ProQuad®Measles, Mumps, Rubella and Varicella Virus Vaccine Live

PROQUAD - measles virus live antigen, a, mumps virus live antigen, a, rubella virus live antigen, a and varicella-zoster virus live antigen, a injection, powder, lyophilized, for suspension 
Merck & Co., Inc.

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ProQuad®
Measles, Mumps, Rubella and Varicella Virus Vaccine Live

DESCRIPTION

ProQuad1 is a combined attenuated live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized preparation of (1) the components of M-M-R1II (Measles, Mumps and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl Lynn™ (B level) strain of mumps virus propagated in chick embryo cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus pools, bovine serum, and human albumin used in manufacturing are all tested to provide assurance that the final product is free of potential adventitious agents.

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

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


1

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

CLINICAL PHARMACOLOGY

Background

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

Mechanism of Action

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

Persistence of Antibody Responses after Vaccination

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

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

CLINICAL STUDIES

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

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

Immunogenicity

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

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

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

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

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

Children Who Received a Second Dose of ProQuad

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

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

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

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

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

Studies With Other Vaccines

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

Herpes Zoster

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

Reye's Syndrome

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

INDICATIONS AND USAGE

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

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

CONTRAINDICATIONS

ProQuad should not be administered:

WARNINGS

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

Hypersensitivity to Eggs

Live measles vaccine and live mumps vaccine are produced in chick embryo cell culture. Persons with a history of anaphylactic or other immediate hypersensitivity reactions (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) subsequent to egg ingestion may be at an enhanced risk of immediate-type hypersensitivity reactions after receiving vaccines containing traces of chick embryo antigen. The potential risk-to-benefit ratio should be carefully evaluated before considering vaccination in such cases. Such individuals may be vaccinated with extreme caution; adequate treatment should be readily available should a reaction occur (see PRECAUTIONS).{11}

Children with egg allergy are at low risk for anaphylactic reactions to measles-containing vaccines (including M-M-R II), and skin testing of children allergic to eggs is not predictive of reactions to M-M-R II vaccine. Persons with allergies to chickens or feathers are not at increased risk of reaction to the vaccine.{11}

Hypersensitivity to Neomycin

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

Thrombocytopenia

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

Theoretical Risk of Transmission of Creutzfeldt-Jakob Disease

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

PRECAUTIONS

General

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

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

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

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

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

Transmission

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

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

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

High-risk individuals susceptible to varicella include:

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

Information for Patients

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

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

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

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

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

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

Drug Interactions

Immune Globulins and Transfusions

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

The appropriate suggested interval between transfusion or IG administration and vaccination will vary with the type of transfusion or indication for, and dose of, IG (e.g., 5 months for Varicella Zoster Immune Globulin [VZIG]).{11} Following administration of ProQuad, any immune globulin (IG) including VZIG should not be given for 1 month thereafter unless its use outweighs the benefits of vaccination.{11}

Salicylates

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

Corticosteroids and Immunosuppressive Drugs

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

Drug/Laboratory Test Interactions

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

Use with Other Vaccines

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

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

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

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

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

Carcinogenesis, Mutagenesis, Teratogenicity, Impairment of Fertility

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

Pregnancy

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

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

In counseling women who are inadvertently vaccinated when pregnant or who become pregnant within 3 months of vaccination, the physician should be aware of the following: (1) Reports have indicated that contracting wild-type measles during pregnancy enhances fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent to natural measles during pregnancy. There are no adequate studies of the attenuated (vaccine) strain of measles virus in pregnancy. However, it would be prudent to assume that the vaccine strain of virus is also capable of inducing adverse fetal effects; (2) Mumps infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect the placenta and fetus, there is no evidence that it causes congenital malformations in humans;{12} (3) In a 10-year survey involving over 700 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome;{13} and (4) Wild-type varicella can sometimes cause congenital varicella infection.

