Merck Files Biologics License Application for PROQUAD With U.S. Food and Drug Administration.

WHITEHOUSE STATION, N.J. -- Merck & Co., Inc. today announced it has filed a Biologics License Application for PROQUAD(R) (Measles, Mumps, Rubella and Varicella (Oka/Merck) Virus Vaccine Live) with the U.S. Food and Drug Administration. PROQUAD is an investigational vaccine for simultaneous vaccination against measles, mumps, rubella and varicella in children 12 months to 12 years of age. PROQUAD combines two established Merck vaccines, M-M-R II(R) (Measles, Mumps, Rubella Virus Vaccine Live) and VARIVAX(R) (Varicella (Oka/Merck) Virus Vaccine Live).

Merck submitted the application for PROQUAD to the FDA on Aug. 31 and received notification of the FDA's acceptance of the application this week. Merck anticipates an FDA action on the application by early July, based on a standard 10 to 12-month FDA review.

Important information about M-M-R II and VARIVAX

M-M-R II is indicated for simultaneous vaccination against measles, mumps and rubella in individuals 12 months of age or older. The Advisory Committee on Immunization Practices (ACIP) recommends administration of the first dose of M-M-R II at 12 to 15 months of age and administration of the second dose of M-M-R II at four to six years of age. M-M-R II is contraindicated in individuals with a history of hypersensitivity to any component of the vaccine, including gelatin. M-M-R II is contraindicated in individuals with blood dyscrasias, leukemia, lymphomas of any type or other malignant neoplasms affecting the bone marrow or lymphatic systems. Due caution should be employed in administration of M-M-R II to persons with a history of cerebral injury, individual or family histories of convulsions, or any other condition in which stress due to fever should be avoided. The following adverse reactions, which have been reported without regard to causality, include: fever, headache, dizziness, rash, injection-site reactions, anaphylaxis and anaphylactoid reactions, thrombocytopenia, arthritis and febrile convulsions. For a list of adverse reactions, please read the attached prescribing information. As for any vaccine, vaccination with M-M-R II may not result in protection in 100 percent of vaccinees.

VARIVAX is indicated for vaccination against varicella in individuals 12 months of age and older. VARIVAX is contraindicated in individuals with a history of hypersensitivity or an anaphylactoid reaction to any component of the vaccine, including gelatin or neomycin, or with any immunodeficient condition or receiving immunosuppressive therapy. The duration of protection from varicella infection after vaccination with VARIVAX is unknown. There are insufficient data to assess the rate of protection against the complications of varicella (e.g., encephalitis, hepatitis, pneumonia) in children. In children, adolescents and adults monitored for up to 42 days post vaccination, the adverse effects most frequently reported were as follows: fever, injection-site complaints; varicella-like rash (injection site) and varicella-like rash (generalized). For a list of adverse reactions, please read the attached prescribing information. Vaccination with VARIVAX may not result in protection of all healthy susceptible children, adolescents and adults.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2003, and in its periodic reports on Form 10-Q and Form 8-K (if any) which the company incorporates by reference.

PROQUAD(R) is the Merck registered trade name for Measles, Mumps, Rubella and Varicella (Oka/Merck) Virus Vaccine Live.

M-M-R II(R) is the Merck registered trade name for Measles, Mumps, Rubella Virus Vaccine Live.

VARIVAX(R) is the Merck registered trade name for Varicella (Oka/Merck) Virus Vaccine Live.

Prescribing information for M-M-R II(R) and VARIVAX(R) are attached.

M-M-R(R) II

(MEASLES, MUMPS, and

RUBELLA VIRUS VACCINE LIVE)

DESCRIPTION

M-M-R* II (Measles, Mumps, and Rubella Virus Vaccine Live) is a live virus vaccine for vaccination against measles (rubeola), mumps and rubella (German measles).

M-M-R II is a sterile lyophilized preparation of (1) ATTENUVAX* (Measles Virus Vaccine Live), a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and propagated in chick embryo cell culture; (2) MUMPSVAX* (Mumps Virus Vaccine Live), the Jeryl Lynn** (B level) strain of mumps virus propagated in chick embryo cell culture; and (3) MERUVAX* II (Rubella Virus Vaccine Live), the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.1,2

The growth medium for measles and mumps is Medium 199 (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing SPGA (sucrose, phosphate, glutamate, and human albumin) as stabilizer and neomycin.

The growth medium for rubella is Minimum Essential Medium (MEM) (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing human serum albumin and neomycin. Sorbitol and hydrolyzed gelatin stabilizer are added to the individual virus harvests.

The cells, virus pools, fetal bovine serum, and human albumin are all screened for the absence of adventitious agents. Human albumin is processed using the Cohn cold ethanol fractionation procedure.

The reconstituted vaccine is for subcutaneous administration. Each 0.5 mL dose contains not less than 1,000 TCID50 (tissue culture infectious doses) of measles virus; 20,000 TCID50 of mumps virus; and 1,000 TCID50 of rubella virus. Each dose of the vaccine is calculated to contain sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), human albumin (0.3 mg), fetal bovine serum (<1 ppm), other buffer and media ingredients and approximately 25 mcg of neomycin. The product contains no preservative.

Before reconstitution, the lyophilized vaccine is a light yellow compact crystalline plug. M-M-R II, when reconstituted as directed, is clear yellow.

CLINICAL PHARMACOLOGY

Measles, mumps, and rubella are three common childhood diseases, caused by measles virus, mumps virus (paramyxoviruses), and rubella virus (togavirus), respectively, that may be associated with serious complications and/or death. For example, pneumonia and encephalitis are caused by measles. Mumps is associated with aseptic meningitis, deafness and orchitis; and rubella during pregnancy may cause congenital rubella syndrome in the infants of infected mothers.

The impact of measles, mumps, and rubella vaccination on the natural history of each disease in the United States can be quantified by comparing the maximum number of measles, mumps, and rubella cases reported in a given year prior to vaccine use to the number of cases of each disease reported in 1995. For measles, 894,134 cases reported in 1941 compared to 288 cases reported in 1995 resulted in a 99.97% decrease in reported cases; for mumps, 152,209 cases reported in 1968 compared to 840 cases reported in 1995 resulted in a 99.45% decrease in reported cases; and for rubella, 57,686 cases reported in 1969 compared to 200 cases reported in 1995 resulted in a 99.65% decrease.3

Clinical studies of 279 triple seronegative children, 11 months to 7 years of age, demonstrated that M-M-R II is highly immunogenic and generally well tolerated. In these studies, a single injection of the vaccine induced measles hemagglutination-inhibition (HI) antibodies in 95%, mumps neutralizing antibodies in 96%, and rubella HI antibodies in 99% of susceptible persons. However, a small percentage (1-5%) of vaccinees may fail to seroconvert after the primary dose (see also INDICATIONS AND USAGE, Recommended Vaccination Schedule).

