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

Merck & Co., Inc. today announced that the U.S. Centers forDisease Control and Prevention's (CDC) Advisory Committee onImmunization Practices (ACIP) unanimously voted to recommend thatchildren 4 to 6 years of age receive a second dose of varicellavaccine for the prevention of chickenpox. The Committee alsorecommended that children, adolescents and adults who received onlyone dose of varicella vaccine receive a second, "catch-up" dose, whichcan be accomplished through routine health-care visits and school- andcollege-entry requirements.

Merck's VARIVAX(R) (varicella vaccine live (Oka/Merck)) andPROQUAD(R) (measles, mumps, rubella, varicella (Oka/Merck) virusvaccine live) are the only vaccines to protect against chickenpox inthe United States. VARIVAX is indicated for vaccination againstvaricella in individuals 12 months of age and older and PROQUAD isindicated 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 haveserious complications - such as severe skin infections, pneumonia andencephalitis (swelling of the brain) that may result inhospitalization, or in rare cases, death.

"While use of the one-dose regimen of the chickenpox vaccine hassignificantly reduced cases of chickenpox, we believe we can still domore," said Keith Reisinger, M.D., medical director, PrimaryPhysicians Research. "Because clinical data has shown that a two-doseregimen can potentially further lower the risk of infection, theACIP's recommendation that children receive a second dose of thevaricella vaccine makes it more likely that most American children canhave even greater protection against this potentially seriousdisease."

Chickenpox Remains a Serious Health Concern

Prior to the introduction of VARIVAX in 1995, an estimated fourmillion people(1) were infected with the chickenpox virus each year inthe U.S., with 11,000 requiring hospitalization.(2) In 1996, the ACIPand the CDC added the varicella vaccine to the list of recommendedchildhood vaccinations. PROQUAD was licensed in 2005 and provides anopportunity to administer simultaneous vaccination against measles,mumps, rubella and varicella, thus reducing the number of injectionschildren receive and increasing varicella vaccination coverage to thenational levels of coverage against measles, mumps and rubella, whichis currently estimated to be 93 percent for children 19 to 35 monthsof age. Vaccination coverage rates for varicella still vary widelyacross 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 ofall healthy, susceptible children, adolescents, and adults.

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

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

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

Two Doses of Varicella Vaccine Lowered Risk of DevelopingChickenpox in Clinical Studies

In a randomized, controlled study in 2,216 children 12 months to12 years of age that compared one dose of varicella vaccine (VARIVAX)to two doses over a 10-year observation period, the estimated vaccineefficacy 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-foldlower risk of developing chickenpox more than 42 days aftervaccination in children receiving two doses than in those who receivedone 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 twodoses of varicella vaccine (VARIVAX) three months apart achieved aprotective level of antibodies six weeks after vaccination compared to85.7 percent of those who received only one dose. The duration ofprotection of VARIVAX is unknown.

Among 981 children who received two doses of VARIVAX three monthsapart and who were followed for 42 days after each dose, the two-doseregimen was generally well tolerated, with a safety profile generallycomparable to that of the one-dose regimen. The incidence ofinjection-site complaints (primarily redness and swelling) observed inthe first four days following vaccination was slightly higher postsecond dose (overall incidence 25.4 percent) than post first dose(overall incidence 21.7 percent), whereas the incidence of systemiccomplaints 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, hasprovided guidance and counsel to the U.S. Department of Health andHuman Services and the CDC on the most effective means to preventvaccine-preventable diseases. The Committee writes recommendationsregarding vaccine use among the pediatric population along withschedules regarding the appropriate periodicity, dosage, andcontraindications applicable to the vaccines. In addition to varicellaand human papillomavirus as recommended by ACIP earlier today, theACIP currently recommends vaccines for routine use in children toprevent diphtheria, Haemophilus influenza type b, hepatitis A,hepatitis B, influenza, measles, meningococcal disease, mumps,pertussis, pneumococcal disease, polio, rotavirus, rubella andtetanus. Merck makes vaccines to help protect against nine of these 16diseases.

Select Important Information about VARIVAX

VARIVAX is indicated for vaccination against varicella inindividuals 12 months of age and older. Children 12 months to 12 yearsof age should receive a 0.5-mL dose administered subcutaneously. If asecond 0.5-mL dose is administered, it should be given a minimum ofthree months later. Adolescents and adults 13 years of age and oldershould receive a 0.5-mL dose administered subcutaneously at electeddate and a second 0.5-mL dose 4 to 8 weeks later.

VARIVAX is contraindicated in certain individuals, including thosewith: 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 malignantneoplasms affecting the bone marrow or lymphatic systems; animmunodeficient condition or receiving immunosuppressive therapy;active, untreated tuberculosis; active febrile illness; or those whoare 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), andvaricella-like rash (generalized).

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

In a study in which children received two doses of VARIVAX threemonths apart, the two-dose regimen of VARIVAX was generally welltolerated, with a safety profile generally comparable to that of theone-dose regimen. The duration of protection from varicella infectionafter vaccination with VARIVAX is unknown; however, long-term efficacystudies have demonstrated continued protection up to 10 years aftervaccination. Vaccination with VARIVAX may not result in protection ofall healthy, susceptible children, adolescents, and adults.

Select Important Information about PROQUAD

PROQUAD is a combined attenuated live virus vaccine indicated forsimultaneous vaccination against measles, mumps, rubella andchickenpox in children 12 months to 12 years of age. No clinical dataare available on the safety, immunogenicity and efficacy of PROQUAD inchildren less than 12 months of age. PROQUAD may be used in children12 months to 12 years of age if a second dose of measles, mumps andrubella vaccine is to be administered.

At least one month should elapse between a dose of ameasles-containing vaccine, such as M-M-R(R) II (Measles, Mumps, andRubella Virus Vaccine Live), and a dose of PROQUAD. If for any reasona second dose of varicella-containing vaccine is required, at leastthree 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 thevaccine; blood dyscrasias, leukemia, lymphomas of any type, or othermalignant neoplasms affecting the bone marrow or lymphatic system; animmunodeficient condition or receiving immunosuppressive therapy;active untreated tuberculosis; an active febrile illness (greater than101.3(degree)F); or those who are pregnant.

In clinical trials with PROQUAD involving children 12 to 23 monthsof age, the most frequently reported injection-site adverseexperiences (greater than 1% of children) werepain/tenderness/soreness, erythema, swelling, ecchymosis, and rash.The most frequently reported systemic vaccine-related adverseexperiences (greater than 1% of children) were fever (greater than102(degree)F), irritability, measles-like rash, varicella-like rash,rash (not otherwise specified), upper respiratory infection, viralexanthema, 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 onemonth prior to entry, 399 received PROQUAD and placebo, while 205received M-M-R II and placebo concomitantly at separate injectionsites. Another 195 healthy children were administered M-M-R II andVARIVAX concomitantly at separate injection sites. In the clinicaltrial described above, the rates of adverse experiences ofinjection-site reactions, nasopharyngitis, and cough, were generallysimilar among the three treatment groups.

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

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

About Merck

Merck & Co., Inc. is a global research-driven pharmaceuticalcompany dedicated to putting patients first. Established in 1891,Merck currently discovers, develops, manufactures and markets vaccinesand medicines to address unmet medical needs. The Company devotesextensive efforts to increase access to medicines through far-reachingprograms that not only donate Merck medicines but help deliver them tothe people who need them. Merck also publishes unbiased healthinformation as a not-for-profit service. For more information, visitwww.merck.com

Forward-Looking Statement

This press release contains "forward-looking statements" as thatterm is defined in the Private Securities Litigation Reform Act of1995. These statements are based on management's current expectationsand involve risks and uncertainties, which may cause results to differmaterially from those set forth in the statements. The forward-lookingstatements may include statements regarding product development,product potential or financial performance. No forward-lookingstatement can be guaranteed, and actual results may differ materiallyfrom those projected. Merck undertakes no obligation to publiclyupdate any forward-looking statement, whether as a result of newinformation, future events, or otherwise. Forward-looking statementsin this press release should be evaluated together with the manyuncertainties that affect Merck's business, particularly thosementioned in the cautionary statements in Item 1 of Merck's Form 10-Kfor the year ended Dec. 31, 2005, and in its periodic reports on Form10-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 annualincidence of varicella-selected states 1990-2001. Morbidity andMortality Weekly Report. 2003;52(37);884-885, page 884.

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

ProQuad(R)

(Measles, Mumps, Rubella and Varicella (Oka/Merck) Virus VaccineLive)

DESCRIPTION

ProQuad*(C) is a combined attenuated live virus vaccine containingmeasles, mumps, rubella, and varicella viruses. ProQuad is a sterilelyophilized preparation of (1) the components of M-M-R* II (Measles,Mumps and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, amore attenuated line of measles virus, derived from Enders' attenuatedEdmonston strain and propagated in chick embryo cell culture; MumpsVirus Vaccine Live, the Jeryl Lynn(TM) (B level) strain of mumps viruspropagated in chick embryo cell culture; Rubella Virus Vaccine Live,the Wistar RA 27/3 strain of live attenuated rubella virus propagatedin WI-38 human diploid lung fibroblasts; and (2) Varicella VirusVaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zostervirus propagated in MRC-5 cells. The cells, virus pools, bovine serum,and human albumin used in manufacturing are all tested to provideassurance that the final product is free of potential adventitiousagents.

