolescents,
and adults (see CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

A history of hypersensitivity
to any component of the vaccine, including gelatin.

A history of anaphylactoid
reaction to neomycin (each dose of reconstituted vaccine contains trace quantities
of neomycin).

Individuals with blood dyscrasias,
leukemia, lymphomas of any type, or other malignant neoplasms affecting the
bone marrow or lymphatic systems.

Individuals receiving immunosuppressive
therapy. Individuals who are on immunosuppressant drugs are more susceptible
to infections than healthy individuals. Vaccination with live attenuated varicella
vaccine can result in a more extensive vaccine-associated rash or disseminated
disease in individuals on immunosuppressant doses of corticosteroids.

Individuals with primary and
acquired immunodeficiency states, including those who are immunosuppressed in
association with AIDS or other clinical manifestations of infection with human
immunodeficiency virus;23 cellular immune deficiencies; and hypogammaglobulinemic
and dysgammaglobulinemic states.

A family history of congenital
or hereditary immunodeficiency, unless the immune competence of the potential
vaccine recipient is demonstrated.

Active untreated tuberculosis.

Any febrile respiratory illness
or other active febrile infection.

Pregnancy; the possible effects
of the vaccine on fetal development are unknown at this time. However, natural
varicella is known to sometimes cause fetal harm. If vaccination of postpubertal
females is undertaken, pregnancy should be avoided for three months following
vaccination (See PRECAUTIONS, Pregnancy).

PRECAUTIONS

General

Adequate treatment provisions,
including epinephrine injection (1:1000), should be available for immediate
use should an anaphylactoid reaction occur.

The duration of protection
from varicella infection after vaccination with VARIVAX is unknown.

It is not known whether VARIVAX
given immediately after exposure to natural varicella virus will prevent illness.

Vaccination should be deferred
for at least 5 months following blood or plasma transfusions, or administration
of immune globulin or varicella zoster immune globulin (VZIG).24

Following administration of
VARIVAX, any immune globulin, including VZIG, should not be given for 2 months
thereafter unless its use outweighs the benefits of vaccination.24

Vaccine recipients should
avoid use of salicylates for 6 weeks after vaccination with VARIVAX as Reye’s
Syndrome has been reported following the use of salicylates during natural varicella
infection (see CLINICAL PHARMACOLOGY, Reye’s Syndrome).

The safety and efficacy of
VARIVAX have not been established in children and young adults who are known
to be infected with human immunodeficiency viruses with and without evidence
of immunosuppression (see also CONTRAINDICATIONS).

Care is to be taken by the
health care provider for safe and effective use of VARIVAX.

The health care provider should
question the patient, parent, or guardian about reactions to a previous dose
of VARIVAX or a similar product.

The health care provider should
obtain the previous immunization history of the vaccinee.

VARIVAX should not be injected
into a blood vessel.

Vaccination should be deferred
in patients with a family history of congenital or hereditary immunodeficiency
until the patient’s own immune system has been evaluated.

A separate sterile needle
and syringe should be used for administration of each dose of VARIVAX to prevent
transfer of infectious diseases.

Needles should be disposed
of properly and should not be recapped.

Transmission

Post-marketing experience
suggests that transmission of vaccine virus may occur rarely between healthy
vaccinees who develop a varicella-like rash and healthy susceptible contacts.
Transmission of vaccine virus from vaccinees without a varicella-like rash has
been reported but has not been confirmed.

Therefore, vaccine recipients
should attempt to avoid, whenever possible, close association with susceptible
high-risk individuals for up to six weeks. In circumstances where contact with
high-risk individuals is unavoidable, the potential risk of transmission of
vaccine virus should be weighed against the risk of acquiring and transmitting
natural varicella virus. Susceptible high-risk individuals include:

— immunocompromised individuals
— pregnant women without
documented history of chickenpox or laboratory evidence of prior infection
— newborn infants of
mothers without documented history of chickenpox or laboratory evidence of prior
infection.

Information for Patients

The health care provider should
inform the patient, parent, or guardian of the benefits and risks of VARIVAX.

Patients, parents, or guardians
should be instructed to report any adverse reactions to their health care provider.

The U.S. Department of Health
and Human Services has established a Vaccine Adverse Event Reporting System
(VAERS) to accept all reports of suspected adverse events after the administration
of any vaccine, including but not limited to the reporting of events required
by the National Childhood Vaccine Injury Act of 1986.25 The VAERS toll-free
number for VAERS forms and information is 1-800-822-7967.