* Registered trademark of MERCK & CO., Inc.

COPYRIGHT (C) MERCK & CO., Inc., 1990, 1999

All rights reserved

** Trademark of MERCK & CO., Inc.

A study4 of 6-month-old and 15-month-old infants born to vaccine-immunized mothers demonstrated that, following vaccination with ATTENUVAX, 74% of the 6-month-old infants developed detectable neutralizing antibody (NT) titers while 100% of the 15-month-old infants developed NT. This rate of seroconversion is higher than that previously reported for 6-month-old infants born to naturally immune mothers tested by HI assay. When the 6-month-old infants of immunized mothers were revaccinated at 15 months, they developed antibody titers equivalent to the 15-month-old vaccinees. The lower seroconversion rate in 6-month-olds has two possible explanations: 1) Due to the limit of the detection level of the assays (NT and enzyme immunoassay (EIA)), the presence of trace amounts of undetectable maternal antibody might interfere with the seroconversion of infants; or 2) The immune system of 6-month-olds is not always capable of mounting a response to measles vaccine as measured by the two antibody assays.

There is some evidence to suggest that infants who are born to mothers who had natural measles and who are vaccinated at less than one year of age may not develop sustained antibody levels when later revaccinated. The advantage of early protection must be weighed against the chance for failure to respond adequately on reimmunization.5,6

Efficacy of measles, mumps, and rubella vaccine was established in a series of double-blind controlled field trials which demonstrated a high degree of protective efficacy afforded by the individual vaccine components.7-12 These studies also established that seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases.13-15

Following vaccination, antibodies associated with protection can be measured by neutralization assays, HI, or ELISA (enzyme linked immunosorbent assay) tests. Neutralizing and ELISA antibodies to measles, mumps, and rubella viruses are still detectable in most individuals 11-13 years after primary vaccination.16-18 See INDICATIONS AND USAGE, Non-Pregnant Adolescents and Adult Females, for Rubella Susceptibility Testing.

The RA 27/3 rubella strain in M-M-R II elicits higher immediate post-vaccination HI, complement-fixing and neutralizing antibody levels than other strains of rubella vaccine19-25 and has been shown to induce a broader profile of circulating antibodies including anti-theta and anti-iota precipitating antibodies.26,27 The RA 27/3 rubella strain immunologically simulates natural infection more closely than other rubella vaccine viruses.27-29 The increased levels and broader profile of antibodies produced by RA 27/3 strain rubella virus vaccine appear to correlate with greater resistance to subclinical reinfection with the wild virus,27,29-31 and provide greater confidence for lasting immunity.

INDICATIONS AND USAGE

Recommended Vaccination Schedule

M-M-R II is indicated for simultaneous vaccination against measles, mumps, and rubella in individuals 12 months of age or older.

Individuals first vaccinated at 12 months of age or older should be revaccinated prior to elementary school entry. Revaccination is intended to seroconvert those who do not respond to the first dose. The Advisory Committee on Immunization Practices (ACIP) recommends administration of the first dose of M-M-R II at 12-15 months of age and administration of the second dose of M-M-R II at 4-6 years of age.59 In addition, some public health jurisdictions mandate the age for revaccination. Consult the complete text of applicable guidelines regarding routine revaccination including that of high-risk adult populations.

Measles Outbreak Schedule

Infants Between 6-12 Months of Age

Local health authorities may recommend measles vaccination of infants between 6-12 months of age in outbreak situations. This population may fail to respond to the components of the vaccine. Safety and effectiveness of mumps and rubella vaccine in infants less than 12 months of age have not been established. The younger the infant, the lower the likelihood of seroconversion (see CLINICAL PHARMACOLOGY). Such infants should receive a second dose of M-M-R II between 12 to 15 months of age followed by revaccination at elementary school entry.59

Unnecessary doses of a vaccine are best avoided by ensuring that written documentation of vaccination is preserved and a copy given to each vaccinee's parent or guardian.

Other Vaccination Considerations

Non-Pregnant Adolescent and Adult Females

Immunization of susceptible non-pregnant adolescent and adult females of childbearing age with live attenuated rubella virus vaccine is indicated if certain precautions are observed (see below and PRECAUTIONS). Vaccinating susceptible postpubertal females confers individual protection against subsequently acquiring rubella infection during pregnancy, which in turn prevents infection of the fetus and consequent congenital rubella injury.33

Women of childbearing age should be advised not to become pregnant for 3 months after vaccination and should be informed of the reasons for this precaution.

The ACIP has stated "If it is practical and if reliable laboratory services are available, women of childbearing age who are potential candidates for vaccination can have serologic tests to determine susceptibility to rubella. However, with the exception of premarital and prenatal screening, routinely performing serologic tests for all women of childbearing age to determine susceptibility (so that vaccine is given only to proven susceptible women) can be effective but is expensive. Also, 2 visits to the health-care provider would be necessary -- one for screening and one for vaccination. Accordingly, rubella vaccination of a woman who is not known to be pregnant and has no history of vaccination is justifiable without serologic testing -- and may be preferable, particularly when costs of serology are high and follow-up of identified susceptible women for vaccination is not assured."33

Postpubertal females should be informed of the frequent occurrence of generally self-limited arthralgia and/or arthritis beginning 2 to 4 weeks after vaccination (see ADVERSE REACTIONS).

Postpartum Women

It has been found convenient in many instances to vaccinate rubella-susceptible women in the immediate postpartum period (see PRECAUTIONS, Nursing Mothers).

Other Populations

Previously unvaccinated children older than 12 months who are in contact with susceptible pregnant women should receive live attenuated rubella vaccine (such as that contained in monovalent rubella vaccine or in M-M-R II) to reduce the risk of exposure of the pregnant woman.