ProQuad, when reconstituted as directed, is a sterile preparationfor subcutaneous administration. Each 0.5-mL dose contains not lessthan 3.00 log10 TCID50 (50% tissue culture infectious dose) of measlesvirus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50 of rubellavirus; and a minimum of 3.99 log10 PFU (plaque-forming units) ofOka/Merck varicella virus.

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

CLINICAL PHARMACOLOGY

Background

Measles, mumps, rubella, and varicella are 4 common childhooddiseases caused by measles virus, mumps virus, rubella virus, andvaricella virus, respectively. These diseases may be associated withserious complications and/or death. For example, measles can beassociated with pneumonia and encephalitis; mumps can be associatedwith aseptic meningitis, deafness, and orchitis; rubella occurringduring pregnancy can cause congenital rubella syndrome in the infantsof infected mothers; and wild-type varicella can be associated withbacterial superinfection, pneumonia, encephalitis, and Reye'ssyndrome.

Mechanism of action

In clinical efficacy studies, seroconversion in response tovaccination against measles, mumps, and rubella paralleled protectionfrom these diseases. Also, in previous studies with varicella vaccine,antibody responses against varicella virus (>=)5 units/mL in aglycoprotein enzyme-linked immunosorbent assay (gpELISA) (notcommercially available) similarly correlated with long-termprotection. Clinical studies with a single dose of ProQuad have shownthat vaccination elicited rates of antibody responses against measles,mumps, and rubella that were similar to those observed aftervaccination with a single dose of M-M-RII (see CLINICAL STUDIES) andseroresponse rates for varicella virus were similar to those observedafter vaccination with a single dose of VARIVAX (see CLINICALSTUDIES). The duration of protection from measles, mumps, rubella, andvaricella 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 wasevaluated in a subset of 2107 children enrolled in the clinicaltrials. 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 vaccineesfollowing 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 11to 13 years after primary vaccination.1 Varicella antibodies werepresent for up to ten years post-vaccination in most of theindividuals tested who received 1 dose of VARIVAX.

CLINICAL STUDIES

Formal studies to evaluate the clinical efficacy of ProQuad havenot been performed.

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

Immunogenicity

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

The presence of detectable antibody was assessed by anappropriately sensitive enzyme-linked immunosorbent assay (ELISA) formeasles, mumps (wild type and vaccine type strains), and rubella, andby gpELISA for varicella. For evaluation of vaccine response rates, apositive result in the measles ELISA corresponded to measles antibodyconcentrations 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 levelwas =>10 ELISA units/mL. A positive result in the rubella ELISAcorresponded to concentrations of =>10 IU rubella antibody/mL whencompared to the WHO International Reference Serum for Rubella;children with varicella antibody levels =>5 gpELISA units/mL wereconsidered to be seropositive since a response rate based on =>5gpELISA units/mL has been shown to be highly correlated with long-termprotection.

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

In 4 randomized clinical trials, 5446 healthy children 12 to 23months of age were administered ProQuad, and 2038 children werevaccinated with M-M-RII and VARIVAX given concomitantly at separateinjection sites. Subjects enrolled in each of these trials had anegative clinical history, no known recent exposure and no vaccinationhistory for varicella, measles, mumps, and rubella. Children wereexcluded from study participation if they had an immune impairment orhad a history of allergy to components of the vaccine(s). Except forin 1 trial (see Studies With Other Vaccines), no concomitant vaccineswere permitted during study participation. Following a single dose ofProQuad, 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 vaccineresponse rate was 91.2% (95% CI: 90.3, 92.0) for varicella. Theseresults were similar to the immune response rates induced byconcomitant administration of single doses of M-M-RII and VARIVAX atseparate injection sites. Fever and measles-like rashes were the onlyadverse experiences that occurred more frequently in recipients of asingle dose of ProQuad compared with recipients of single doses ofM-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, asubgroup (N=1035) of the 5446 children administered a single dose ofProQuad were administered a second dose of ProQuad approximately 3months after the first dose. Children were excluded from receiving asecond dose of ProQuad if they were recently exposed to or developedvaricella, measles, mumps, and/or rubella prior to receipt of thesecond dose. No concomitant vaccines were administered to thesechildren. The proportion of initially seronegative vaccinees withpositive 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) forvaricella (=>5 gpELISA units/mL). The geometric mean titers (GMTs)following the second dose of ProQuad increased approximately 2-foldeach for measles, mumps, and rubella, and approximately 41-fold forvaricella.

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

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

In a clinical trial involving 799 healthy 4- to 6-year-oldchildren who had received M-M-RII and VARIVAX at least 1 month priorto study entry, 399 received ProQuad and placebo while 205 receivedM-M-RII and placebo concomitantly at separate injection sites. Another195 healthy children were administered M-M-RII and VARIVAXconcomitantly at separate injection sites. Children were eligible ifthey were previously administered primary doses of M-M-RII andVARIVAX, either concomitantly or non-concomitantly, at 12 months ofage or older. Children were excluded if they were recently exposed tomeasles, mumps, rubella, and/or varicella, had an immune impairment,or had a history of allergy to components of the vaccine(s). Noconcomitant 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) formumps, 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 meanfold-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 weresimilar to those following a second dose of M-M-RII and VARIVAXadministered concomitantly at separate injection sites. Additionally,GMTs for measles, mumps, and rubella were similar to those following asecond dose of M-M-RII given concomitantly with placebo. The rates ofadverse experiences, including the most commonly reported adverseexperiences of injection site reactions, nasopharyngitis and coughwere generally similar among the 3 treatment groups.

Studies With Other Vaccines

In a clinical trial involving 1913 healthy children 12 to 15months of age, 949 received ProQuad plus Diphtheria and TetanusToxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) andHaemophilus Influenzae type b Conjugate (Meningococcal ProteinConjugate) and Hepatitis B (Recombinant) Vaccine concomitantly atseparate injection sites. Another 485 healthy children receivedProQuad at the initial visit followed by DTaP and Haemophilus bConjugate and Hepatitis B (Recombinant) Vaccine given concomitantly 6weeks later while 479 children were immunized with M-M-RII and VARIVAXgiven 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 2groups at approximately 6 weeks post-vaccination indicating theProQuad and Haemophilus b Conjugate (Meningococcal Protein Conjugate)and Hepatitis B (Recombinant) Vaccine may be administeredconcomitantly at separate injection sites. There are insufficient datato support concomitant immunization with diphtheria, tetanus andacellular pertussis vaccine. No clinically significant differences inadverse experiences were reported between treatment groups.

Herpes Zoster

2 cases of herpes zoster were reported in 2108 healthy subjects 12to 23 months of age who were vaccinated with ProQuad in clinicaltrials and followed for 1 year. Both cases were unremarkable and nosequelae were reported (see ADVERSE REACTIONS, Other).

Reye's Syndrome

Reye's syndrome following wild-type varicella infection hasoccurred in children and adolescents, the majority of whom hadreceived salicylates. In clinical studies of ProQuad or VARIVAX, therecommendation was made to avoid the use of salicylates for 6 weeksafter vaccination. There were no reports of Reye's syndrome inrecipients 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 ofage.

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

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 personswith a history of cerebral injury, individual or family history ofconvulsions, or any other condition in which stress due to fevershould be avoided. The physician should be alert to the temperatureelevations that may occur following vaccination (see ADVERSEREACTIONS). Vaccination with a live attenuated vaccine, such asvaricella, can result in a more extensive vaccine-associated rash ordisseminated disease in individuals on immunosuppressive drugs.

Hypersensitivity to Eggs

Live measles vaccine and live mumps vaccine are produced in chickembryo cell culture. Persons with a history of anaphylactic or otherimmediate hypersensitivity reactions (e.g., hives, swelling of themouth and throat, difficulty breathing, hypotension, or shock)subsequent to egg ingestion may be at an enhanced risk ofimmediate-type hypersensitivity reactions after receiving vaccinescontaining traces of chick embryo antigen. The potentialrisk-to-benefit ratio should be carefully evaluated before consideringvaccination in such cases. Such individuals may be vaccinated withextreme caution; adequate treatment should be readily available shoulda reaction occur (see PRECAUTIONS).10

Children with egg allergy are at low risk for anaphylacticreactions to measles-containing vaccines (including MMR), and skintesting of children allergic to eggs is not predictive of reactions toMMR vaccine. Persons with allergies to chickens or feathers are not atincreased 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, rubellaor varicella containing vaccine.

Thrombocytopenia

No clinical data are available regarding the development orworsening of thrombocytopenia in individuals vaccinated with ProQuad.Cases of thrombocytopenia have been reported after use of measlesvaccine, measles, mumps and rubella vaccine and after varicellavaccination. Post-marketing experience with live measles, mumps, andrubella vaccine indicates that individuals with currentthrombocytopenia may develop more severe thrombocytopenia followingvaccination. In addition, individuals who experienced thrombocytopeniafollowing the first dose of a live measles, mumps, and rubella vaccinemay develop thrombocytopenia with repeat doses. Serologic testing forantibody to measles, mumps or rubella should be considered in order todetermine if additional doses of vaccine are needed. The potentialrisk-to-benefit ratio should be carefully evaluated before consideringvaccination with ProQuad in such cases.

Theoretical Risk of Transmission of Creutzfeld-Jakob Disease

This product contains albumin, a derivative of human blood. Basedon effective donor screening and product manufacturing processes, itcarries an extremely remote risk for transmission of viral diseases.Although there is a theoretical risk for transmission ofCreutzfeld-Jakob disease (CJD), no cases of transmission of CJD orviral disease have ever been identified that were associated with theuse of albumin.

