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

Posted on: Thursday, 29 June 2006, 18:00 CDT

Merck's VARIVAX(R) and PROQUAD(R) Are the Only Chickenpox-Containing

Vaccines Available in the U.S.

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 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.

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,

Source: Business Wire

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