Pregnancy should be avoided
for three months following vaccination.

Drug Interactions

See PRECAUTIONS, General,
regarding the administration of immune globulins, salicylates, and transfusions.
Drug Interactions, Use with Other Vaccines

Results from clinical studies
indicate that VARIVAX can be administered concomitantly with M-M-R II, COMVAX,
or TETRAMUNE (see CLINICAL PHARMACOLOGY, Studies with Other Vaccines).

Limited data from an experimental
product containing varicella vaccine suggest that VARIVAX can be administered
concomitantly with DTaP (diphtheria, tetanus, acellular pertussis) and PedvaxHIB
using separate sites and syringes (see CLINICAL PHARMACOLOGY, Studies with Other
Vaccines).5 However, there are no data relating to simultaneous administration
of VARIVAX with DTP or OPV. Carcinogenesis, Mutagenesis, Impairment of Fertility

VARIVAX has not been evaluated
for its carcinogenic or mutagenic potential, or its potential to impair fertility.

Pregnancy

Pregnancy Category C: Animal
reproduction studies have not been conducted with VARIVAX. It is also not known
whether VARIVAX can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Therefore, VARIVAX should not be administered
to pregnant females; furthermore, pregnancy should be avoided for three months
following vaccination (see CONTRAINDICATIONS).

Merck & Co., Inc. maintains
a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to
VARIVAX. Patients and healthcare providers are encouraged to report any exposure
to VARIVAX during pregnancy by calling (800) 986-8999.

Nursing Mothers

It is not known whether varicella
vaccine virus is secreted in human milk. Therefore, because some viruses are
secreted in human milk, caution should be exercised if VARIVAX is administered
to a nursing woman.

Geriatric Use

Clinical studies of VARIVAX
did not include sufficient numbers of seronegative subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the
elderly and younger subjects.

Pediatric Use

No clinical data are available
on safety or efficacy of VARIVAX in children less than one year of age and administration
to infants under twelve months of age is not recommended.

ADVERSE REACTIONS

In clinical trials,4,5,9-15
VARIVAX was administered to over 11,000 healthy children, adolescents, and adults.
VARIVAX was generally well tolerated.

In a double-blind, placebo-controlled
study among 914 healthy children and adolescents who were serologically confirmed
to be susceptible to varicella, the only adverse reactions that occurred at
a significantly (p<0.05) greater rate in vaccine recipients than in placebo
recipients were pain and redness at the injection site.4 Children 1 to 12 Years
of Age One-Dose Regimen in Children

In clinical trials involving
healthy children monitored for up to 42 days after a single dose of VARIVAX,
the frequency of fever, injection-site complaints, or rashes were reported as
follows:

                               
Table 1
                
Fever, Local Reactions, or Rashes (%)|
                
————————————-
                 
            in Children
                             
———–
                    
0 to 42 Days Postvaccination
                    
—————————-

———————————————————————-
    
Reaction       N   Post Dose 1 Peak
Occurrence in Postvaccination
                                   
Days

———————————————————————-
Fever
 >=102(degree)F
 (39(degree)C)
 Oral             
8827   14.7%                   
0-42

———————————————————————-
Injection-site
 complaints
 (pain/soreness,  
8916   19.3%                    
0-2
 swelling and/or
 erythema, rash,
 pruritus,
 hematoma,
 induration,
 stiffness)

———————————————————————-
Varicella-like rash
 (injection site) 
8916    3.4%                   
8-19
Median number of
 lesions                    
2

———————————————————————-
Varicella-like rash
 (generalized)    
8916    3.8%                   
5-26
Median number of
 lesions                    
5

———————————————————————-

In addition, the most frequently
(>=1%) reported adverse experiences, without regard to causality, are listed
in decreasing order of frequency: upper respiratory illness, cough, irritability/nervousness,
fatigue, disturbed sleep, diarrhea, loss of appetite, vomiting, otitis, diaper
rash/contact rash, headache, teething, malaise, abdominal pain, other rash,
nausea, eye complaints, chills, lymphadenopathy, myalgia, lower respiratory
illness, allergic reactions (including allergic rash, hives), stiff neck, heat
rash/prickly heat, arthralgia, eczema/dry skin/dermatitis, constipation, itching.