PRECAUTIONS

General

Prior to administering the vaccine, obtain the prospectivevaccinee's vaccination history and determine whether the individualhad any previous reactions to any vaccine including ProQuad, VARIVAXor any measles, mumps or rubella containing vaccines.

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

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

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

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

Transmission

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

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

Post-licensing experience with VARIVAX suggests that transmissionof varicella vaccine virus may occur rarely between healthy vaccinerecipients who develop a varicella-like rash and contacts susceptibleto varicella, as well as high-risk individuals susceptible tovaricella.

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 extentpossible, close association with high-risk individuals susceptible tovaricella for up to 6 weeks following vaccination. In circumstanceswhere contact with high-risk individuals susceptible to varicella isunavoidable, the potential risk of transmission of the varicellavaccine virus should be weighed against the risk of acquiring andtransmitting wild-type varicella virus.

Information for Patients

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

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

The health care provider should tell the vaccine recipient or hisor her parent or guardian that the vaccine recipient should avoid useof salicylates for 6 weeks after vaccination with ProQuad (see DRUGINTERACTIONS).

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

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

Patients, parents, or guardians should be instructed to report anyadverse reactions to their health care provider. The U.S. Departmentof Health and Human Services has established a Vaccine Adverse EventReporting System (VAERS) to accept all reports of suspected adverseevents after the administration of any vaccine, including but notlimited to the reporting of events required by the National ChildhoodVaccine Injury Act of 1986. The VAERS toll-free number for VAERS formsand information is 1-800-822-7967 or information may be submittedelectronically via http://www.fda.gov/cber/vaers/vaers.htm

Drug Interactions

Immune Globulins and Transfusions

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

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

Salicylates

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

Corticosteroids and Immunosuppressive Drugs

ProQuad may be used in individuals who are receiving topicalcorticosteroids or low-dose corticosteroids for asthma prophylaxis orreplacement therapy, e.g., for Addison's disease. ProQuad should notbe given to individuals receiving immunosuppressive doses ofcorticosteroids or other immunosuppressive drugs.

Drug/Laboratory Test Interactions

Live attenuated measles, mumps, and rubella virus vaccines givenindividually may result in a temporary depression of tuberculin skinsensitivity. Therefore, if a tuberculin test is to be done, it shouldbe administered either any time before, simultaneously with, or atleast 4 to 6 weeks after ProQuad.

Use with Other Vaccines

At least 1 month should elapse between a dose of ameasles-containing vaccine such as M-M-RII, and a dose of ProQuad. Iffor any reason a second dose of varicella-containing vaccine isrequired, at least 3 months should elapse between administration ofthe 2 doses.

ProQuad may be administered concomitantly with Haemophilusinfluenzae type b conjugate (meningococcal protein conjugate) andhepatitis B (recombinant) vaccine.

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

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

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

Carcinogenesis, Mutagenesis, Teratogenicity, Impairment ofFertility

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

Pregnancy

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

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

In counseling women who are inadvertently vaccinated when pregnantor who become pregnant within 3 months of vaccination, the physicianshould be aware of the following: (1) Reports have indicated thatcontracting wild-type measles during pregnancy enhances fetal risk.Increased rates of spontaneous abortion, stillbirth, congenitaldefects and prematurity have been observed subsequent to naturalmeasles during pregnancy. There are no adequate studies of theattenuated (vaccine) strain of measles virus in pregnancy. However, itwould be prudent to assume that the vaccine strain of virus is alsocapable of inducing adverse fetal effects; (2) Mumps infection duringthe first trimester of pregnancy may increase the rate of spontaneousabortion. Although mumps vaccine virus has been shown to infect theplacenta and fetus, there is no evidence that it causes congenitalmalformations in humans;11 and (3) In a 10-year survey involving over700 pregnant women who received rubella vaccine within 3 months beforeor after conception (of whom 189 received the Wistar RA 27/3 strain),none of the newborns had abnormalities compatible with congenitalrubella syndrome;12 (4) Wild-type varicella can sometimes causecongenital varicella infection.

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

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

Nursing Mothers

The secretion of viruses in human milk has not been studied inmeasles and mumps vaccine viruses. Studies have shown that lactatingpostpartum women vaccinated with live rubella vaccine may secrete thevirus in breast milk and transmit it to breast-fed infants. Limitedevidence in the literature suggests that virus, viral DNA, or viralantigen could not be detected in the breast milk of women who werevaccinated postpartum with the vaccine strain of varicella virus.13-14For additional information on transmission of vaccine virus fromvaccine recipients to susceptible infants see Transmission. ProQuadshould not be administered to nursing women.

Pediatric Use

No clinical data are available on the safety, immunogenicity, andefficacy 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 agein clinical trials without concomitant administration with othervaccines. The safety of ProQuad was compared with the safety ofM-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 dayspost-vaccination. The only systemic vaccine-related adverseexperiences that were reported at a significantly greater rate inindividuals who received ProQuad than in individuals who receivedM-M-RII and VARIVAX concomitantly at separate injection sites werefever (=>102(degree)F (=>38.9(degree)C) oral equivalent or abnormal)(21.5% versus 14.9%, respectively, and measles-like rash (3.0% versus2.1%, respectively). Both fever and measles-like rash usually occurredwithin 5 to 12 days following the vaccination, were of short duration,and resolved with no long-term sequelae. Pain/tenderness/soreness atthe injection site was reported at a statistically lower rate inindividuals who received ProQuad than in individuals who receivedM-M-RII and VARIVAX concomitantly at separate injection sites (22.0%versus 26.7%, respectively). The only vaccine-related injection-siteadverse experience that was more frequent among recipients of ProQuadthan recipients of M-M-RII and VARIVAX was rash at the injection site(2.3% versus 1.5%, respectively). Table 1 summarizes the frequenciesof injection-site and systemic adverse experiences that were reportedas vaccine related by the investigator among =>1% of children in theseclinical 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 adverseexperiences (incidence =>0.2% but <1%) were observed in individualsfollowing a single dose of ProQuad. Solicited adverse experiences aredesignated 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, nasalcongestion, 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 studiesand with marketed use of either M-M-RII, the monovalent componentvaccines of M-M-RII, or VARIVAX. These adverse effects are listedbelow without regard to causality or frequency.

Infections and infestations

Atypical measles, candidiasis, cellulitis, herpes zoster,infection, influenza, measles, orchitis, parotitis, respiratoryinfection, skin infection.

Blood and the lymphatic system disorders

Lymphadenitis, regional lymphadenopathy, thrombocytopenia.

Immune system disorders

Anaphylactoid reaction, anaphylaxis and related phenomenon such asangioneurotic edema, facial edema, and peripheral edema, anaphylaxisin 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-Barresyndrome, 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 (seeCONTRAINDICATIONS), 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, orneck, swelling.

General disorders and administration site conditions

Injection-site complaints (burning and/or stinging of shortduration, 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 havebeen identified post approval for the monovalent components ofProQuad. Because these reactions are described in the literature orreported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish acausal relationship.

Death from various, and in some cases unknown, causes has beenreported rarely following vaccination with measles, mumps, and rubellavaccines; however, a causal relationship has not been established inhealthy individuals. Death as a direct consequence of disseminatedmeasles vaccine virus infection has been reported in severelyimmunocompromised individuals in whom a measles containing vaccine iscontraindicated and who were inadvertently vaccinated. However, therewere no deaths or permanent sequelae reported in a publishedpost-marketing surveillance study in Finland involving 1.5 millionchildren and adults who were vaccinated with M-M-RII during 1982 to1993.15

Encephalitis and encephalopathy have been reported approximatelyonce for every 3 million doses of the combination of measles, mumps,and rubella vaccine contained in M-M-RII. Post-marketing surveillanceof the more than 400 million doses that have been distributedworldwide (1978 to 2003) indicates that serious adverse events such asencephalitis and encephalopathy continue to be rarely reported. In nocase has it been shown conclusively that reactions were actuallycaused by the vaccine; however, the data suggest the possibility thatsome of these cases may have been caused by measles vaccines. The riskof such serious neurological disorders following live measles virusvaccine administration remains far less than that for encephalitis andencephalopathy with wild-type measles (1 per 2000 reported cases).

Arthralgia and/or arthritis (usually transient and rarelychronic), and polyneuritis are features of infection with wild-typerubella and vary in frequency and severity with age and gender, beinggreatest in adult females and least in prepubertal children. Followingvaccination in children, reactions in joints are generally uncommon (0to 3%) and of brief duration. In women, incidence rates for arthritisand arthralgia are generally higher than those seen in children (12 to26%), and the reactions tend to be more marked and of longer duration.Symptoms may persist for a matter of months or on rare occasions foryears. In adolescent girls, the reactions appear to be intermediate inincidence between those seen in children and adult women. In women 35to 45 years old these reactions are generally well tolerated andrarely interfere with normal activities.

Chronic arthritis has been associated with wild-type rubellainfection and has been related to persistent virus and/or viralantigen isolated from body tissues. Only rarely have vaccinerecipients developed chronic joint symptoms.