Individuals planning travel outside the United States, if not immune, can acquire measles, mumps or rubella and import these diseases into the United States. Therefore, prior to international travel, individuals known to be susceptible to one or more of these diseases can receive either a monovalent vaccine (measles, mumps or rubella), or a combination vaccine as appropriate. However, M-M-R II is preferred for persons likely to be susceptible to mumps and rubella; and if monovalent measles vaccine is not readily available, travelers should receive M-M-R II regardless of their immune status to mumps or rubella.34-36

Vaccination is recommended for susceptible individuals in high-risk groups such as college students, health-care workers, and military personnel.33,34,37

According to ACIP recommendations, most persons born in 1956 or earlier are likely to have been infected with measles naturally and generally need not be considered susceptible. All children, adolescents, and adults born after 1956 are considered susceptible and should be vaccinated, if there are no contraindications. This includes persons who may be immune to measles but who lack adequate documentation of immunity such as: (1) physician-diagnosed measles, (2) laboratory evidence of measles immunity, or (3) adequate immunization with live measles vaccine on or after the first birthday.34

The ACIP recommends that "Persons vaccinated with inactivated vaccine followed within 3 months by live vaccine should be revaccinated with two doses of live vaccine. Revaccination is particularly important when the risk of exposure to natural measles virus is increased, as may occur during international travel."34

Post-Exposure Vaccination

Vaccination of individuals exposed to natural measles may provide some protection if the vaccine can be administered within 72 hours of exposure. If, however, vaccine is given a few days before exposure, substantial protection may be afforded.34,38,39 There is no conclusive evidence that vaccination of individuals recently exposed to natural mumps or natural rubella will provide protection.33,37

Use With Other Vaccines

See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.

CONTRAINDICATIONS

Hypersensitivity to any component of the vaccine, including gelatin.40

Do not give M-M-R II to pregnant females; the possible effects of the vaccine on fetal development are unknown at this time. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for three months following vaccination (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females and PRECAUTIONS, Pregnancy).

Anaphylactic or anaphylactoid reactions to neomycin (each dose of reconstituted vaccine contains approximately 25 mcg of neomycin).

Febrile respiratory illness or other active febrile infection. However, the ACIP has recommended that all vaccines can be administered to persons with minor illnesses such as diarrhea, mild upper respiratory infection with or without low-grade fever, or other low-grade febrile illness.41

Patients receiving immunosuppressive therapy. This contraindication does not apply to patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

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

Primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manifestations of infection with human immunodeficiency viruses;41-43 cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. Measles inclusion body encephalitis60 (MIBE), pneumonitis61 and death as a direct consequence of disseminated measles vaccine virus infection has been reported in immunocompromised individuals inadvertently vaccinated with measles-containing vaccine.

Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated.

WARNINGS

Due caution should be employed in administration of M-M-R II to persons with a history of cerebral injury, individual or family histories of convulsions, or any other condition in which stress due to fever should be avoided. The physician should be alert to the temperature elevation which may occur following vaccination (see ADVERSE REACTIONS).

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

Hypersensitivity to Eggs

Live measles vaccine and live mumps vaccine are produced in chick embryo cell culture. Persons with a history of anaphylactic, anaphylactoid, or other immediate reactions (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) subsequent to egg ingestion may be at an enhanced risk of immediate-type hypersensitivity reactions after receiving vaccines containing traces of chick embryo antigen. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases. Such individuals may be vaccinated with extreme caution, having adequate treatment on hand should a reaction occur (see PRECAUTIONS).45

However, the AAP has stated, "Most children with a history of anaphylactic reactions to eggs have no untoward reactions to measles or MMR vaccine. Persons are not at increased risk if they have egg allergies that are not anaphylactic, and they should be vaccinated in the usual manner. In addition, skin testing of egg-allergic children with vaccine has not been predictive of which children will have an immediate hypersensitivity reaction...Persons with allergies to chickens or chicken feathers are not at increased risk of reaction to the vaccine."44

Hypersensitivity to Neomycin

The AAP states, "Persons who have experienced anaphylactic reactions to topically or systemically administered neomycin should not receive measles vaccine. Most often, however, neomycin allergy manifests as a contact dermatitis, which is a delayed-type (cell-mediated) immune response rather than anaphylaxis. In such persons, an adverse reaction to neomycin in the vaccine would be an erythematous, pruritic nodule or papule, 48 to 96 hours after vaccination. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine."44

Thrombocytopenia

Individuals with current thrombocytopenia may develop more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia with the first dose of M-M-R II (or its component vaccines) may develop thrombocytopenia with repeat doses. Serologic status may be evaluated to determine whether or not additional doses of vaccine are needed. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases (see ADVERSE REACTIONS).

PRECAUTIONS

General

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

Special care should be taken to ensure that the injection does not enter a blood vessel.

Children and young adults who are known to be infected with human immunodeficiency viruses and are not immunosuppressed may be vaccinated. However, vaccinees who are infected with HIV should be monitored closely for vaccine-preventable diseases because immunization may be less effective than for uninfected persons (see CONTRAINDICATIONS).42,43

Vaccination should be deferred for 3 months or longer following blood or plasma transfusions, or administration of immune globulin (human).44

Excretion of small amounts of the live attenuated rubella virus from the nose or throat has occurred in the majority of susceptible individuals 7-28 days after vaccination. There is no confirmed evidence to indicate that such virus is transmitted to susceptible persons who are in contact with the vaccinated individuals. Consequently, transmission through close personal contact, while accepted as a theoretical possibility, is not regarded as a significant risk.33 However, transmission of the rubella vaccine virus to infants via breast milk has been documented (see Nursing Mothers).

There are no reports of transmission of live attenuated measles or mumps viruses from vaccinees to susceptible contacts.

It has been reported that live attenuated measles, mumps and rubella virus vaccines given individually may result in a temporary depression of tuberculin skin sensitivity. Therefore, if a tuberculin test is to be done, it should be administered either before or simultaneously with M-M-R II.

Children under treatment for tuberculosis have not experienced exacerbation of the disease when immunized with live measles virus vaccine;46 no studies have been reported to date of the effect of measles virus vaccines on untreated tuberculous children. However, individuals with active untreated tuberculosis should not be vaccinated.

As for any vaccine, vaccination with M-M-R II may not result in protection in 100% of vaccinees.

The health-care provider should determine the current health status and previous vaccination history of the vaccinee.

The health-care provider should question the patient, parent, or guardian about reactions to a previous dose of M-M-R II or other measles-, mumps- or rubella-containing vaccines.

Information for Patients

The health-care provider should provide the vaccine information required to be given with each vaccination to the patient, parent or guardian.

The health-care provider should inform the patient, parent or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination see WARNINGS, PRECAUTIONS, ADVERSE REACTIONS.

Patients, parents or guardians should be instructed to report any serious adverse reactions to their health-care provider who in turn should report such events to the U.S. Department of Health and Human Services through the Vaccine Adverse Event Reporting System (VAERS), 1-800-822-7967.47

Pregnancy should be avoided for 3 months following vaccination, and patients should be informed of the reasons for this precaution (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females, CONTRAINDICATIONS, and PRECAUTIONS, Pregnancy).