Pneumonitis has been reported
rarely (<1%) in children vaccinated with VARIVAX; a causal relationship has
not been established.

Febrile seizures have occurred
rarely (<0.1%) in children vaccinated with VARIVAX; a causal relationship
has not been established. Two-Dose Regimen in Children

Nine hundred eighty-one (981)
subjects in a clinical trial received 2 doses of VARIVAX 3 months apart and
were actively followed for 42 days after each dose. The 2-dose regimen of varicella
vaccine was generally well tolerated, with a safety profile generally comparable
to that of the 1-dose regimen. The incidence of injection-site clinical complaints
(primarily erythema and swelling) observed in the first 4 days following vaccination
was slightly higher Postdose 2 (overall incidence 25.4%) than Postdose 1 (overall
incidence 21.7%), whereas the incidence of systemic clinical complaints in the
42-day follow-up period was lower Postdose 2 (66.3%) than Postdose 1 (85.8%).
Adolescents and Adults 13 Years of Age and Older

In clinical trials involving
healthy adolescents and adults, the majority of whom received two doses of VARIVAX
and were monitored for up to 42 days after any dose, the frequency of fever,
injection-site complaints, or rashes were reported as follows:

                               
Table 2

   Fever,
Local Reactions, or Rashes (%) in Adolescents and Adults 0
   —————————————————————–
                     
to 42 Days Postvaccination
           
          ————————–

———————————————————————-
                     
Post  Peak Occurrence      Post  Peak Occurrence
                                 
in                        
in
    Reaction     
N  Dose 1 Postvaccination N   Dose 2 Postvaccination
                                
Days                      
Days

———————————————————————-
Fever
 >=100(degree)F
 (37.7(degree)C)
 Oral          
1584   10.2%         14-27
956     9.5%     0-42

———————————————————————-
Injection-site
 complaints
 (soreness,    
1606   24.4%          
0-2 955    32.5%      0-2
 erythema,
 swelling, rash,
 pruritus,
 pyrexia,
 hematoma,
 induration,
 numbness)

———————————————————————-
Varicella-like
 rash (injection
 site)                   
3%                        
1%      0-6
Median number of
 lesions       
1606      2           6-20
955       2      

———————————————————————-
Varicella-like
 rash
 (generalized)         
5.5%                      
0.9%     0-23
Median number of
 lesions       
1606      5          
7-21 955     5.5     

———————————————————————-

In addition, the most frequently
(>=1%) reported adverse experiences, without regard to causality, are listed
in decreasing order of frequency: upper respiratory illness, headache, fatigue,
cough, myalgia, disturbed sleep, nausea, malaise, diarrhea, stiff neck, irritability/nervousness,
lymphadenopathy, chills, eye complaints, abdominal pain, loss of appetite, arthralgia,
otitis, itching, vomiting, other rashes, constipation, lower respiratory illness,
allergic reactions (including allergic rash, hives), contact rash, cold/canker
sore.

As with any vaccine, there
is the possibility that broad use of the vaccine could reveal adverse reactions
not observed in clinical trials.

The following additional adverse
reactions have been reported since the vaccine has been marketed:

Body as a Whole

Anaphylaxis in individuals
with or without an allergic history. Hemic and Lymphatic System

Thrombocytopenia (including
ITP).

Nervous/Psychiatric

Encephalitis; cerebrovascular
accident; transverse myelitis; Guillain-Barre syndrome; Bell’s palsy; ataxia;
non-febrile seizures; aseptic meningitis; dizziness; paresthesia. Respiratory

Pharyngitis, Pneumonia/Pneumonitis.

Skin

Stevens-Johnson syndrome;
erythema multiforme; Henoch-Schonlein purpura; secondary bacterial infections
of skin and soft tissue, including impetigo and cellulitis; herpes zoster.

DOSAGE AND ADMINISTRATION

FOR SUBCUTANEOUS
—————-
ADMINISTRATION Do not
inject
—————————-
intravascularly
—————

Children

Children 12 months to 12 years
of age should receive a 0.5-mL dose administered subcutaneously.

If a second 0.5-mL dose is
administered, it should be given a minimum of 3 months later. Adolescents and
Adults

Adolescents and adults 13
years of age and older should receive a 0.5-mL dose administered subcutaneously
at elected date and a second 0.5-mL dose 4 to 8 weeks later.

VARIVAX is for subcutaneous
administration. The outer aspect of the upper arm (deltoid) is the preferred
site of injection.