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

Cases of aseptic meningitis have been reported to VAERS followingmeasles, mumps, and rubella vaccination. Although a causalrelationship between other strains of mumps vaccine and asepticmeningitis 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 notto exceed that previously determined in a population-based study ofhealthy children who had experienced wild-type varicella.16 Inclinical trials, 8 cases of herpes zoster were reported in 9454vaccinated individuals 12 months to 12 years of age during 42,556person-years of follow-up. This resulted in a calculated incidence ofat least 18.8 cases per 100,000 person-years. All 8 cases reportedafter VARIVAX were mild and no sequelae were reported. The long-termeffect of VARIVAX on the incidence of herpes zoster is unknown atpresent.

DOSAGE AND ADMINISTRATION

Dosage

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

Preparation

CAUTION: Preservatives, antiseptics, detergents, and otheranti-viral substances may inactivate the vaccine. Use only sterilesyringes that are free of preservatives, antiseptics, detergents andother anti-viral substances for reconstitution and injection ofProQuad.

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

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

Visually inspect the vaccine before and after reconstitution forparticulate matter and discoloration prior to administration. Beforereconstitution, the lyophilized vaccine is a white to pale yellowcompact crystalline plug. ProQuad, when reconstituted, is a clear paleyellow to light pink liquid.

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

TO MINIMIZE LOSS OF POTENCY, THE VACCINE SHOULD BE ADMINISTEREDIMMEDIATELY AFTER RECONSTITUTION. DISCARD RECONSTITUTED VACCINE IF ITIS 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 toprevent transmission of infectious agents from one individual toanother.

The vaccine is to be injected subcutaneously in the outer aspectof the deltoid region of the upper arm or in the higher anterolateralarea of the thigh.

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

Use With Other Vaccines

If another vaccine is administered concomitantly, a differentinjection 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 vialof lyophilized vaccine, NDC 0006-4984-00 (package A); and (2) aseparate package of 10 vials of sterile water diluent (package B).

No. 4999 -- ProQuad is supplied as follows: (1) a package of 10single-dose vials of lyophilized vaccine, NDC 0006-4999-00 (packageA); 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, thevaccine must be maintained at a temperature of -4(degree)F(-20(degree)C) or colder.

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

DO NOT STORE LYOPHILIZED VACCINE IN THE REFRIGERATOR.

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

Protect the vaccine from light at all times since such exposuremay 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 to77(degree)F, 20 to 25(degree)C), or in a refrigerator (36 to46(degree)F, 2 to 8(degree)C).

REFERENCES

1. Weibel RE, et al. Clinical and laboratory studies of combinedlive measles, mumps, and rubella vaccines using the RA 27/3 rubellavirus. 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 attenuatedmeasles-virus vaccine: VI. clinical, antigenic and prophylacticeffects 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 asmeasured in a field evaluation. N Engl J Med. 276(5):252-8, 1967.

5. Sugg WC, Finger JA, Levine RH, Pagano JS. Field evaluation oflive virus mumps vaccine. J Pediatr. 72(4):461-6, 1968.

6. The Benevento and Compobasso Pediatricians Network for theControl of Vaccine-Preventable Diseases, D'Argenio P, Citarella A,Selvaggi MTM. Field evaluation of the clinical effectiveness ofvaccines 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 inclinical practice. N Engl J Med. 344(13):955-960, 2001.

9. Kuter B, et al. Ten year follow-up of healthy children whoreceived one or two injections of varicella vaccine. Pediatr InfectDis J. 23(2):132-137, 2004.

10. Committee on Infectious Diseases, American Academy ofPediatrics. In: Pickering LK, Baker CJ, Overturf GD, et al., eds. RedBook: 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 AdvisoryCommittee (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 varicellavaccination: Is the vaccine virus excreted in breast milk? Obstetricsand Gynecology. 102(5): 970-977, 2003.

14. Dolbear GL, Moffat J, Falkner C and Wojtowycz M. A PilotStudy: Is attenuated varicella virus present in breast milk afterpostpartum 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 vaccinationprogram. N Engl J Med. 331(21):1397-1402, 1994.

16. Guess HA, et al. Population-based studies of varicellacomplications. Pediatrics. 78(4 Pt 2):723-727, 1986.

Issued August 2005

Printed in USA
7999915

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

DESCRIPTION

VARIVAX* (Varicella Virus Vaccine Live (Oka/Merck)) is a
preparation of the Oka/Merck strain of live, attenuated varicella
virus. The virus was initially obtained from a child with natural
varicella, then introduced into human embryonic lung cell cultures,
adapted to and propagated in embryonic guinea pig cell cultures and
finally propagated in human diploid cell cultures (WI-38). Further
passage of the virus for varicella vaccine was performed at Merck
Research Laboratories (MRL) in human diploid cell cultures (MRC-5)
that were free of adventitious agents. This live, attenuated varicella
vaccine is a lyophilized preparation containing sucrose, phosphate,
glutamate, and processed gelatin as stabilizers.
VARIVAX, when reconstituted as directed, is a sterile preparation
for subcutaneous administration. Each 0.5 mL dose contains the
following: a minimum of 1350 PFU (plaque forming units) of Oka/Merck
varicella virus when reconstituted and stored at room temperature for
30 minutes, approximately 25 mg of sucrose, 12.5 mg hydrolyzed
gelatin, 3.2 mg sodium chloride, 0.5 mg monosodium L-glutamate, 0.45
mg of sodium phosphate dibasic, 0.08 mg of potassium phosphate
monobasic, 0.08 mg of potassium chloride; residual components of MRC-5
cells including DNA and protein; and trace quantities of sodium
phosphate monobasic, EDTA, neomycin, and fetal bovine serum. The
product contains no preservative.
To maintain potency, the lyophilized vaccine must be kept frozen
at an average temperature of - 15(degree)C (+5(degree)F) or colder and
must be used before the expiration date (see HOW SUPPLIED, Stability
and Storage). Storage in any freezer (e.g., chest, frost-free) that
reliably maintains an average temperature of - 15(degree)C
(+5(degree)F) or colder and has a separate sealed freezer door is
acceptable.

CLINICAL PHARMACOLOGY

Varicella is a highly communicable disease in children,
adolescents, and adults caused by the varicella-zoster virus (VZV).
The disease usually consists of 300 to 500 maculopapular and/or
vesicular lesions accompanied by a fever (oral temperature
>=100(degree)F) in up to 70% of individuals.1,2 Approximately 3.5
million cases of varicella occurred annually from 1980-1994 in the
United States with the peak incidence occurring in children five to
nine years of age.3 The incidence rate of chickenpox in the total
population was 8.3-9.1% per year in children 1-9 years of age before
licensure of VARIVAX.4,6 The attack rate of natural varicella
following household exposure among healthy susceptible children was
shown to be 87% in unvaccinated populations.2 Although it is generally
a benign, self-limiting disease, varicella may be associated with
serious complications (e.g., bacterial superinfection, pneumonia,
encephalitis, Reye's Syndrome), and/or death. Evaluation of Clinical
Efficacy Afforded by VARIVAX
The following section presents clinical efficacy data on a 1-dose
regimen and a 2-dose regimen in children, and a 2-dose regimen in
adolescents and adults. Clinical Data in Children One-Dose Regimen in
Children
In combined clinical trials5 of VARIVAX at doses ranging from
1000-17,000 PFU, the majority of subjects who received VARIVAX and
were exposed to wild-type virus were either completely protected from
chickenpox or developed a milder form (for clinical description see
below) of the disease. The protective efficacy of VARIVAX was
evaluated in three different ways: 1) by comparing chickenpox rates in
vaccinees versus historical controls, 2) by assessment of protection
from disease following household exposure, and 3) by a
placebo-controlled, double-blind clinical trial.
In early clinical trials,5 a total of 4240 children 1 to 12 years
of age received 1000-1625 PFU of attenuated virus per dose of VARIVAX
and have been followed for up to nine years post single-dose
vaccination. In this group there was considerable variation in
chickenpox rates among studies and study sites, and much of the
reported data was acquired by passive follow-up. It was observed that
0.3%-3.8% of