Laboratory Tests

See INDICATIONS AND USAGE, Non-Pregnant Adolescents and Adult Females, for Rubella Susceptibility Testing, and CLINICAL PHARMACOLOGY.

Drug Interactions

See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.

Immunosuppressive Therapy

The immune status of patients about to undergo immunosuppressive therapy should be evaluated so that the physician can consider whether vaccination prior to the initiation of treatment is indicated (see CONTRAINDICATIONS and PRECAUTIONS).

The ACIP has stated that "patients with leukemia in remission who have not received chemotherapy for at least 3 months may receive live-virus vaccines. Short-term (<2 weeks), low- to moderate-dose systemic corticosteroid therapy, topical steroid therapy (e.g. nasal, skin), long-term alternate-day treatment with low to moderate doses of short-acting systemic steroid, and intra-articular, bursal, or tendon injection of corticosteroids are not immunosuppressive in their usual doses and do not contraindicate the administration of (measles, mumps or rubella vaccine)."33,34,37

Immune Globulin

Administration of immune globulins concurrently with M-M-R II may interfere with the expected immune response.33,34,44

See also PRECAUTIONS, General.

Carcinogenesis, Mutagenesis, Impairment of Fertility

M-M-R II has not been evaluated for carcinogenic or mutagenic potential, or potential to impair fertility.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with M-M-R II. It is also not known whether M-M-R II can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, the vaccine should not be administered to pregnant females; furthermore, pregnancy should be avoided for 3 months following vaccination (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females and CONTRAINDICATIONS).

In counseling women who are inadvertently vaccinated when pregnant or who become pregnant within 3 months of vaccination, the physician should be aware of the following: (1) In a 10-year survey involving over 700 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome;48 (2) Mumps infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect the placenta and fetus, there is no evidence that it causes congenital malformations in humans;37 and (3) Reports have indicated that contracting natural measles during pregnancy enhances fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent to natural measles during pregnancy.57,58 There are no adequate studies of the attenuated (vaccine) strain of measles virus in pregnancy. However, it would be prudent to assume that the vaccine strain of virus is also capable of inducing adverse fetal effects.

Nursing Mothers

It is not known whether measles or mumps vaccine virus is secreted in human milk. Recent studies have shown that lactating postpartum women immunized with live attenuated rubella vaccine may secrete the virus in breast milk and transmit it to breast-fed infants.49 In the infants with serological evidence of rubella infection, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella.50,51 Caution should be exercised when M-M-R II is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of measles vaccine in infants below the age of 6 months have not been established (see also CLINICAL PHARMACOLOGY). Safety and effectiveness of mumps and rubella vaccine in infants less than 12 months of age have not been established.

Geriatric Use

Clinical studies of M-M-R II 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.

ADVERSE REACTIONS

The following adverse reactions are listed in decreasing order of severity, without regard to causality, within each body system category and have been reported during clinical trials, with use of the marketed vaccine, or with use of monovalent or bivalent vaccine containing measles, mumps, or rubella:

Body as a Whole

Panniculitis; atypical measles; fever; syncope; headache; dizziness; malaise; irritability.

Cardiovascular System

Vasculitis.

Digestive System

Pancreatitis; diarrhea; vomiting; parotitis; nausea.

Endocrine System

Diabetes mellitus.

Hemic and Lymphatic System

Thrombocytopenia (see WARNINGS, Thrombocytopenia); purpura; regional lymphadenopathy; leukocytosis.

Immune System

Anaphylaxis and anaphylactoid reactions have been reported as well as related phenomena such as angioneurotic edema (including peripheral or facial edema) and bronchial spasm in individuals with or without an allergic history.

Musculoskeletal System

Arthritis; arthralgia; myalgia.

Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of natural rubella and vary in frequency and severity with age and sex, being greatest in adult females and least in prepubertal children. This type of involvement as well as myalgia and paresthesia, have also been reported following administration of MERUVAX II.

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

Following vaccination in children, reactions in joints are uncommon and generally of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (children: 0-3%; women: 12-26%),17,52,53 and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and in adult women. Even in women older than 35 years, these reactions are generally well tolerated and rarely interfere with normal activities.

Nervous System

Encephalitis; encephalopathy; measles inclusion body encephalitis (MIBE) (see CONTRAINDICATIONS); subacute sclerosing panencephalitis (SSPE); Guillain-Barre Syndrome (GBS); febrile convulsions; afebrile convulsions or seizures; ataxia; polyneuritis; polyneuropathy; ocular palsies; paresthesia.

Experience from more than 80 million doses of all live measles vaccines given in the U.S. through 1975 indicates that significant central nervous system reactions such as encephalitis and encephalopathy, occurring within 30 days after vaccination, have been temporally associated with measles vaccine very rarely.54 In no case has it been shown that reactions were actually caused by vaccine. The Centers for Disease Control and Prevention has pointed out that "a certain number of cases of encephalitis may be expected to occur in a large childhood population in a defined period of time even when no vaccines are administered". However, the data suggest the possibility that some of these cases may have been caused by measles vaccines. The risk of such serious neurological disorders following live measles virus vaccine administration remains far less than that for encephalitis and encephalopathy with natural measles (one per two thousand reported cases).

Post-marketing surveillance of the more than 200 million doses of M-M-R and M-M-R II that have been distributed worldwide over 25 years (1971-1996) indicates that serious adverse events such as encephalitis and encephalopathy continue to be rarely reported.17

There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of natural measles but did receive measles vaccine. Some of these cases may have resulted from unrecognized measles in the first year of life or possibly from the measles vaccination. Based on estimated nationwide measles vaccine distribution, the association of SSPE cases to measles vaccination is about one case per million vaccine doses distributed. This is far less than the association with natural measles, 6-22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study conducted by the Centers for Disease Control and Prevention suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent higher risk of SSPE.55

Cases of aseptic meningitis have been reported to VAERS following measles, mumps, and rubella vaccination. Although a causal relationship between the Urabe strain of mumps vaccine and aseptic meningitis has been shown, there are no data to link Jeryl Lynn mumps vaccine to aseptic meningitis.

Respiratory System

Pneumonitis (see CONTRAINDICATIONS); sore throat; cough; rhinitis.

Skin

Stevens-Johnson Syndrome; erythema multiforme; urticaria; rash.

Local reactions including burning/stinging at injection site; wheal and flare; redness (erythema); swelling; induration; tenderness; vesiculation at injection site.