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

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

Nursing Mothers

The secretion of viruses in human milk has not been studied in measles and mumps vaccine viruses. Studies have shown that lactating postpartum women vaccinated with live rubella vaccine may secrete the virus in breast milk and transmit it to breast-fed infants. Limited evidence in the literature suggests that virus, viral DNA, or viral antigen could not be detected in the breast milk of women who were vaccinated postpartum with the vaccine strain of varicella virus.{14-15} For additional information on transmission of vaccine virus from vaccine recipients to susceptible infants, see Transmission. ProQuad should not be administered to nursing women.

Pediatric Use

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

Geriatric Use

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

ADVERSE REACTIONS

Children 12 to 23 Months of Age

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

Table 1: Vaccine-Related Injection-Site and Systemic Adverse Experiences Reported in ≥1% of Children Who Received 1 Dose of ProQuad or M-M-R II and VARIVAX at 12 to 23 Months of Age (0-42 Days Postvaccination)
*
Injection-site adverse experiences for M-M-R II and VARIVAX are based on occurrence with either of the vaccines administered.
Designates a solicited adverse experience. Injection-site adverse experiences were solicited only from Days 0-4 postvaccination.
Temperature reported as oral equivalent or abnormal.



Adverse Experiences

ProQuad

(N = 4497)

%

M-M-R II and VARIVAX

(N = 2038)

%

Injection Site*

        Pain/tenderness/soreness

        Erythema

        Swelling

        Ecchymosis

        Rash


22.0

14.4

8.4

1.5

2.3


26.7

15.8

9.8

2.3

1.5

Systemic

        Fever ≥102°F (≥38.9°C)

        Irritability

        Measles-like rash

        Varicella-like rash

        Rash (not otherwise specified)

        Upper respiratory infection

        Viral exanthema

        Diarrhea


21.5

6.7

3.0

2.1

1.6

1.3

1.2

1.2


14.9

6.7

2.1

2.2

1.4

1.1

1.1

1.3

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

Infections and infestations: otitis, otitis media, pharyngitis, viral infection.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: crying, insomnia, sleep disorder.

Nervous system disorders: somnolence.

Respiratory, thoracic, and mediastinal disorders: cough, nasal congestion, respiratory congestion, rhinorrhea.

Gastrointestinal disorders: vomiting.

Skin and subcutaneous tissue disorders: miliaria rubra, rubella-like rash.

General disorders and administration site conditions: malaise.

Post-marketing reports

The following additional adverse events have been reported with ProQuad in post-marketing experience.

Infections and infestations: herpes zoster, varicella.

Immune system disorders: anaphylactic reaction.

Nervous system disorders: ataxia, convulsion, encephalitis (see below), febrile seizure (see below).

Skin and subcutaneous tissue disorders: pruritus.

Adverse Experiences after vaccination with M-M-R II or VARIVAX

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

Infections and infestations

Atypical measles, candidiasis, cellulitis, infection, influenza, measles, orchitis, parotitis, respiratory infection, skin infection.

Blood and the lymphatic system disorders

Lymphadenitis, regional lymphadenopathy, thrombocytopenia.

Immune system disorders

Anaphylactoid reaction, anaphylaxis and related phenomena such as angioneurotic edema, facial edema, and peripheral edema, anaphylaxis in individuals with or without an allergic history.

Psychiatric disorders

Agitation, apathy, nervousness.

Nervous system disorders

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

Eye disorders

Edema of the eyelid, irritation, optic neuritis, retinitis, retrobulbar neuritis.

Ear and labyrinth disorders

Ear pain, nerve deafness.

Vascular disorders

Extravasation.

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Abdominal pain, flatulence, hematochezia, mouth ulcer.

Skin and subcutaneous tissue disorders

Erythema multiforme, Henoch-Schönlein purpura, herpes simplex, impetigo, panniculitis, purpura, skin induration, Stevens-Johnson syndrome, sunburn.

Musculoskeletal, connective tissue and bone disorders

Arthritis and/or arthralgia (usually transient and rarely chronic [see below]), musculoskeletal pain, myalgia, pain of the hip, leg, or neck, swelling.

Reproductive system and breast disorders

Epididymitis.