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

vaccinees per year reported chickenpox (called breakthrough cases).
This represents an approximate 83% (95% confidence interval (CI), 82%,
84%) decrease from the age-adjusted expected incidence rates in
susceptible subjects over this same period.19 In those who developed
breakthrough chickenpox postvaccination, the majority experienced mild
disease (median of the maximum number of lesions <50). In one study, a
total of 47% (27/58) of breakthrough cases had <50 lesions compared
with 8% (7/92) in unvaccinated individuals, and 7% (4/58) of
breakthrough cases had >300 lesions compared with 50% (46/92) in
unvaccinated individuals.7
Among a subset of vaccinees who were actively followed in these
early trials for up to nine years postvaccination, 179 individuals had
household exposure to chickenpox. There were no reports of
breakthrough chickenpox in 84% (150/179) of exposed children, while
16% (29/179) reported a mild form of chickenpox (38% (11/29) of the
cases with a maximum total number of <50 lesions; no individuals with
>300 lesions). This represents an 81% reduction in the expected number
of varicella cases utilizing the historical attack rate of 87%
following household exposure to chickenpox in unvaccinated individuals
in the calculation of efficacy.
In later clinical trials5 with the current vaccine, a total of
1114 children 1 to 12 years of age received 2900-9000 PFU of
attenuated virus per dose of VARIVAX and have been actively followed
for up to 10 years post single-dose vaccination. It was observed that
0.2%-2.3% of vaccinees per year reported breakthrough chickenpox for
up to 10 years post single-dose vaccination. This represents an
estimated efficacy of 94% (95% CI, 93%, 96%), compared with the
age-adjusted expected incidence rates in susceptible subjects over the
same period.4,6,19 In those who developed breakthrough chickenpox
postvaccination, the majority experienced mild disease, with the
median of the maximum total number of lesions <50. The severity of
reported breakthrough chickenpox, as measured by number of lesions and
maximum temperature, appeared not to increase with time since
vaccination.
Among a subset of vaccinees who were actively followed in these
later trials for up to 10 years postvaccination, 95 individuals were
exposed to an unvaccinated individual with wild-type chickenpox in a
household setting. There were no reports of breakthrough chickenpox in
92% (87/95) of exposed children, while 8% (8/95) reported a mild form
of chickenpox (maximum total number of lesions <50; observed range, 10
to 34). This represents an estimated efficacy of 90% (95% CI, 82%,
96%) based on the historical attack rate of 87% following household
exposure to chickenpox in unvaccinated individuals in the calculation
of efficacy.
Although no placebo-controlled trial was carried out with VARIVAX
using the current vaccine, a placebo-controlled trial was conducted
using a formulation containing 17,000 PFU per dose.4,8 In this trial,
a single dose of VARIVAX protected 96-100% of children against
chickenpox over a two-year period. The study enrolled healthy
individuals 1 to 14 years of age (n=491 vaccine, n=465 placebo). In
the first year, 8.5% of placebo recipients contracted chickenpox,
while no vaccine recipient did, for a calculated protection rate of
100% during the first varicella season. In the second year, when only
a subset of individuals agreed to remain in the blinded study (n=163
vaccine, n=161 placebo), 96% protective efficacy was calculated for
the vaccine group as compared to placebo.
There are insufficient data to assess the rate of protection
against the complications of chickenpox (e.g., encephalitis,
hepatitis, pneumonia) in children. Two-Dose Regimen in Children
In a clinical trial, a total of 2216 children 12 months to 12
years of age with a negative history of varicella were randomized to
receive either 1 dose of VARIVAX (n=1114) or 2 doses of VARIVAX
(n=1102) given 3 months apart. Subjects were actively followed for
varicella, any varicella-like illness, or herpes zoster and any
exposures to varicella or herpes zoster on an annual basis for 10
years after vaccination. Persistence of VZV antibody was measured
annually for 9 years. Most cases of varicella reported in recipients
of 1 dose or 2 doses of vaccine were mild.26 The estimated vaccine
efficacy for the 10-year observation period was 94% for 1 dose and 98%
for 2 doses (p<0.001). This translates to a 3.4-fold lower risk of
developing varicella >42 days postvaccination during the 10-year
observation period in children who received 2 doses than in those who
received 1 dose (2.2% vs. 7.5%, respectively). Clinical Data in
Adolescents and Adults Two-Dose Regimen in Adolescents and Adults
In early clinical trials, a total of 796 adolescents and adults
received 905-1230 PFU of attenuated virus per dose of VARIVAX and have
been followed for up to six years following 2-dose vaccination. A
total of 50 clinical varicella cases were reported >42 days following
2-dose vaccination. Based on passive followup, the annual chickenpox
breakthrough event rate ranged from <0.1% to 1.9%. The median of the
maximum total number of lesions ranged from 15 to 42 per year.
Although no placebo-controlled trial was carried out in
adolescents and adults, the protective efficacy of VARIVAX was
determined by evaluation of protection when vaccinees received 2 doses
of VARIVAX 4 or 8 weeks apart and were subsequently exposed to
chickenpox in a household setting.5 Among the subset of vaccinees who
were actively followed in these early trials for up to six years, 76
individuals had household exposure to chickenpox. There were no
reports of breakthrough chickenpox in 83% (63/76) of exposed
vaccinees, while 17% (13/76) reported a mild form of chickenpox. Among
13 vaccinated individuals who developed breakthrough chickenpox after
a household exposure, 62% (8/13) of the cases reported maximum total
number of lesions <50, while no individual reported >75 lesions. The
attack rate of unvaccinated adults exposed to a single contact in a
household has not been previously studied. Utilizing the previously
reported historical attack rate of 87% for natural varicella following
household exposure to chickenpox among unvaccinated children in the
calculation of efficacy, this represents an approximate 80% reduction
in the expected number of cases in the household setting.
In later clinical trials, a total of 220 adolescents and adults
received 3315-9000 PFU of attenuated virus per dose of VARIVAX and
have been actively followed for up to six years following 2-dose
vaccination. A total of 3 clinical varicella cases were reported >42
days following 2-dose vaccination. Two cases reported <50 lesions and
none reported >75. The annual chickenpox breakthrough event rate
ranged from 0% to 1.2%. Among the subset of vaccinees who were
actively followed in these later trials for up to five years, 16
individuals were exposed to an unvaccinated individual with wild-type
chickenpox in a household setting. There were no reports of
breakthrough chickenpox among the exposed vaccinees.
There are insufficient data to assess the rate of protection of
VARIVAX against the serious complications of chickenpox in adults
(e.g., encephalitis, hepatitis, pneumonitis) and during pregnancy
(congenital varicella syndrome). Immunogenicity of VARIVAX
The following section presents immunogenicity data on a 1-dose
regimen and a 2-dose regimen in children, and a 2-dose regimen in
adolescents and adults. One-Dose Regimen in Children
Clinical trials with several formulations of the vaccine
containing attenuated virus ranging from 1000 to 17,000 PFU per dose
have demonstrated that VARIVAX induces detectable immune responses in
a high proportion of individuals and is generally well tolerated in
healthy individuals ranging from 12 months to 55 years of age.4,5,9-15
Seroconversion is defined by the acquisition of any detectable VZV
antibodies, based on an optical density (OD) cutoff, corresponding
approximately to a lower limit of 0.6 glycoprotein enzyme-linked
immunosorbent assay (gpELISA) units/mL.
The gpELISA is a highly sensitive assay that is not commercially
available. Seroconversion was observed in 97% of vaccinees at
approximately 4-6 weeks postvaccination in 6889 susceptible children
12 months to 12 years of age. Rates of breakthrough disease were
significantly lower among children with VZV antibody titers >=5
gpELISA units/mL compared with children with titers <5 gpELISA
units/mL. Titers >=5 gpELISA units/mL were induced in approximately
76% of children vaccinated with a single dose of vaccine at
1000-17,000 PFU per dose.
VARIVAX also induces cell-mediated immune responses in vaccinees.
The relative contributions of humoral immunity and cell-mediated
immunity to protection from chickenpox are unknown. Two-Dose Regimen
in Children
In a multicenter study, healthy children 12 months to 12 years of
age received either 1 dose of VARIVAX or 2 doses administered 3 months
apart. The immunogenicity results are shown in the following table.

----------------------------------------------------------------------
VARIVAX 1-Dose VARIVAX 2-Dose Regimen (N =
Regimen (N = 1102)
1114)

----------------------------------------------------------------------
6 Weeks 6 Weeks Postdose 6 Weeks Postdose
Postvaccination 1 2
----------------------------------------------------------------------
Seroconversion Rate 98.9% (882/892) 99.5% (847/851) 99.9% (768/769)

----------------------------------------------------------------------
Percent with VZV
Antibody Titer >=5
gpELISA units/mL 84.9% (757/892) 87.3% (743/851) 99.5% (765/769)
----------------------------------------------------------------------
Geometric mean titers 12.0 12.8 141.5
----------------------------------------------------------------------

--------------------------------------------------------------------
(gpELISA units/mL)
--------------------------------------------------------------------