VARIVAX SHOULD BE STORED FROZEN
at an average temperature of -15(degree)C (+5(degree)F) or colder until it is
reconstituted for injection (see HOW SUPPLIED, Storage). Any freezer (e.g.,
chest, frost-free) that reliably maintains an average temperature of -15(degree)C
and has a separate sealed freezer door is acceptable for storing VARIVAX. The
diluent should be stored separately at room temperature or in the refrigerator.
To reconstitute the vaccine, first withdraw 0.7 mL of diluent into a syringe.
Inject all the diluent in the syringe into the vial of lyophilized vaccine and
gently agitate to mix thoroughly. Withdraw the entire contents into a syringe
and inject the total volume (about 0.5 mL) of reconstituted vaccine subcutaneously,
preferably into the outer aspect of the upper arm (deltoid) or the anterolateral
thigh. IT IS RECOMMENDED THAT THE VACCINE BE ADMINISTERED IMMEDIATELY AFTER
RECONSTITUTION, TO MINIMIZE LOSS OF POTENCY. DISCARD IF RECONSTITUTED VACCINE
IS NOT USED WITHIN 30 MINUTES.

CAUTION: A sterile syringe
free of preservatives, antiseptics, and detergents should be used for each injection
and/or reconstitution of VARIVAX because these substances may inactivate the
vaccine virus.

It is important to use a separate
sterile syringe and needle for each patient to prevent transmission of infectious
agents from one individual to another.

To reconstitute the vaccine,
use only the Merck sterile diluent supplied with VARIVAX, M-M-R II, or the component
vaccines of M-M-R II, since it is free of preservatives or other anti-viral
substances which might inactivate the vaccine virus.

Do not freeze reconstituted
vaccine.

Do not give immune globulin,
including Varicella Zoster Immune

————————————————————–
Globulin, concurrently
with VARIVAX (see also PRECAUTIONS).
———————————–

Parenteral drug products should
be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. VARIVAX when reconstituted is a clear,
colorless to pale yellow liquid.

HOW SUPPLIED

No. 4826/4309 — VARIVAX is
supplied as follows: (1) a single-dose vial of lyophilized vaccine, NDC 0006-4826-00
(package A); and (2) a box of 10 vials of diluent (package B).
No. 4827/4309 — VARIVAX
is supplied as follows: (1) a box of 10 single-dose vials of lyophilized vaccine
(package A), NDC 0006-4827-00; and (2) a box of 10 vials of diluent (package
B).

Stability

VARIVAX retains a potency
level of 1500 PFU or higher per dose for
at
least 24 months in a frost-free freezer with an average temperature
of
-15(degree)C (+5(degree)F) or colder.

VARIVAX has a minimum potency
level of approximately 1350 PFU 30
minutes
after reconstitution at room temperature (20-25(degree)C,
68-77(degree)F).

Prior to reconstitution, VARIVAX
retains potency when stored for
up
to 72 continuous hours at refrigerator temperature (2-8(degree)C,
36-46(degree)F).

For information regarding
stability under conditions other than
those
recommended, call 1-800-9-VARIVAX.

Storage

During shipment, to ensure
that there is no loss of potency, the
vaccine
must be maintained at a temperature of -15(degree)C
(+5(degree)F)
or colder.

Before reconstitution, store
the lyophilized vaccine in a freezer at an average temperature of – 15(degree)C
(+5(degree)F) or colder. Any freezer (e.g., chest, frost-free) that reliably
maintains an average temperature of -15(degree)C and has a separate sealed freezer
door is acceptable for storing VARIVAX.

VARIVAX may be stored at refrigerator
temperature (2-8(degree)C, 36-46(degree)F) for up to 72 continuous hours prior
to reconstitution. Vaccine stored at 2-8(degree)C which is not used within 72
hours of removal from -15(degree)C storage should be discarded.

Before reconstitution, protect
from light.

The diluent should be stored
separately at room temperature (20-25(degree)C, 68-77(degree)F), or in the refrigerator.