Special Senses -- Ear

Nerve deafness; otitis media.

Special Senses -- Eye

Retinitis; optic neuritis; papillitis; retrobulbar neuritis; conjunctivitis.

Urogenital System

Orchitis.

Other

Death from various, and in some cases unknown, causes has been reported rarely following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established. No deaths or permanent sequelae were reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982-1993.56

Under the National Childhood Vaccine Injury Act of 1986, health-care providers and manufacturers are required to record and report certain suspected adverse events occurring within specific time periods after vaccination. However, the U.S. Department of Health and Human Services (DHHS) has established a Vaccine Adverse Event Reporting System (VAERS) which will accept all reports of suspected events.47 A VAERS report form as well as information regarding reporting requirements can be obtained by calling VAERS 1-800-822-7967.

DOSAGE AND ADMINISTRATION

FOR SUBCUTANEOUS ADMINISTRATION

Do not inject intravenously

The dose for any age is 0.5 mL administered subcutaneously, preferably into the outer aspect of the upper arm.

The recommended age for primary vaccination is 12 to 15 months.

Revaccination with M-M-R II is recommended prior to elementary school entry. See also INDICATIONS AND USAGE, Recommended Vaccination Schedule.

Children first vaccinated when younger than 12 months of age should receive another dose between 12 to 15 months of age followed by revaccination prior to elementary school entry.59 See also INDICATIONS AND USAGE, Measles Outbreak Schedule.

Immune Globulin (IG) is not to be given concurrently with M-M-R II.

CAUTION: A sterile syringe free of preservatives, antiseptics, and detergents should be used for each injection and/or reconstitution of the vaccine because these substances may inactivate the live virus vaccine. A 25 gauge, 5/8" needle is recommended.

To reconstitute, use only the diluent supplied, since it is free of preservatives or other antiviral substances which might inactivate the vaccine.

Single Dose Vial -- First withdraw the entire volume of diluent into the syringe to be used for reconstitution. Inject all the diluent in the syringe into the vial of lyophilized vaccine, and agitate to mix thoroughly. If the lyophilized vaccine cannot be dissolved, discard. Withdraw the entire contents into a syringe and inject the total volume of restored vaccine subcutaneously.

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

10 Dose Vial (available only to government agencies/institutions) -- Withdraw the entire contents (7 mL) of the diluent vial into the sterile syringe to be used for reconstitution, and introduce into the 10 dose vial of lyophilized vaccine. Agitate to ensure thorough mixing. If the lyophilized vaccine cannot be dissolved, discard. The outer labeling suggests "For Jet Injector or Syringe Use." Use with separate sterile syringes is permitted for containers of 10 doses or less. The vaccine and diluent do not contain preservatives; therefore, the user must recognize the potential contamination hazards and exercise special precautions to protect the sterility and potency of the product. The use of aseptic techniques and proper storage prior to and after restoration of the vaccine and subsequent withdrawal of the individual doses is essential. Use 0.5 mL of the reconstituted vaccine for subcutaneous injection.

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

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. M-M-R II, when reconstituted, is clear yellow.

Use With Other Vaccines

M-M-R II should be given one month before or after administration of other live viral vaccines.

M-M-R II has been administered concurrently with VARIVAX* (Varicella Virus Vaccine Live (Oka/Merck)), and PedvaxHIB* (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)) using separate sites and syringes. No impairment of immune response to individual tested vaccine antigens was demonstrated. The type, frequency, and severity of adverse experiences observed with M-M-R II were similar to those seen when each vaccine was given alone.

Routine administration of DTP (diphtheria, tetanus, pertussis) and/or OPV (oral poliovirus vaccine) concurrently with measles, mumps and rubella vaccines is not recommended because there are limited data relating to the simultaneous administration of these antigens.

However, other schedules have been used. The ACIP has stated "Although data are limited concerning the simultaneous administration of the entire recommended vaccine series (i.e., DTP, OPV, MMR, and Hib vaccines, with or without hepatitis B vaccine), data from numerous studies have indicated no interference between routinely recommended childhood vaccines (either live, attenuated, or killed). These findings support the simultaneous use of all vaccines as recommended."32

HOW SUPPLIED

No. 4749 -- M-M-R II is supplied as a single-dose vial of lyophilized vaccine, NDC 0006-4749-00, and a vial of diluent.

No. 4681/4309 -- M-M-R II is supplied as follows: (1) a box of 10 single-dose vials of lyophilized vaccine (package A), NDC 0006-4681-00; and (2) a box of 10 vials of diluent (package B). To conserve refrigerator space, the diluent may be stored separately at room temperature.

Available only to government agencies/institutions:

No. 4682X -- M-M-R II is supplied as one 10 dose vial of lyophilized vaccine.

NDC 0006-4682-00, and one 7 mL vial of diluent.

Storage

During shipment, to ensure that there is no loss of potency, the vaccine must be maintained at a temperature of 10(degree)C (50(degree)F) or colder. Freezing during shipment will not affect potency.

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

Before reconstitution, store the vial of lyophilized vaccine at 2-8(degree)C (36-46(degree)F) or colder. The diluent may be stored in the refrigerator with the lyophilized vaccine or separately at room temperature.

It is recommended that the vaccine be used as soon as possible after reconstitution. Store reconstituted vaccine in the vaccine vial in a dark place at 2-8(degree)C (36-46(degree)F) and discard if not used within 8 hours.

REFERENCES

1. Plotkin, S.A.; Cornfeld, D.; Ingalls, T.H.: Studies of immunization with living rubella virus: Trials in children with a strain cultured from an aborted fetus, Am. J. Dis. Child. 110: 381-389, 1965.

2. Plotkin, S.A.; Farquhar, J.; Katz, M.; Ingalls, T.H.: A new attenuated rubella virus grown in human fibroblasts: Evidence for reduced nasopharyngeal excretion, Am. J. Epidemiol. 86: 468-477, 1967.

3. Monthly Immunization Table, MMWR 45(1): 24-25, January 12, 1996.

4. Johnson, C.E.; et al: Measles Vaccine Immunogenicity in 6- Versus 15-Month-Old Infants Born to Mothers in the Measles Vaccine Era, Pediatrics, 93(6): 939-943, 1994.

5. Linneman, C.C.; et al: Measles Immunity After Vaccination: Results in Children Vaccinated Before 10 Months of Age, Pediatrics, 69(3): 332-335, March 1982.

6. Stetler, H.C.; et al: Impact of Revaccinating Children Who Initially Received Measles Vaccine Before 10 Months of Age, Pediatrics 77(4): 471-476, April 1986.