General disorders and administration site conditions

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

Post-marketing surveillance

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

Death from various, and in some cases unknown, causes has been reported rarely following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals. Death as a direct consequence of disseminated measles vaccine virus infection has been reported in severely immunocompromised individuals in whom a measles-containing vaccine is contraindicated and who were inadvertently vaccinated. However, there were no deaths or permanent sequelae reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982 to 1993.{16}

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

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

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

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

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

The reported rate of zoster in recipients of VARIVAX appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella.{17} In clinical trials, 8 cases of herpes zoster were reported in 9454 vaccinated individuals 12 months to 12 years of age during 42,556 person-years of follow-up. This resulted in a calculated incidence of at least 18.8 cases per 100,000 person-years. All 8 cases reported after VARIVAX were mild and no sequelae were reported. The long-term effect of VARIVAX on the incidence of herpes zoster is unknown at present.

Febrile seizures have been reported in children receiving ProQuad. Consistent with clinical study data on the timing of fever and measles-like rash, an interim analysis of a post marketing observational study in children (N=14,263) receiving their first dose of vaccine has shown that febrile seizures occurred more frequently 5-12 days following vaccination with ProQuad (0.5 per 1000) when compared with data from children in a historical, age- and gender-matched, control group vaccinated with M-M-R II and VARIVAX (N=14,263) concomitantly (0.2 per 1000). In the 0-30 day time period following vaccination, the incidence of febrile seizures with ProQuad (1.0 per 1000) was not greater than that observed in children receiving M-M-R II and VARIVAX concomitantly (1.3 per 1000).

DOSAGE AND ADMINISTRATION

Dosage

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

Preparation

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

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

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

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

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

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

Method of Administration

FOR SUBCUTANEOUS ADMINISTRATION

DO NOT INJECT INTRAVASCULARLY

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

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

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

Use With Other Vaccines

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

See PRECAUTIONS, Drug Interactions, Use with Other Vaccines.

HOW SUPPLIED

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

Storage

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

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

ProQuad may be stored at refrigerator temperature (36 to 46°F, 2 to 8°C) for up to 72 hours prior to reconstitution. Vaccine stored at 36 to 46°F which is not used within 72 hours of removal from 5°F storage should be discarded.

For information regarding stability under conditions other than those recommended, call 1-800-MERCK-90.

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

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

DO NOT FREEZE RECONSTITUTED VACCINE.

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

REFERENCES

  1. Weibel RE, et al. Clinical and laboratory studies of combined live measles, mumps, and rubella vaccines using the RA 27/3 rubella virus. Proc Soc Exp Biol Med. 165(2):323-326, 1980.
  2. Hilleman MR, Stokes J, Jr., Buynak EB, Weibel R, Halenda R, Goldner H. Studies of live attenuated measles virus vaccine in man: II. appraisal of efficacy. Am J Public Health. 52(2):44-56, 1962.
  3. Krugman S, Giles JP, Jacobs AM. Studies on an attenuated measles-virus vaccine: VI. clinical, antigenic and prophylactic effects of vaccine in institutionalized children. N Engl J Med. 263(4):174-7, 1960.
  4. Hilleman MR, Weibel RE, Buynak EB, Stokes J, Jr., Whitman JE, Jr. Live, attenuated mumps-virus vaccine. 4. Protective efficacy as measured in a field evaluation. N Engl J Med. 276(5):252-8, 1967.
  5. Sugg WC, Finger JA, Levine RH, Pagano JS. Field evaluation of live virus mumps vaccine. J Pediatr. 72(4):461-6, 1968.
  6. The Benevento and Compobasso Pediatricians Network for the Control of Vaccine-Preventable Diseases, D'Argenio P, Citarella A, Selvaggi MTM. Field evaluation of the clinical effectiveness of vaccines against pertussis, measles, rubella and mumps. Vaccine. 16(8):818-22, 1998.
  7. Furukawa T, Miyata T, Kondo K, Kuno K, Isomura S, Takekoshi T. Rubella vaccination during an epidemic. JAMA. 213(6):987-90, 1970.
  8. Vazquez M, et al. The effectiveness of the varicella vaccine in clinical practice. N Engl J Med. 344(13):955-960, 2001.
  9. Kuter B, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J. 23(2):132-137, 2004.
  10. Levy O, et al. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis. 188(7):948-53, 2003.
  11. Committee on Infectious Diseases, American Academy of Pediatrics. In: Pickering LK, Baker CJ, Overturf GD, et al., eds. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics. 419-29, 2003.
  12. Recommendations of the Immunization Practices Advisory Committee (ACIP), Mumps Prevention. MMWR. 38(22):388-392, 397-400, 1989.
  13. Rubella vaccination during pregnancy--United States, 1971-1986. MMWR Morb Mortal Wkly Rep. 36(28):457-61, 1987.
  14. Bohlke K, Galil K, Jackson LA, et al. Postpartum varicella vaccination: Is the vaccine virus excreted in breast milk? Obstetrics and Gynecology. 102(5): 970-977, 2003.
  15. Dolbear GL, Moffat J, Falkner C and Wojtowycz M. A Pilot Study: Is attenuated varicella virus present in breast milk after postpartum immunization? Obstetrics and Gynecology. 101(4 Suppl.): 47S-47S, 2003.
  16. Peltola H, et al. The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program. N Engl J Med. 331(21):1397-1402, 1994.
  17. Guess HA, et al. Population-based studies of varicella complications. Pediatrics. 78(4 Pt 2):723-727, 1986.

