CDC Advisory Committee on Immunization Practices Unanimously Recommends Addition of a Second...

CDC Advisory Committee on Immunization Practices Unanimously Recommends Addition of a Second Dose of Chickenpox-Containing Vaccine to Childhood Immunization Schedule

Merck's VARIVAX(R) and PROQUAD(R) Are the Only Chickenpox-Containing Vaccines Available in the U.S.


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Whitehouse Station, NJ–(HISPANIC
PR WIRE – BUSINESS WIRE)–June 30, 2006–Merck & Co., Inc. today announced
that the U.S. Centers for Disease Control and Prevention’s (CDC) Advisory Committee
on Immunization Practices (ACIP) unanimously voted to recommend that children
4 to 6 years of age receive a second dose of varicella vaccine for the prevention
of chickenpox. The Committee also recommended that children, adolescents and
adults who received only one dose of varicella vaccine receive a second, "catch-up"
dose, which can be accomplished through routine health-care visits and school-
and college-entry requirements.

Merck’s VARIVAX(R) (varicella
vaccine live (Oka/Merck)) and PROQUAD(R) (measles, mumps, rubella, varicella
(Oka/Merck) virus vaccine live) are the only vaccines to protect against chickenpox
in the United States. VARIVAX is indicated for vaccination against varicella
in individuals 12 months of age and older and PROQUAD is indicated for simultaneous
vaccination against measles, mumps, rubella, and varicella in children 12 months
to 12 years of age. Chickenpox is highly contagious, easily spread, and sometimes
can have serious complications – such as severe skin infections, pneumonia and
encephalitis (swelling of the brain) that may result in hospitalization, or
in rare cases, death.

"While use of the one-dose
regimen of the chickenpox vaccine has significantly reduced cases of chickenpox,
we believe we can still do more," said Keith Reisinger, M.D., medical director,
Primary Physicians Research. "Because clinical data has shown that a two-dose
regimen can potentially further lower the risk of infection, the ACIP’s recommendation
that children receive a second dose of the varicella vaccine makes it more likely
that most American children can have even greater protection against this potentially
serious disease."

Chickenpox Remains a
Serious Health Concern

Prior to the introduction
of VARIVAX in 1995, an estimated four million people(1) were infected with the
chickenpox virus each year in the U.S., with 11,000 requiring hospitalization.(2)
In 1996, the ACIP and the CDC added the varicella vaccine to the list of recommended
childhood vaccinations. PROQUAD was licensed in 2005 and provides an opportunity
to administer simultaneous vaccination against measles, mumps, rubella and varicella,
thus reducing the number of injections children receive and increasing varicella
vaccination coverage to the national levels of coverage against measles, mumps
and rubella, which is currently estimated to be 93 percent for children 19 to
35 months of age. Vaccination coverage rates for varicella still vary widely
across states, from 70 to 94 percent in children age 19 to 35 months; in 2004,
an estimated 12.5 percent of children were not vaccinated. Vaccination with
VARIVAX or PROQUAD may not result in protection of all healthy, susceptible
children, adolescents, and adults.

"Merck is proud that
the use of our vaccines has contributed to the reduction in the incidence of
chickenpox over the past 11 years," said Mark Feinberg, M.D., Ph.D., vice
president of Policy, Public Health and Medical Affairs, Merck Vaccines. "With
widespread use of two doses of varicella vaccine, we hope to see fewer chickenpox
outbreaks, especially in schools, and to we hope to see additional decreases
in the number of children susceptible to the disease."

The ACIP also voted to recommend
that a second dose of varicella vaccine be included in the CDC Vaccines for
Children (VFC) program. Since 1994, the VFC program has provided vaccines to
children who are Medicaid-eligible, uninsured, underinsured or Native American.

Eligible children may receive
recommended vaccines through VFC once the CDC contracts for the purchase of
the vaccine.

Two Doses of Varicella
Vaccine Lowered Risk of Developing Chickenpox in Clinical Studies

In a randomized, controlled
study in 2,216 children 12 months to 12 years of age that compared one dose
of varicella vaccine (VARIVAX) to two doses over a 10-year observation period,
the estimated vaccine efficacy was 94.4 percent for one dose and 98.3 percent
for two doses. During the 10-year observation period, this translates into a
3.3-fold lower risk of developing chickenpox more than 42 days after vaccination
in children receiving two doses than in those who received one dose (2.2 percent
vs. 7.5 percent, respectively). In this trial, 99.6 percent of children 12 months
to 12 years of age who received two doses of varicella vaccine (VARIVAX) three
months apart achieved a protective level of antibodies six weeks after vaccination
compared to 85.7 percent of those who received only one dose. The duration of
protection of VARIVAX is unknown.

Among 981 children who received
two doses of VARIVAX three months apart and who were followed for 42 days after
each dose, the two-dose regimen was generally well tolerated, with a safety
profile generally comparable to that of the one-dose regimen. The incidence
of injection-site complaints (primarily redness and swelling) observed in the
first four days following vaccination was slightly higher post second dose (overall
incidence 25.4 percent) than post first dose (overall incidence 21.7 percent),
whereas the incidence of systemic complaints in the 42-day follow up period
was lower post second dose (66.3 percent) than post first dose (85.8 percent).

Since 1964, the ACIP, a
panel of 15 immunization experts, has provided guidance and counsel to the U.S.
Department of Health and Human Services and the CDC on the most effective means
to prevent vaccine-preventable diseases. The Committee writes recommendations
regarding vaccine use among the pediatric population along with schedules regarding
the appropriate periodicity, dosage, and contraindications applicable to the
vaccines. In addition to varicella and human papillomavirus as recommended by
ACIP earlier today, the ACIP currently recommends vaccines for routine use in
children to prevent diphtheria, Haemophilus influenza type b, hepatitis A, hepatitis
B, influenza, measles, meningococcal disease, mumps, pertussis, pneumococcal
disease, polio, rotavirus, rubella and tetanus. Merck makes vaccines to help
protect against nine of these 16 diseases.