7. Hilleman, M.R.; Buynak, E.B.; Weibel, R.E.; et al: Development and Evaluation of the Moraten Measles Virus Vaccine, JAMA 206(3): 587-590, 1968.

8. Weibel, R.E.; Stokes, J.; Buynak, E.B.; et al: Live, Attenuated Mumps Virus Vaccine 3. Clinical and Serologic Aspects in a Field Evaluation, N. Engl. J. Med. 276: 245-251, 1967.

9. Hilleman, M.R.; Weibel, R.E.; Buynak, E.B.; et al: Live, Attenuated Mumps Virus Vaccine 4. Protective Efficacy as Measured in a Field Evaluation, N. Engl. J. Med. 276: 252-258, 1967.

10. Cutts, F.T.; Henderson, R.H.; Clements, C.J.; et al: Principles of measles control, Bull WHO 69(1): 1-7, 1991.

11. Weibel, R.E.; Buynak, E.B.; Stokes, J.; et al: Evaluation Of Live Attenuated Mumps Virus Vaccine, Strain Jeryl Lynn, First International Conference on Vaccines Against Viral and Rickettsial Diseases of Man, World Health Organization, No. 147, May 1967.

12. Leibhaber, H.; Ingalls, T.H.; LeBouvier, G.L.; et al: Vaccination With RA 27/3 Rubella Vaccine, Am. J. Dis. Child. 123: 133-136, February 1972.

13. Rosen, L.: Hemagglutination and Hemagglutination-Inhibition with Measles Virus, Virology 13: 139-141, January 1961.

14. Brown, G.C.; et al: Fluorescent-Antibody Marker for Vaccine-Induced Rubella Antibodies, Infection and Immunity 2(4): 360-363, 1970.

15. Buynak, E.B.; et al: Live Attenuated Mumps Virus Vaccine 1. Vaccine Development, Proceedings of the Society for Experimental Biology and Medicine, 123: 768-775, 1966.

16. Weibel, R.E.; Carlson, A.J.; Villarejos, V.M.; Buynak, E.B.; McLean, A.A.; Hilleman, M.R.: Clinical and Laboratory Studies of Combined Live Measles, Mumps, and Rubella Vaccines Using the RA 27/3 Rubella Virus, Proc. Soc. Exp. Biol. Med. 165: 323-326, 1980.

17. Unpublished data from the files of Merck Research Laboratories.

18. Watson, J.C.; Pearson, J.S.; Erdman, D.D.; et al: An Evaluation of Measles Revaccination Among School-Entry Age Children, 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract #268, 143, 1991.

19. Fogel, A.; Moshkowitz, A.; Rannon, L.; Gerichter, Ch.B.: Comparative trials of RA 27/3 and Cendehill rubella vaccines in adult and adolescent females, Am. J. Epidemiol. 93: 392-393, 1971.

20. Andzhaparidze, O.G.; Desyatskova, R.G.; Chervonski, G.I.; Pryanichnikova, L.V.: Immunogenicity and reactogenicity of live attenuated rubella virus vaccines, Am. J. Epidemiol. 91: 527-530, 1970.

21. Freestone, D.S.; Reynolds, G.M.; McKinnon, J.A.; Prydie, J.: Vaccination of schoolgirls against rubella. Assessment of serological status and a comparative trial of Wistar RA 27/3 and Cendehill strain live attenuated rubella vaccines in 13-year-old schoolgirls in Dudley, Br. J. Prev. Soc. Med. 29: 258-261, 1975.

22. Grillner, L.; Hedstrom, C.E.; Bergstrom, H.; Forssman, L.; Rigner, A.; Lycke, E.: Vaccination against rubella of newly delivered women, Scand. J. Infect. Dis. 5: 237-241, 1973.

23. Grillner, L.: Neutralizing antibodies after rubella vaccination of newly delivered women: a comparison between three vaccines, Scand. J. Infect. Dis. 7: 169-172, 1975.

24. Wallace, R.B.; Isacson, P.: Comparative trial of HPV-77, DE-5 and RA 27/3 live-attenuated rubella vaccines, Am. J. Dis. Child. 124: 536-538, 1972.

25. Lalla, M.; Vesikari, T.; Virolainen, M.: Lymphoblast proliferation and humoral antibody response after rubella vaccination, Clin. Exp. Immunol. 15: 193-202, 1973.

26. LeBouvier, G.L.; Plotkin, S.A.: Precipitin responses to rubella vaccine RA 27/3, J. Infect. Dis. 123: 220-223, 1971.

27. Horstmann, D.M.: Rubella: The challenge of its control, J. Infect. Dis. 123: 640-654, 1971.

28. Ogra, P.L.; Kerr-Grant, D.; Umana, G.; Dzierba, J.; Weintraub, D.: Antibody response in serum and nasopharynx after naturally acquired and vaccine-induced infection with rubella virus, N. Engl. J. Med. 285: 1333-1339, 1971.

29. Plotkin, S.A.; Farquhar, J.D.; Ogra, P.L.: Immunologic properties of RA 27/3 rubella virus vaccine, J. Am. Med. Assoc. 225: 585-590, 1973.

30. Liebhaber, H.; Ingalls, T.H.; LeBouvier, G.L.; Horstmann, D.M.: Vaccination with RA 27/3 rubella vaccine. Persistence of immunity and resistance to challenge after two years, Am. J. Dis. Child. 123: 133-136, 1972.

31. Farquhar, J.D.: Follow-up on rubella vaccinations and experience with subclinical reinfection, J. Pediatr. 81: 460-465, 1972.

32. Centers for Disease Control and Prevention. Recommended childhood immunization schedule -- United States, January-June 1996, MMWR 44(51 & 52): 940-943, January 5, 1996.

33. Rubella Prevention: Recommendation of the Immunization Practices Advisory Committee (ACIP), MMWR 39(RR-15): 1-18, November 23, 1990.

34. Measles Prevention: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR 38(S-9): 5-22, December 29, 1989.

35. Jong, E.C., The Travel and Tropical Medicine Manual, W.B. Saunders Company, p. 12-16, 1987.

36. Committee on Immunization Council of Medical Societies, American College of Physicians, Phila., PA, Guide for Adult Immunization, First Edition, 1985.

37. Recommendations of the Immunization Practices Advisory Committee (ACIP), Mumps Prevention, MMWR 38(22): 388-400, June 9, 1989.