The results from this study and other studies in which a second
dose of vaccine was administered 3 to 6 years after the initial dose
demonstrate significant boosting of the VZV antibody response with a
second dose. VZV antibody levels after 2 doses given 3 to 6 years
apart are comparable to those obtained when the 2 doses are given 3
months apart. Two-Dose Regimen in Adolescents and Adults
In a multicenter study involving susceptible adolescents and
adults 13 years of age and older, 2 doses of VARIVAX administered 4 to
8 weeks apart induced a seroconversion rate of approximately 75% in
539 individuals 4 weeks after the first dose and of 99% in 479
individuals 4 weeks after the second dose. The average antibody
response in vaccinees who received the second dose 8 weeks after the
first dose was higher than that in vaccinees who received the second
dose 4 weeks after the first dose. In another multicenter study
involving adolescents and adults, 2 doses of VARIVAX administered 8
weeks apart induced a seroconversion rate of 94% in 142 individuals 6
weeks after the first dose and 99% in 122 individuals 6 weeks after
the second dose. Persistence of Immune Response
The following section presents immune persistence data on a 1-dose
regimen and a 2-dose regimen in children, and a 2-dose regimen in
adolescents and adults. One-Dose Regimen in Children
In clinical studies involving healthy children who received 1 dose
of vaccine, detectable VZV antibodies were present in 99.0%
(3886/3926) at 1 year, 99.3% (1555/1566) at 2 years, 98.6% (1106/1122)
at 3 years, and 99.4% (1168/1175) at 4 years, 99.2% (737/743) at 5
years, 100% (142/142) at 6 years, 97.4% (38/39) at 7 years, 100%
(34/34) at 8 years, and 100% (16/16) at 10 years postvaccination.
Two-Dose Regimen in Children
In recipients of 1 dose of VARIVAX over 9 years of follow-up, the
geometric mean titer (GMT) and the percent of subjects with VZV
antibody titers >=5 gpELISA units/mL generally increased. The GMTs and
percent of subjects with VZV antibody titers >=5 gpELISA units/mL in
the 2-dose recipients were higher than those in the 1-dose recipients
for the first year of follow-up and generally comparable thereafter.
The cumulative rate of VZV antibody persistence with both regimens
remained very high at year 9 (99.0% for the 1-dose group and 98.8% for
the 2-dose group). Two-Dose Regimen in Adolescents and Adults
In clinical studies involving healthy adolescents and adults who
received 2 doses of vaccine, detectable VZV antibodies were present in
97.9% (568/580) at 1 year, 97.1% (34/35) at 2 years, 100% (144/144) at
3 years, 97.0% (98/101) at 4 years, 97.4% (76/78) at 5 years, and 100%
(34/34) at 6 years postvaccination.
A boost in antibody levels has been observed in vaccinees
following exposure to natural varicella which could account for the
apparent long-term persistence of antibody levels after vaccination in
these studies. The duration of protection from varicella obtained
using VARIVAX in the absence of wild-type boosting is unknown. VARIVAX
also induces cell-mediated immune responses in vaccinees. The relative
contributions of humoral immunity and cell-mediated immunity to
protection from chickenpox are unknown. Transmission
In the placebo-controlled trial, transmission of vaccine virus was
assessed in household settings (during the 8-week postvaccination
period) in 416 susceptible placebo recipients who were household
contacts of 445 vaccine recipients. Of the 416 placebo recipients,
three developed chickenpox and seroconverted, nine reported a
varicella-like rash and did not seroconvert, and six had no rash but
seroconverted. If vaccine virus transmission occurred, it did so at a
very low rate and possibly without recognizable clinical disease in
contacts. These cases may represent either natural varicella from
community contacts or a low incidence of transmission of vaccine virus
from vaccinated contacts (see PRECAUTIONS, Transmission).4,16
Post-marketing experience suggests that transmission of vaccine virus
may occur rarely between healthy vaccinees who develop a
varicella-like rash and healthy susceptible contacts. Transmission of
vaccine virus from vaccinees without a varicella-like rash has been
reported but has not been confirmed. Herpes Zoster
Overall, 9454 healthy children (12 months to 12 years of age) and
1648 adolescents and adults (13 years of age and older) have been
vaccinated with Oka/Merck live attenuated varicella vaccine in
clinical trials. Eight cases of herpes zoster have been reported in
children during 42,556 person years of follow-up in clinical trials,
resulting in a calculated incidence of at least 18.8 cases per 100,000
person years. The completeness of this reporting has not been
determined. One case of herpes zoster has been reported in the
adolescent and adult age group during 5410 person years of follow-up
in clinical trials resulting in a calculated incidence of 18.5 cases
per 100,000 person years.5
All nine cases were mild and without sequelae. Two cultures (one
child and one adult) obtained from vesicles were positive for
wild-type VZV as confirmed by restriction endonuclease analysis.5,17
The long-term effect of VARIVAX on the incidence of herpes zoster,
particularly in those vaccinees exposed to natural varicella, is
unknown at present.
In children, the reported rate of herpes zoster in vaccine
recipients appears not to exceed that previously determined in a
population-based study of healthy children who had experienced natural
varicella.5,18,19 The incidence of herpes zoster in adults who have
had natural varicella infection is higher than that in children.20
Reye's Syndrome
Reye's Syndrome has occurred in children and adolescents following
natural varicella infection, the majority of whom had received
salicylates.21 In clinical studies in healthy children and adolescents
in the United States, physicians advised varicella vaccine recipients
not to use salicylates for six weeks after vaccination. There were no
reports of Reye's Syndrome in varicella vaccine recipients during
these studies. Studies with Other Vaccines
In combined clinical studies involving 1080 children 12 to 36
months of age, 653 received VARIVAX and M-M-R* II (Measles, Mumps, and
Rubella Virus Vaccine Live) concomitantly at separate sites and 427
received the vaccines six weeks apart. Seroconversion rates and
antibody levels were comparable between the two groups at
approximately six weeks post-vaccination to each of the virus vaccine
components. No differences were noted in adverse reactions reported in
those who received VARIVAX concomitantly with M-M-R II at separate
sites and those who received VARIVAX and M-M-R II at different times
(see PRECAUTIONS, Drug Interactions, Use with Other Vaccines).5
In a clinical study involving 318 children 12 months to 42 months
of age, 160 received an investigational vaccine (a formulation
combining measles, mumps, rubella, and varicella in one syringe)
concomitantly with booster doses of DTaP (diphtheria, tetanus,
acellular pertussis) and OPV (oral poliovirus vaccine) while 144
received M-M-R II concomitantly with booster doses of DTaP and OPV
followed by VARIVAX 6 weeks later. At six weeks postvaccination,
seroconversion rates for measles, mumps, rubella, and VZV and the
percentage of vaccinees whose titers were boosted for diphtheria,
tetanus, pertussis, and polio were comparable between the two groups,
but anti-VZV levels were decreased when the investigational vaccine
containing varicella was administered concomitantly with DTaP. No
clinically significant differences were noted in adverse reactions
between the two groups.5
In another clinical study involving 307 children 12 to 18 months
of age, 150 received an investigational vaccine (a formulation
combining measles, mumps, rubella, and varicella in one syringe)
concomitantly with a booster dose of PedvaxHIB* (Haemophilus b
Conjugate Vaccine (Meningococcal Protein Conjugate)) while 130
received M-M-R II concomitantly with a booster dose of PedvaxHIB
followed by VARIVAX 6 weeks later. At six weeks postvaccination,
seroconversion rates for measles, mumps, rubella, and VZV, and
geometric mean titers for PedvaxHIB were comparable between the two
groups, but anti-VZV levels were decreased when the investigational
vaccine containing varicella was administered concomitantly with
PedvaxHIB. No clinically significant differences in adverse reactions
were seen between the two groups.5
In a clinical study involving 609 children 12 to 23 months of age,
305 received VARIVAX, M-M-R II, and

**

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

** Registered trademark of Lederle Laboratories
or 6 weeks apart. There were no clinically important differences in
reaction rates when the three vaccines were administered concomitantly
versus 6 weeks apart.
In a clinical study involving 822 children 12 to 15 months of age,
410 received COMVAX* (Haemophilus b Conjugate (Meningococcal Protein
Conjugate) and Hepatitis B (Recombinant) vaccine), M-M-R II, and
VARIVAX concomitantly at separate sites, and 412 received COMVAX
followed by M-M-R II and VARIVAX given concomitantly at separate
sites, 6 weeks later. At six weeks postvaccination, the immune
responses for the subjects who received the concomitant doses of
COMVAX, M-M-R II, and VARIVAX were similar to those of the subjects
who received COMVAX followed 6 weeks later by M-M-R II and VARIVAX
with respect to all antigens administered. All three vaccines were
generally well tolerated regardless of whether they were administered
concomitantly at separate sites or 6 weeks apart. There were no
clinically important differences in reaction rates when the three
vaccines were administered concomitantly versus 6 weeks apart.
VARIVAX is recommended for subcutaneous administration. However,
during clinical trials, some children received VARIVAX intramuscularly
resulting in seroconversion rates similar to those in children who
received the vaccine by the subcutaneous route.22 Persistence of
antibody and efficacy in those receiving intramuscular doses have not
been defined.

INDICATIONS AND USAGE

VARIVAX is indicated for vaccination against varicella in
individuals 12 months of age and older.
The duration of protection of VARIVAX is unknown; however,
long-term efficacy studies have demonstrated continued protection up
to 10 years after vaccination.26 In addition, a boost in antibody
levels has been observed in vaccinees following exposure to natural
varicella as well as following a second dose of VARIVAX.5
In a highly vaccinated population, immunity for some individuals
may wane due to lack of exposure to natural varicella as a result of
shifting epidemiology. Post-marketing surveillance studies are ongoing
to evaluate the need and timing for booster vaccination.
Vaccination with VARIVAX may not result in protection of all
healthy, susceptible children, adolescents, and adults (see CLINICAL
PHARMACOLOGY).

CONTRAINDICATIONS

A history of hypersensitivity to any component of the vaccine,
including gelatin.
A history of anaphylactoid reaction to neomycin (each dose of
reconstituted vaccine contains trace quantities of neomycin).
Individuals with blood dyscrasias, leukemia, lymphomas of any
type, or other malignant neoplasms affecting the bone marrow or
lymphatic systems.
Individuals receiving immunosuppressive therapy. Individuals who
are on immunosuppressant drugs are more susceptible to infections than
healthy individuals. Vaccination with live attenuated varicella
vaccine can result in a more extensive vaccine-associated rash or
disseminated disease in individuals on immunosuppressant doses of
corticosteroids.
Individuals with primary and acquired immunodeficiency states,
including those who are immunosuppressed in association with AIDS or
other clinical manifestations of infection with human immunodeficiency
virus;23 cellular immune deficiencies; and hypogammaglobulinemic and
dysgammaglobulinemic states.
A family history of congenital or hereditary immunodeficiency,
unless the immune competence of the potential vaccine recipient is
demonstrated.
Active untreated tuberculosis.
Any febrile respiratory illness or other active febrile infection.
Pregnancy; the possible effects of the vaccine on fetal
development are unknown at this time. However, natural varicella is
known to sometimes cause fetal harm. If vaccination of postpubertal
females is undertaken, pregnancy should be avoided for three months
following vaccination (See PRECAUTIONS, Pregnancy).