REFERENCES

1. Balfour, H.H.; et al.:
Acyclovir Treatment of Varicella in Otherwise Healthy Children, Pediatrics.,
116: 633-639, 1990.
2. Ross, A.H.: Modification of Chickenpox in Family Contacts by Administration
of Gamma Globulin, N Engl J Med. 267: 369-376, 1962.
3. Preblud, S.R.: Varicella: Complications and Costs, Pediatrics, 78(4 Pt 2):
728-735, 1986.
4. Weibel, R.E.; et al.: Live Attenuated Varicella Virus Vaccine, N Engl J Med.
310(22): 1409-1415, 1984.
5. Unpublished data; files of Merck Research Laboratories.
6. Wharton, M.; et al.: Health Impact of Varicella in the 1980’s. Thirtieth
Interscience Conference on Antimicrobial Agents and Chemotherapy, (Abstract
#1138), 1990.
7. Bernstein, H.H.; et al.: Clinical Survey of Natural Varicella Compared with
Breakthrough Varicella After Immunization with Live Attenuated Oka/Merck Varicella
Vaccine. Pediatrics 92: 833-837, 1993.
8. Kuter, B.J.; et al.: Oka/Merck Varicella Vaccine in Healthy Children: Final
Report of a 2-Year Efficacy Study and 7-Year Follow-up Studies, Vaccine, 9:
643-647, 1991.
9. Arbeter, A.M.; et al.: Varicella Vaccine Trials in Healthy Children, A Summary
of Comparative and Follow-up Studies, AJDC 138: 434-438, 1984.
10. Weibel, R.E.; et al.: Live Oka/Merck Varicella Vaccine in Healthy Children,
JAMA 254(17): 2435-2439, 1985.
11. Chartrand, D.M.; et al.: New Varicella Vaccine Production Lots in Healthy
Children and Adolescents, Abstracts of the 1988 Inter-Science Conference Antimicrobial
Agents and Chemotherapy: 237(Abstract #731).
12. Johnson, C.E.; et al.: Live Attenuated Vaccine in Healthy 12 to 24 month
old Children, Pediatrics 81: 512-518, 1988.
13. Gershon, A.A.; et al.: Immunization of Healthy Adults with Live Attenuated
Varicella Vaccine, J Infect Dis, 158(1): 132-137, 1988.
14. Gershon, A.A.; et al.: Live Attenuated Varicella Vaccine: Protection in
Healthy Adults Compared with Leukemic Children, J Infect Dis, 161: 661-666,
1990.
15. White, C.J.; et al.: Varicella Vaccine (VARIVAX) in Healthy Children and
Adolescents: Results From Clinical Trials, 1987 to 1989, Pediatrics, 87(5):
604-610, 1991.
16. Asano, Y.; et al.: Contact Infection from Live Varicella Vaccine Recipients,
Lancet 1(7966): 965, 1976.
17. Hammerschlag, M.R.; et al.: Herpes Zoster in an Adult Recipient of Live
Attenuated Varicella Vaccine, J Infect Dis 160(3): 535-537, 1989.
18. White, C.J.: Letters to the Editor, Pediatrics 318: 354, 1992.
19. Guess, H.A.; et al.: Population-Based Studies of Varicella Complications,
Pediatrics 78(4 Pt 2): 723-727, 1986.
20. Ragozzino, M.; et al.: Population-Based Study of Herpes Zoster and Its Sequelae,
Medicine 61(5): 310-316, 1982.
21. Morbidity and Mortality Weekly Report 34(1): 13-16, Jan. 11, 1985.
22. Dennehy, P.H.; et al.: Immunogenicity of Subcutaneous Versus Intramuscular
Oka/Merck Varicella Vaccination in Healthy Children, Pediatrics 88(3): 604-607,
1991.
23. Center for Disease Control: Immunization of Children Infected with Human
T-Lymphotropic Virus Type III/Lymphadenopathy — Associated Virus, Ann Intern
Med, 106: 75-78, 1987.
24. Recommendations of the Advisory Committee on Immunization Practices (ACIP);
General Recommendations on Immunization, MMWR 43(No. RR-1): 15-18, Jan. 28,
1994.
25. Vaccine Adverse Event Reporting System — United States, MMWR 39(41): 730-733,
1990.
26. Kuter, B.J.; et al.: Ten Year Follow-up of Healthy Children who Received
One or Two Injections of Varicella Vaccine, Pediatr Infect Dis J, 23:132-37,
2004.

Issued April 2006 Printed in USA

 

 

El Comité Asesor sobre Prácticas de Inmunización de los CDC vota de manera unánime a favor de la recomendación de agregar una segunda dosis de rutina de la vacuna contra la varicela al cronograma de inmunización infantil