2.1 Dose and Schedule

A single dose of ProQuad is approximately 0.5 mL.

The first dose is administered at 12 to 15 months of age but may be given anytime through 12 years of age.

The second dose is administered at 4 to 6 years of age.

At least 1 month should elapse between a dose of a measles-containing vaccine and a dose of ProQuad. At least 3 months should elapse between a dose of varicella-containing vaccine and ProQuad.

2.2 Preparation for Administration

The sterile diluent for ProQuad is provided in either a vial or prefilled syringe.

Sterile Diluent Vial

Use a sterile syringe free of preservatives, antiseptics, and detergents for each injection and/or reconstitution of the vaccine because these substances may inactivate the live virus vaccine. To reconstitute, use the sterile diluent vial supplied with ProQuad. The sterile diluent does not contain preservatives or other antiviral substances which might inactivate the vaccine viruses.

To reconstitute the vaccine, withdraw the entire volume of the supplied sterile diluent from the vial and slowly inject into the lyophilized vaccine vial. Gently agitate to dissolve completely. Discard if the lyophilized vaccine cannot be dissolved.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect the vaccine before and after reconstitution 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. Do not use the reconstituted vaccine if particulates are present or if it appears discolored.

Withdraw and administer the entire volume of the reconstituted vaccine.

Administer ProQuad immediately after reconstitution. If not used immediately, the reconstituted vaccine may be stored at room temperature, protected from light, for up to 30 minutes. Discard reconstituted vaccine if it is not used within 30 minutes.

Sterile Diluent Prefilled Syringe

To reconstitute, use the sterile diluent prefilled syringe supplied with the vaccine since it does not contain preservatives or other antiviral substances which might inactivate the vaccine viruses.

Attach a needle to the prefilled syringe.

Reconstitute the vaccine by slowly injecting the entire volume of sterile diluent contained in the prefilled syringe into the lyophilized vaccine vial. Gently agitate to dissolve completely. Discard if the lyophilized vaccine cannot be dissolved.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect the vaccine before and after reconstitution 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. Do not use the reconstituted vaccine if particulates are present or if it appears discolored.

Withdraw and administer the entire volume of the reconstituted vaccine.

Administer ProQuad immediately after reconstitution. If not used immediately, the reconstituted vaccine may be stored at room temperature, protected from light, for up to 30 minutes. Discard reconstituted vaccine if it is not used within 30 minutes.

2.3 Administration

Inject the vaccine intramuscularly or subcutaneously.

4.1 Hypersensitivity

Do not administer ProQuad to individuals with a history of hypersensitivity to any component of the vaccine (including gelatin) {1} or to a previous dose of M-M-R II (Measles, Mumps, Rubella, Live), ProQuad or VARIVAX (Varicella Virus Vaccine Live) vaccine, or any other measles, mumps, and rubella or varicella-containing vaccine. Do not administer ProQuad to individuals with a history of anaphylaxis to neomycin [see Description (11)].

4.2 Immunosuppression

Do not administer ProQuad vaccine to individuals who are immunodeficient or immunosuppressed due to disease or medical therapy. Measles inclusion body encephalitis {2} (MIBE), pneumonitis {3} and death as a direct consequence of disseminated measles vaccine virus infection have been reported in immunocompromised individuals inadvertently vaccinated with measles-containing vaccine. In this population, disseminated mumps and rubella vaccine virus infection have also been reported. Disseminated varicella disease and extensive vaccine-associated rash have been reported in individuals who are immunosuppressed or immunodeficient who were inadvertently vaccinated with a varicella-containing vaccine {4}.

4.3 Moderate or Severe Febrile Illness

Do not administer ProQuad to individuals with an active febrile illness with fever >101.3°F (>38.5°C).

4.4 Active Untreated Tuberculosis

Do not administer ProQuad vaccine to individuals with active untreated tuberculosis (TB).

4.5 Pregnancy

Do not administer ProQuad to individuals who are pregnant or planning on becoming pregnant in the next 3 months [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].

5.1 Fever and Febrile Seizures

Administration of ProQuad (dose 1) to children 12 to 23 months old who have not been previously vaccinated against measles, mumps, rubella, or varicella, nor had a history of the wild-type infections, is associated with higher rates of fever and febrile seizures at 5 to 12 days after vaccination when compared to children vaccinated with a first dose of M-M-R II and VARIVAX administered concomitantly [see Adverse Reactions (6.3)]. Exercise caution when administering ProQuad to persons with an individual or family history of febrile seizures.