Select Important Information
about VARIVAX

VARIVAX is indicated for
vaccination against varicella in individuals 12 months of age and older. 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 three
months later. 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 contraindicated
in certain individuals, including those with: a history of hypersensitivity
to any component of the vaccine, including gelatin; a history of anaphylactoid
reaction to neomycin; blood dyscrasias, leukemia, lymphomas of any type, or
other malignant neoplasms affecting the bone marrow or lymphatic systems; an
immunodeficient condition or receiving immunosuppressive therapy; active, untreated
tuberculosis; active febrile illness; or those who are pregnant.

In children, adolescents,
and adults monitored for up to 42 days, the adverse effects most frequently
reported were as follows: fever, injection-site complaints, varicella-like rash
(injection site), and varicella-like rash (generalized).

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

In a study in which children
received two doses of VARIVAX three months apart, the two-dose regimen of VARIVAX
was generally well tolerated, with a safety profile generally comparable to
that of the one-dose regimen. The duration of protection from varicella infection
after vaccination with VARIVAX is unknown; however, long-term efficacy studies
have demonstrated continued protection up to 10 years after vaccination. Vaccination
with VARIVAX may not result in protection of all healthy, susceptible children,
adolescents, and adults.

Select Important Information
about PROQUAD

PROQUAD is a combined attenuated
live virus vaccine indicated for simultaneous vaccination against measles, mumps,
rubella and chickenpox in children 12 months to 12 years of age. No clinical
data are available on the safety, immunogenicity and efficacy of PROQUAD in
children less than 12 months 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.

At least one month should
elapse between a dose of a measles-containing vaccine, such as M-M-R(R) II (Measles,
Mumps, and Rubella Virus Vaccine Live), and a dose of PROQUAD. If for any reason
a second dose of varicella-containing vaccine is required, at least three months
should elapse between administration of the two doses.

PROQUAD should not be administered
to certain individuals, including those with: a history of anaphylactic reactions
to neomycin; a history of hypersensitivity to gelatin or any other component
of the vaccine; blood dyscrasias, leukemia, lymphomas of any type, or other
malignant neoplasms affecting the bone marrow or lymphatic system; an immunodeficient
condition or receiving immunosuppressive therapy; active untreated tuberculosis;
an active febrile illness (greater than 101.3(degree)F); or those who are pregnant.

In clinical trials with
PROQUAD involving children 12 to 23 months of age, the most frequently reported
injection-site adverse experiences (greater than 1% of children) were pain/tenderness/soreness,
erythema, swelling, ecchymosis, and rash. The most frequently reported systemic
vaccine-related adverse experiences (greater than 1% of children) were fever
(greater than 102(degree)F), irritability, measles-like rash, varicella-like
rash, rash (not otherwise specified), upper respiratory infection, viral exanthema,
and diarrhea.

In a clinical trial involving
799 healthy 4- to 6- year-old-children who had received M-M-R II and VARIVAX
at least one month prior to entry, 399 received PROQUAD and placebo, while 205
received M-M-R II and placebo concomitantly at separate injection sites. Another
195 healthy children were administered M-M-R II and VARIVAX concomitantly at
separate injection sites. In the clinical trial described above, the rates of
adverse experiences of injection-site reactions, nasopharyngitis, and cough,
were generally similar among the three treatment groups.

Vaccination with PROQUAD
may not offer 100 percent protection from measles, mumps, rubella and chickenpox
(varicella) infection.

The duration of protection
from measles, mumps, rubella, and varicella infection after vaccination with
PROQUAD is unknown.

About Merck

Merck & Co., Inc. is
a global research-driven pharmaceutical company dedicated to putting patients
first. Established in 1891, Merck currently discovers, develops, manufactures
and markets vaccines and medicines to address unmet medical needs. The Company
devotes extensive efforts to increase access to medicines through far-reaching
programs that not only donate Merck medicines but help deliver them to the people
who need them. Merck also publishes unbiased health information as a not-for-profit
service. For more information, visit http://www.merck.com

Forward-Looking Statement

This press release contains
"forward-looking statements" as that term is defined in the Private
Securities Litigation Reform Act of 1995. These statements are based on management’s
current expectations and involve risks and uncertainties, which may cause results
to differ materially from those set forth in the statements. The forward-looking
statements may include statements regarding product development, product potential
or financial performance. No forward-looking statement can be guaranteed, and
actual results may differ materially from those projected. Merck undertakes
no obligation to publicly update any forward-looking statement, whether as a
result of new information, future events, or otherwise. Forward-looking statements
in this press release should be evaluated together with the many uncertainties
that affect Merck’s business, particularly those mentioned in the cautionary
statements in Item 1 of Merck’s Form 10-K for the year ended Dec. 31, 2005,
and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates
by reference.

See attached prescribing
information for VARIVAX and 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.

(1)Centers for Disease Control
and Prevention. Decline in annual incidence of varicella-selected states 1990-2001.
Morbidity and Mortality Weekly Report. 2003;52(37);884-885, page 884.

(2)Galil K, Brown C, Lin F,
Seward J. Hospitalizations for varicella in the Unites States, 1988 to 1999.
Pediatric Infectious Disease Journal. 2002;21(10):931-935, page 932

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.

rPatients, 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 zoste

CDC Advisory Committee on Immunization Practices Unanimously Recommends Addition of a Second Dose of Chickenpox-Containing Vaccine to Childhood Immunization Schedule