38. King, G.E.; Markowitz, L.E.; Patriarca, P.A.; et al: Clinical Efficacy of Measles Vaccine During the 1990 Measles Epidemic, Pediatr. Infect. Dis. J. 10(12): 883-888, December 1991.

39. Krasinski, K.; Borkowsky, W.: Measles and Measles Immunity in Children Infected With Human Immunodeficiency Virus, JAMA 261(17): 2512-2516, 1989.

40. Kelso, J.M.; Jones, R.T.; Yunginger, J.W.: Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin, J. Allergy Clin. Immunol. 91: 867-872, 1993.

41. General Recommendations on Immunization, Recommendations of the Advisory Committee on Immunization Practices, MMWR 43(RR-1): 1-38, January 28, 1994.

42. Center for Disease Control: Immunization of Children Infected with Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus, Annals of Internal Medicine, 106: 75-78, 1987.

43. Krasinski, K.; Borkowsky, W.; Krugman, S.: Antibody following measles immunization in children infected with human T-cell lymphotropic virus-type III/lymphadenopathy associated virus (HTLV-III/LAV) (Abstract). In: Program and abstracts of the International Conference on Acquired Immunodeficiency Syndrome, Paris, France, June 23-25, 1986.

44. Peter, G.; et al (eds): Report of the Committee on Infectious Diseases, Twenty-fourth Edition, American Academy of Pediatrics, 344-357, 1997.

45. Isaacs, D.; Menser, M.: Modern Vaccines, Measles, Mumps, Rubella, and Varicella, Lancet 335: 1384-1387, June 9, 1990.

46. Starr, S.; Berkovich, S.: The effect of measles, gamma globulin modified measles, and attenuated measles vaccine on the course of treated tuberculosis in children, Pediatrics 35: 97-102, January 1965.

47. Vaccine Adverse Event Reporting System -- United States, MMWR 39(41): 730-733, October 19, 1990.

48. Rubella vaccination during pregnancy -- United States, 1971-1981. MMWR 31(35): 477-481, September 10, 1982.

49. Losonsky, G.A.; Fishaut, J.M.; Strussenber, J.; Ogra, P.L.: Effect of immunization against rubella on lactation products. II. Maternal-neonatal interactions, J. Infect. Dis. 145: 661-666, 1982.

50. Landes, R.D.; Bass, J.W.; Millunchick, E.W.; Oetgen, W.J.: Neonatal rubella following postpartum maternal immunization, J. Pediatr. 97: 465-467, 1980.

51. Lerman, S.J.: Neonatal rubella following postpartum maternal immunization, J. Pediatr. 98: 668, 1981. (Letter)

52. Gershon, A.; et al: Live attenuated rubella virus vaccine: comparison of responses to HPV-77-DE5 and RA 27/3 strains, Am. J. Med. Sci. 279(2): 95-97, 1980.

53. Weibel, R.E.; et al: Clinical and laboratory studies of live attenuated RA 27/3 and HPV-77-DE rubella virus vaccines, Proc. Soc. Exp. Biol. Med. 165: 44-49, 1980.

54. CDC. Important Information about Measles, Mumps, and Rubella, and Measles, Mumps, and Rubella Vaccines. 1980. 1983.

55. CDC, Measles Surveillance, Report No. 11, p. 14, September 1982.

56. Peltola, H.; et al: The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two dose vaccination program. N. Engl. J. Med. 331: 1397-1402, 1994.

57. Eberhart-Phillips, J.E.; et al: Measles in pregnancy: a descriptive study of 58 cases. Obstetrics and Gynecology, 82(5): 797-801, November 1993.

58. Jespersen, C.S.; et al: Measles as a cause of fetal defects: A retrospective study of ten measles epidemics in Greenland. Acta Paediatr Scand. 66: 367-372, May 1977.

59. Measles, Mumps, and Rubella -- Vaccine Use and Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and Control of Mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 47(RR-8): May 22, 1998.

60. Bitnum, A.; et al: Measles Inclusion Body Encephalitis Caused by the Vaccine Strain of Measles Virus. Clin. Infect. Dis. 29: 855-861, 1999.

61. Angel, J.B.; et al; Vaccine Associated Measles Pneumonitis in an Adult with AIDS. Annals of Internal Medicine, 129: 104-106, 1998.

Manuf. And Dist. By:

Merck & Co., Inc., Whitehouse Station, NJ 08889 USA

Issued October 2003

Printed in USA

MERCK & CO., INC.

Whitehouse Station, NJ 08889, USA7999911

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 -15degreesC (+5degreesF) 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 -15degreesC (+5degreesF) 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. The disease usually consists of 300 to 500 maculopapular and/or vesicular lesions accompanied by a fever (oral temperature (>=)100degreesF) 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

Clinical Data in Children

In combined clinical trials(5) 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 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 trials(5) with the current vaccine, a total of 1164 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 six years post single-dose vaccination. It was observed that 0.2%-2.4% of vaccinees per year reported breakthrough chickenpox for up to six years post single-dose vaccination. This represents an approximate 93% (95% CI, 92%, 95%) decrease from 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 five years postvaccination, 64 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox in 91% (58/64) of exposed children, while 9% (6/64) reported a mild form of chickenpox (maximum total number of lesions <50, ranging from 6 to 40 lesions). This represents an 89% 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.

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.

Clinical Data 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 follow-up, 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

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 as defined by the acquisition of any detectable varicella antibodies (gpELISA >0.3, a highly sensitive assay which is not commercially available) 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 varicella antibody titers (>=)5 compared to children with titers <5. Titers (>=)5 were induced in approximately 76% of children vaccinated with a single dose of vaccine at 1000-17,000 PFU per dose. In a multicenter study involving susceptible adolescents and adults 13 years of age and older, two doses of VARIVAX administered four to eight weeks apart induced a seroconversion rate (gpELISA >0.3) of approximately 75% in 539 individuals four weeks after the first dose and of 99% in 479 individuals four weeks after the second dose. The average antibody response in vaccinees who received the second dose eight weeks after the first dose was higher than that in those who received the second dose four weeks after the first dose. In another multicenter study involving adolescents and adults, two doses of VARIVAX administered eight weeks apart induced a seroconversion rate (gpELISA >0.3) of 94% in 142 individuals six weeks after the first dose and 99% in 122 individuals six weeks after the second dose.(5)

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.

Persistence of Immune Response

In clinical studies involving healthy children who received 1 dose of vaccine, detectable varicella antibodies (gpELISA >0.6 units) 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.