PRECAUTIONS

General
Adequate treatment provisions, including epinephrine injection
(1:1000), should be available for immediate use should an
anaphylactoid reaction occur.
The duration of protection from varicella infection after
vaccination with VARIVAX is unknown.
It is not known whether VARIVAX given immediately after exposure
to natural varicella virus will prevent illness.
Vaccination should be deferred for at least 5 months following
blood or plasma transfusions, or administration of immune globulin or
varicella zoster immune globulin (VZIG).24
Following administration of VARIVAX, any immune globulin,
including VZIG, should not be given for 2 months thereafter unless its
use outweighs the benefits of vaccination.24
Vaccine recipients should avoid use of salicylates for 6 weeks
after vaccination with VARIVAX as Reye's Syndrome has been reported
following the use of salicylates during natural varicella infection
(see CLINICAL PHARMACOLOGY, Reye's Syndrome).
The safety and efficacy of VARIVAX have not been established in
children and young adults who are known to be infected with human
immunodeficiency viruses with and without evidence of
immunosuppression (see also CONTRAINDICATIONS).
Care is to be taken by the health care provider for safe and
effective use of VARIVAX.
The health care provider should question the patient, parent, or
guardian about reactions to a previous dose of VARIVAX or a similar
product.
The health care provider should obtain the previous immunization
history of the vaccinee.
VARIVAX should not be injected into a blood vessel.
Vaccination should be deferred in patients with a family history
of congenital or hereditary immunodeficiency until the patient's own
immune system has been evaluated.
A separate sterile needle and syringe should be used for
administration of each dose of VARIVAX to prevent transfer of
infectious diseases.
Needles should be disposed of properly and should not be recapped.
Transmission
Post-marketing experience suggests that transmission of vaccine
virus may occur rarely between healthy vaccinees who develop a
varicella-like rash and healthy susceptible contacts. Transmission of
vaccine virus from vaccinees without a varicella-like rash has been
reported but has not been confirmed.
Therefore, vaccine recipients should attempt to avoid, whenever
possible, close association with susceptible high-risk individuals for
up to six weeks. In circumstances where contact with high-risk
individuals is unavoidable, the potential risk of transmission of
vaccine virus should be weighed against the risk of acquiring and
transmitting natural varicella virus. Susceptible high-risk
individuals include:
-- immunocompromised individuals
-- pregnant women without documented history of chickenpox or
laboratory evidence of prior infection
-- newborn infants of mothers without documented history of
chickenpox or laboratory evidence of prior infection.

Information for Patients
The health care provider should inform the patient, parent, or
guardian of the benefits and risks of VARIVAX.
Patients, parents, or guardians should be instructed to report any
adverse reactions to their health care provider.
The U.S. Department of Health and Human Services has established a
Vaccine Adverse Event Reporting System (VAERS) to accept all reports
of suspected adverse events after the administration of any vaccine,
including but not limited to the reporting of events required by the
National Childhood Vaccine Injury Act of 1986.25 The VAERS toll-free
number for VAERS forms and information is 1-800-822-7967.
Pregnancy should be avoided for three months following
vaccination. Drug Interactions
See PRECAUTIONS, General, regarding the administration of immune
globulins, salicylates, and transfusions.
Drug Interactions, Use with Other Vaccines
Results from clinical studies indicate that VARIVAX can be
administered concomitantly with M-M-R II, COMVAX, or TETRAMUNE (see
CLINICAL PHARMACOLOGY, Studies with Other Vaccines).
Limited data from an experimental product containing varicella
vaccine suggest that VARIVAX can be administered concomitantly with
DTaP (diphtheria, tetanus, acellular pertussis) and PedvaxHIB using
separate sites and syringes (see CLINICAL PHARMACOLOGY, Studies with
Other Vaccines).5 However, there are no data relating to simultaneous
administration of VARIVAX with DTP or OPV. Carcinogenesis,
Mutagenesis, Impairment of Fertility
VARIVAX has not been evaluated for its carcinogenic or mutagenic
potential, or its potential to impair fertility. Pregnancy
Pregnancy Category C: Animal reproduction studies have not been
conducted with VARIVAX. It is also not known whether VARIVAX can cause
fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Therefore, VARIVAX should not be administered
to pregnant females; furthermore, pregnancy should be avoided for
three months following vaccination (see CONTRAINDICATIONS).
Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetal
outcomes of pregnant women exposed to VARIVAX. Patients and healthcare
providers are encouraged to report any exposure to VARIVAX during
pregnancy by calling (800) 986-8999. Nursing Mothers
It is not known whether varicella vaccine virus is secreted in
human milk. Therefore, because some viruses are secreted in human
milk, caution should be exercised if VARIVAX is administered to a
nursing woman. Geriatric Use
Clinical studies of VARIVAX did not include sufficient numbers of
seronegative subjects aged 65 and over to determine whether they
respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the
elderly and younger subjects. Pediatric Use
No clinical data are available on safety or efficacy of VARIVAX in
children less than one year of age and administration to infants under
twelve months of age is not recommended.

ADVERSE REACTIONS

In clinical trials,4,5,9-15 VARIVAX was administered to over
11,000 healthy children, adolescents, and adults. VARIVAX was
generally well tolerated.
In a double-blind, placebo-controlled study among 914 healthy
children and adolescents who were serologically confirmed to be
susceptible to varicella, the only adverse reactions that occurred at
a significantly (p<0.05) greater rate in vaccine recipients than in
placebo recipients were pain and redness at the injection site.4
Children 1 to 12 Years of Age One-Dose Regimen in Children
In clinical trials involving healthy children monitored for up to
42 days after a single dose of VARIVAX, the frequency of fever,
injection-site complaints, or rashes were reported as follows:

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

----------------------------------------------------------------------
Reaction N Post Dose 1 Peak Occurrence in Postvaccination
Days
----------------------------------------------------------------------
Fever
>=102(degree)F
(39(degree)C)
Oral 8827 14.7% 0-42

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

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

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

----------------------------------------------------------------------

In addition, the most frequently (>=1%) reported adverse
experiences, without regard to causality, are listed in decreasing
order of frequency: upper respiratory illness, cough,
irritability/nervousness, fatigue, disturbed sleep, diarrhea, loss of
appetite, vomiting, otitis, diaper rash/contact rash, headache,
teething, malaise, abdominal pain, other rash, nausea, eye complaints,
chills, lymphadenopathy, myalgia, lower respiratory illness, allergic
reactions (including allergic rash, hives), stiff neck, heat
rash/prickly heat, arthralgia, eczema/dry skin/dermatitis,
constipation, itching.
Pneumonitis has been reported rarely (<1%) in children vaccinated
with VARIVAX; a causal relationship has not been established.
Febrile seizures have occurred rarely (<0.1%) in children
vaccinated with VARIVAX; a causal relationship has not been
established. Two-Dose Regimen in Children
Nine hundred eighty-one (981) subjects in a clinical trial
received 2 doses of VARIVAX 3 months apart and were actively followed
for 42 days after each dose. The 2-dose regimen of varicella vaccine
was generally well tolerated, with a safety profile generally
comparable to that of the 1-dose regimen. The incidence of
injection-site clinical complaints (primarily erythema and swelling)
observed in the first 4 days following vaccination was slightly higher
Postdose 2 (overall incidence 25.4%) than Postdose 1 (overall
incidence 21.7%), whereas the incidence of systemic clinical
complaints in the 42-day follow-up period was lower Postdose 2 (66.3%)
than Postdose 1 (85.8%). Adolescents and Adults 13 Years of Age and
Older
In clinical trials involving healthy adolescents and adults, the
majority of whom received two doses of VARIVAX and were monitored for
up to 42 days after any dose, the frequency of fever, injection-site
complaints, or rashes were reported as follows:

Table 2

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

----------------------------------------------------------------------

Post Peak Occurrence Post Peak Occurrence
in in
Reaction N Dose 1 Postvaccination N Dose 2 Postvaccination
Days Days
----------------------------------------------------------------------
Fever
>=100(degree)F
(37.7(degree)C)
Oral 1584 10.2% 14-27 956 9.5% 0-42

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

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

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

----------------------------------------------------------------------

In addition, the most frequently (>=1%) reported adverse
experiences, without regard to causality, are listed in decreasing
order of frequency: upper respiratory illness, headache, fatigue,
cough, myalgia, disturbed sleep, nausea, malaise, diarrhea, stiff
neck, irritability/nervousness, lymphadenopathy, chills, eye
complaints, abdominal pain, loss of appetite, arthralgia, otitis,
itching, vomiting, other rashes, constipation, lower respiratory
illness, allergic reactions (including allergic rash, hives), contact
rash, cold/canker sore.
As with any vaccine, there is the possibility that broad use of
the vaccine could reveal adverse reactions not observed in clinical
trials.

The following additional adverse reactions have been reported
since the vaccine has been marketed:
Body as a Whole
Anaphylaxis in individuals with or without an allergic history.
Hemic and Lymphatic System
Thrombocytopenia (including ITP).
Nervous/Psychiatric
Encephalitis; cerebrovascular accident; transverse myelitis;
Guillain-Barre syndrome; Bell's palsy; ataxia; non-febrile seizures;
aseptic meningitis; dizziness; paresthesia. Respiratory
Pharyngitis, Pneumonia/Pneumonitis.
Skin
Stevens-Johnson syndrome; erythema multiforme; Henoch-Schonlein
purpura; secondary bacterial infections of skin and soft tissue,
including impetigo and cellulitis; herpes zoster.