Dist. by:
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Issued February 2008

Printed in USA

9633807


PROQUAD 
measles, mumps, rubella and varicella virus vaccine live   injection, powder, lyophilized, for suspension
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0006-4999
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
measles virus live antigen, A (MEASLES VIRUS ANTIGEN) Active1000 TISSUE CULTURE INFECTIOUS DOSE 50%  In 0.5 MILLILITER
MUMPS VIRUS LIVE ANTIGEN, A (MUMPS VIRUS ANTIGEN) Active20000 TISSUE CULTURE INFECTIOUS DOSE 50%  In 0.5 MILLILITER
RUBELLA VIRUS LIVE ANTIGEN, A (RUBELLA VIRUS ANTIGEN) Active1000 TISSUE CULTURE INFECTIOUS DOSE 50%  In 0.5 MILLILITER
VARICELLA-ZOSTER VIRUS LIVE ANTIGEN, A (VARICELLA-ZOSTER VIRUS ANTIGEN) Active9772 PLAQUE-FORMING UNITS  In 0.5 MILLILITER
ALBUMIN HUMANInactive0.31 MILLIGRAM  In 0.5 MILLILITER
bovine calf serumInactive0.5 MICROGRAM  In 0.5 MILLILITER
hydrolyzed gelatinInactive11 MILLIGRAM  In 0.5 MILLILITER
monosodium L-glutamateInactive0.4 MILLIGRAM  In 0.5 MILLILITER
NEOMYCINInactive16 MICROGRAM  In 0.5 MILLILITER
POTASSIUM CHLORIDEInactive60 MICROGRAM  In 0.5 MILLILITER
POTASSIUM PHOSPHATE, DIBASICInactive36 MICROGRAM  In 0.5 MILLILITER
POTASSIUM PHOSPHATE, MONOBASICInactive72 MICROGRAM  In 0.5 MILLILITER
SODIUM BICARBONATEInactive0.17 MILLIGRAM  In 0.5 MILLILITER
SODIUM CHLORIDEInactive2.4 MILLIGRAM  In 0.5 MILLILITER
SODIUM PHOSPHATE, DIBASICInactive0.34 MILLIGRAM  In 0.5 MILLILITER
SORBITOLInactive1.8 MILLIGRAM  In 0.5 MILLILITER
SUCROSEInactive21 MILLIGRAM  In 0.5 MILLILITER
MRC-5 DNAInactive 
MRC-5 proteinInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10006-4999-0010 VIAL In 1 CARTONcontains a VIAL, SINGLE-DOSE
10.5 mL (MILLILITER) In 1 VIAL, SINGLE-DOSEThis package is contained within the CARTON (0006-4999-00)

Revised: 11/2008Merck & Co., Inc.