In clinical studies involving healthy adolescents and adults who received 2 doses of vaccine, detectable varicella antibodies (gpELISA >0.6 units) 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 varicella zoster virus 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 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 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 varicella and the percentage of vaccinees whose titers were boosted for diphtheria, tetanus, pertussis, and polio were comparable between the two groups, but anti-varicella 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 varicella, and geometric mean titers for PedvaxHIB were comparable between the two groups, but anti-varicella 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 varicella were similar between the two groups. Postvaccination GMTs for all antigens were similar in both treatment groups except for varicella, 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, varicella 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 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 injections 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 injections have not been defined.

INDICATIONS AND USAGE

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

Revaccination

The duration of protection of VARIVAX is unknown at present and the need for booster doses is not defined. However, a boost in antibody levels has been observed in vaccinees following exposure to natural varicella as well as following a booster dose of VARIVAX administered four to six years postvaccination.(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 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 [phone].

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 11,102 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

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
----------------------------------------------------------------------
                                                   Peak Occurrence in
            Reaction              N   Post Dose 1 Postvaccination Days
----------------------------------------------------------------------
Fever >=102 degrees F
 (39 degrees C) Oral             8827        14.7%               0-42
----------------------------------------------------------------------
Injection-site complaints
 (pain/soreness, swelling and/or
 erythema, rash, pruritus,
 hematoma, induration,
 stiffness)                      8916        19.3%                0-2
----------------------------------------------------------------------
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.

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
----------------------------------------------------------------------
                                  Peak                      Peak
    Reaction                  Occurrence in             Occurrence in
                        Post Postvaccination      Post Postvaccination
                   N   Dose 1      Days       N  Dose 2      Days
----------------------------------------------------------------------
Fever >=100
 degrees F
 (37.7 degrees
 C) Oral          1584  10.2%         14-27  956   9.5%          0-42
----------------------------------------------------------------------
Injection-site
 complaints
 (soreness,
 erythema,
 swelling, rash,
 pruritus,
 pyrexia,
 hematoma,
 induration,
 numbness)        1606  24.4%           0-2  955  32.5%           0-2
----------------------------------------------------------------------
Varicella-like
 rash
 (injection site) 1606     3%          6-20  955     1%           0-6

  Median number
   of lesions              2                         2
----------------------------------------------------------------------
Varicella-like
 rash
 (generalized)    1606   5.5%          7-21  955   0.9%          0-23

  Median number
   of lesions              5                       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.

Nervous/Psychiatric

Encephalitis; cerebrovascular accident; transverse myelitis; Guillain-Barre syndrome; Bell's palsy; ataxia; non-febrile seizures; 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 intravenously

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

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 degrees C (+5 degrees 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 -15degreesC 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 the syringe to be used for reconstitution. 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 degrees C (+5 degrees F) or colder.

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

Prior to reconstitution, VARIVAX retains potency when stored for up to 72 continuous hours at refrigerator temperature (2-8 degrees C, 36-46 degrees 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 -20 degrees C (-4 degrees F) or colder.

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

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

Before reconstitution, protect from light.

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

* Registered trademark of MERCK & CO., Inc.

COPYRIGHT (C) MERCK & CO., Inc., 1995, 1999, 2001

All rights reserved

** Registered trademark of Lederle Laboratories

REFERENCES

1. Balfour, H.H.; et al.: Acyclovir Treatment of Varicella in Otherwise Healthy Children, Pediatrics., 116: 633-639, 1990.

2. Ross, A.H.: Modification of Chickenpox in Family Contacts by Administration of Gamma Globulin, N Engl J Med. 267: 369-376, 1962.

3. Preblud, S.R.: Varicella: Complications and Costs, Pediatrics, 78(4 Pt 2): 728-735, 1986.

4. Weibel, R.E.; et al.: Live Attenuated Varicella Virus Vaccine, N Engl J Med. 310(22): 1409-1415, 1984.

5. Unpublished data; files of Merck Research Laboratories.

6. Wharton, M.; et al.: Health Impact of Varicella in the 1980's. Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy, (Abstract #1138), 1990.

7. Bernstein, H.H.; et al.: Clinical Survey of Natural Varicella Compared with Breakthrough Varicella After Immunization with Live Attenuated Oka/Merck Varicella Vaccine. Pediatrics 92: 833-837, 1993.

8. Kuter, B.J.; et al.: Oka/Merck Varicella Vaccine in Healthy Children: Final Report of a 2-Year Efficacy Study and 7-Year Follow-up Studies, Vaccine, 9: 643-647, 1991.

9. Arbeter, A.M.; et al.: Varicella Vaccine Trials in Healthy Children, A Summary of Comparative and Follow-up Studies, AJDC 138: 434-438, 1984.

10. Weibel, R.E.; et al.: Live Oka/Merck Varicella Vaccine in Healthy Children, JAMA 254(17): 2435-2439, 1985.

11. Chartrand, D.M.; et al.: New Varicella Vaccine Production Lots in Healthy Children and Adolescents, Abstracts of the 1988 Inter-Science Conference Antimicrobial Agents and Chemotherapy: 237(Abstract #731).

12. Johnson, C.E.; et al.: Live Attenuated Vaccine in Healthy 12 to 24 month old Children, Pediatrics 81: 512-518, 1988.

13. Gershon, A.A.; et al.: Immunization of Healthy Adults with Live Attenuated Varicella Vaccine, J Infect Dis, 158(1): 132-137, 1988.

14. Gershon, A.A.; et al.: Live Attenuated Varicella Vaccine: Protection in Healthy Adults Compared with Leukemic Children, J Infect Dis, 161: 661-666, 1990.

15. White, C.J.; et al.: Varicella Vaccine (VARIVAX) in Healthy Children and Adolescents: Results From Clinical Trials, 1987 to 1989, Pediatrics, 87(5): 604-610, 1991.

16. Asano, Y.; et al.: Contact Infection from Live Varicella Vaccine Recipients, Lancet 1(7966): 965, 1976.

17. Hammerschlag, M.R.; et al.: Herpes Zoster in an Adult Recipient of Live Attenuated Varicella Vaccine, J Infect Dis 160(3): 535-537, 1989.

18. White, C.J.: Letters to the Editor, Pediatrics 318: 354, 1992.

19. Guess, H.A.; et al.: Population-Based Studies of Varicella Complications, Pediatrics 78(4 Pt 2): 723-727, 1986.

20. Ragozzino, M.; et al.: Population-Based Study of Herpes Zoster and Its Sequelae, Medicine 61(5): 310-316, 1982.

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

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

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

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

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

MERCK & CO., INC.

Whitehouse Station, NJ 08889, USA

Issued December 2003

Printed in USA