DOSAGE AND ADMINISTRATION

FOR SUBCUTANEOUS
----------------
ADMINISTRATION Do not inject
----------------------------
intravascularly
---------------
Children
Children 12 months to 12 years of age should receive a 0.5-mL dose
administered subcutaneously.
If a second 0.5-mL dose is administered, it should be given a
minimum of 3 months later. Adolescents and Adults
Adolescents and adults 13 years of age and older should receive a
0.5-mL dose administered subcutaneously at elected date and a second
0.5-mL dose 4 to 8 weeks later.
VARIVAX is for subcutaneous administration. The outer aspect of
the upper arm (deltoid) is the preferred site of injection.
VARIVAX SHOULD BE STORED FROZEN at an average temperature of
-15(degree)C (+5(degree)F) or colder until it is reconstituted for
injection (see HOW SUPPLIED, Storage). Any freezer (e.g., chest,
frost-free) that reliably maintains an average temperature of
-15(degree)C and has a separate sealed freezer door is acceptable for
storing VARIVAX. The diluent should be stored separately at room
temperature or in the refrigerator. To reconstitute the vaccine, first
withdraw 0.7 mL of diluent into a syringe. Inject all the diluent in
the syringe into the vial of lyophilized vaccine and gently agitate to
mix thoroughly. Withdraw the entire contents into a syringe and inject
the total volume (about 0.5 mL) of reconstituted vaccine
subcutaneously, preferably into the outer aspect of the upper arm
(deltoid) or the anterolateral thigh. IT IS RECOMMENDED THAT THE
VACCINE BE ADMINISTERED IMMEDIATELY AFTER RECONSTITUTION, TO MINIMIZE
LOSS OF POTENCY. DISCARD IF RECONSTITUTED VACCINE IS NOT USED WITHIN
30 MINUTES.
CAUTION: A sterile syringe free of preservatives, antiseptics, and
detergents should be used for each injection and/or reconstitution of
VARIVAX because these substances may inactivate the vaccine virus.
It is important to use a separate sterile syringe and needle for
each patient to prevent transmission of infectious agents from one
individual to another.
To reconstitute the vaccine, use only the Merck sterile diluent
supplied with VARIVAX, M-M-R II, or the component vaccines of M-M-R
II, since it is free of preservatives or other anti-viral substances
which might inactivate the vaccine virus.
Do not freeze reconstituted vaccine.
Do not give immune globulin, including Varicella Zoster Immune
--------------------------------------------------------------
Globulin, concurrently with VARIVAX (see also PRECAUTIONS).
-----------------------------------
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever
solution and container permit. VARIVAX when reconstituted is a clear,
colorless to pale yellow liquid.

HOW SUPPLIED

No. 4826/4309 -- VARIVAX is supplied as follows: (1) a single-dose
vial of lyophilized vaccine, NDC 0006-4826-00 (package A); and (2) a
box of 10 vials of diluent (package B).
No. 4827/4309 -- VARIVAX is supplied as follows: (1) a box of 10
single-dose vials of lyophilized vaccine (package A), NDC
0006-4827-00; and (2) a box of 10 vials of diluent (package B).
Stability
VARIVAX retains a potency level of 1500 PFU or higher per dose for
at least 24 months in a frost-free freezer with an average temperature
of -15(degree)C (+5(degree)F) or colder.
VARIVAX has a minimum potency level of approximately 1350 PFU 30
minutes after reconstitution at room temperature (20-25(degree)C,
68-77(degree)F).
Prior to reconstitution, VARIVAX retains potency when stored for
up to 72 continuous hours at refrigerator temperature (2-8(degree)C,
36-46(degree)F).
For information regarding stability under conditions other than
those recommended, call 1-800-9-VARIVAX. Storage
During shipment, to ensure that there is no loss of potency, the
vaccine must be maintained at a temperature of -15(degree)C
(+5(degree)F) or colder.
Before reconstitution, store the lyophilized vaccine in a freezer
at an average temperature of - 15(degree)C (+5(degree)F) or colder.
Any freezer (e.g., chest, frost-free) that reliably maintains an
average temperature of -15(degree)C and has a separate sealed freezer
door is acceptable for storing VARIVAX.
VARIVAX may be stored at refrigerator temperature (2-8(degree)C,
36-46(degree)F) for up to 72 continuous hours prior to reconstitution.
Vaccine stored at 2-8(degree)C which is not used within 72 hours of
removal from -15(degree)C storage should be discarded.
Before reconstitution, protect from light.
The diluent should be stored separately at room temperature
(20-25(degree)C, 68-77(degree)F), or in the refrigerator.

REFERENCES

1. 1. Balfour, H.H.; et al.: Acyclovir Treatment of Varicella in
Otherwise Healthy Children, Pediatrics., 116: 633-639, 1990.
2. 2. Ross, A.H.: Modification of Chickenpox in Family Contacts by
Administration of Gamma Globulin, N Engl J Med. 267: 369-376, 1962.
3. 3. Preblud, S.R.: Varicella: Complications and Costs,
Pediatrics, 78(4 Pt 2): 728-735, 1986.
4. 4. Weibel, R.E.; et al.: Live Attenuated Varicella Virus
Vaccine, N Engl J Med. 310(22): 1409-1415, 1984.
5. 5. Unpublished data; files of Merck Research Laboratories.
6. 6. Wharton, M.; et al.: Health Impact of Varicella in the
1980's. Thirtieth Interscience Conference on Antimicrobial Agents and
Chemotherapy, (Abstract #1138), 1990.
7. 7. Bernstein, H.H.; et al.: Clinical Survey of Natural
Varicella Compared with Breakthrough Varicella After Immunization with
Live Attenuated Oka/Merck Varicella Vaccine. Pediatrics 92: 833-837,
1993.
8. 8. Kuter, B.J.; et al.: Oka/Merck Varicella Vaccine in Healthy
Children: Final Report of a 2-Year Efficacy Study and 7-Year Follow-up
Studies, Vaccine, 9: 643-647, 1991.
9. 9. Arbeter, A.M.; et al.: Varicella Vaccine Trials in Healthy
Children, A Summary of Comparative and Follow-up Studies, AJDC 138:
434-438, 1984.
10. 10. Weibel, R.E.; et al.: Live Oka/Merck Varicella Vaccine in
Healthy Children, JAMA 254(17): 2435-2439, 1985.
11. 11. Chartrand, D.M.; et al.: New Varicella Vaccine Production
Lots in Healthy Children and Adolescents, Abstracts of the 1988
Inter-Science Conference Antimicrobial Agents and Chemotherapy:
237(Abstract #731).
12. 12. Johnson, C.E.; et al.: Live Attenuated Vaccine in Healthy
12 to 24 month old Children, Pediatrics 81: 512-518, 1988.
13. 13. Gershon, A.A.; et al.: Immunization of Healthy Adults with
Live Attenuated Varicella Vaccine, J Infect Dis, 158(1): 132-137,
1988.
14. 14. Gershon, A.A.; et al.: Live Attenuated Varicella Vaccine:
Protection in Healthy Adults Compared with Leukemic Children, J Infect
Dis, 161: 661-666, 1990.
15. 15. White, C.J.; et al.: Varicella Vaccine (VARIVAX) in
Healthy Children and Adolescents: Results From Clinical Trials, 1987
to 1989, Pediatrics, 87(5): 604-610, 1991.
16. 16. Asano, Y.; et al.: Contact Infection from Live Varicella
Vaccine Recipients, Lancet 1(7966): 965, 1976.
17. 17. Hammerschlag, M.R.; et al.: Herpes Zoster in an Adult
Recipient of Live Attenuated Varicella Vaccine, J Infect Dis 160(3):
535-537, 1989.
18. 18. White, C.J.: Letters to the Editor, Pediatrics 318: 354,
1992.
19. 19. Guess, H.A.; et al.: Population-Based Studies of Varicella
Complications, Pediatrics 78(4 Pt 2): 723-727, 1986.
20. 20. Ragozzino, M.; et al.: Population-Based Study of Herpes
Zoster and Its Sequelae, Medicine 61(5): 310-316, 1982.

21. Morbidity and Mortality Weekly Report 34(1): 13-16, Jan. 11,
1985.

22. Dennehy, P.H.; et al.: Immunogenicity of Subcutaneous Versus
Intramuscular Oka/Merck Varicella Vaccination in Healthy Children,
Pediatrics 88(3): 604-607, 1991.

23. Center for Disease Control: Immunization of Children Infected
with Human T-Lymphotropic Virus Type III/Lymphadenopathy --
Associated Virus, Ann Intern Med, 106: 75-78, 1987.

24. Recommendations of the Advisory Committee on Immunization
Practices (ACIP); General Recommendations on Immunization, MMWR 43(No.
RR-1): 15-18, Jan. 28, 1994.

25. Vaccine Adverse Event Reporting System -- United States, MMWR
39(41): 730-733, 1990.

26. Kuter, B.J.; et al.: Ten Year Follow-up of Healthy Children
who Received One or Two Injections of Varicella Vaccine, Pediatr
Infect Dis J, 23:132-37, 2004.

Issued April 2006 Printed in USA