5.2 Hypersensitivity to Eggs

Individuals 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 ProQuad vaccine. The potential risks and known benefits should be evaluated before considering vaccination in these individuals [see Contraindications (4.1)] {5}.

5.3 Thrombocytopenia

Transient thrombocytopenia has been reported within 4-6 weeks following vaccination with measles, mumps and rubella vaccine. Carefully evaluate the potential risk and benefit of vaccination in children with thrombocytopenia or in those who experienced thrombocytopenia after vaccination with a previous dose of a measles, mumps, and rubella-containing vaccine [see Adverse Reactions (6.2)] {6-8}.

5.4 Family History of Immunodeficiency

Vaccination should be deferred in individuals with a family history of congenital or hereditary immunodeficiency until the individual's immune status has been evaluated and the individual has been found to be immunocompetent.

5.5 Use in HIV-Infected Individuals

The Advisory Committee on Immunization Practices (ACIP) has recommendations on the use of varicella vaccine in HIV-infected individuals.

5.6 Risk of Vaccine Virus Transmission

Post-licensing experience suggests that transmission of varicella vaccine virus (Oka/Merck) resulting in varicella infection including disseminated disease may occur between vaccine recipients (who develop or do not develop a varicella-like rash) and contacts susceptible to varicella including healthy as well as high-risk individuals.

High-risk individuals susceptible to varicella include:

• Immunocompromised individuals;
• Pregnant women without documented positive history of varicella (chickenpox) or laboratory evidence of prior infection;
• Newborn infants of mothers without documented positive history of varicella or laboratory evidence of prior infection and all newborn infants born at <28 weeks gestation regardless of maternal varicella immunity.

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.

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 Use in Specific Populations (8.2)].

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

5.7 Immune Globulins and Transfusions

Immune Globulins (IG) and other blood products should not be given concurrently with ProQuad [see Drug Interactions (7.1)]. These products may contain antibodies that interfere with vaccine virus replication and decrease the expected immune response.

The ACIP has specific recommendations for intervals between administration of antibody containing products and live virus vaccines.

5.8 Salicylate Therapy

Avoid the use of salicylates (aspirin) or salicylate-containing products in children and adolescents 12 months through 12 years of age, for six weeks following vaccination with ProQuad due to the association of Reye syndrome with salicylate therapy and wild-type varicella infection [see Drug Interactions (7.2) and Patient Counseling Information (17)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. Vaccine-related adverse reactions reported during clinical trials were assessed by the study investigators to be possibly, probably, or definitely vaccine-related and are summarized below.

6.2 Post-Marketing Experience

The following adverse events have been identified during post-approval use of either the components of ProQuad or ProQuad. Because the events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Infections and infestations

Subacute sclerosing panencephalitis, encephalitis, aseptic meningitis, meningitis, measles, atypical measles, pneumonia, respiratory infection, infection, varicella (vaccine strain), influenza, wild-type or vaccine strain herpes zoster, orchitis, epididymitis, cellulitis, skin infection, retinitis, bronchitis, parotitis, sinusitis, impetigo, herpes simplex, candidiasis, rhinitis.

The vaccine virus (Oka/Merck strain) contained in ProQuad may establish latency of varicella zoster virus in immunocompetent individuals, with the potential for later development of herpes zoster.

Cases of encephalitis or meningitis caused by vaccine strain varicella virus have been reported in immunocompromised and immunocompetent individuals previously vaccinated with VARIVAX (same varicella vaccine strain as in ProQuad) months to years after vaccination. Reported cases were commonly associated with preceding or concurrent herpes zoster rash.

Blood and the lymphatic system disorders

Aplastic anemia, thrombocytopenia, regional lymphadenopathy, lymphadenitis.

Immune system disorders

Anaphylaxis and related phenomena such as angioneurotic edema, facial edema, and peripheral edema, anaphylactoid reaction.

Psychiatric disorders

Agitation, apathy, nervousness.

Nervous system disorders

Measles inclusion body encephalitis, acute disseminated encephalomyelitis, transverse myelitis, cerebrovascular accident, encephalopathy, Guillain-Barré syndrome, optic neuritis, Bell’s palsy, polyneuropathy, ataxia, hypersomnia, afebrile convulsions or seizures, febrile seizure, headache, syncope, dizziness, tremor, paresthesia.

Eye disorders

Necrotizing retinitis (in immunocompromised individuals), retrobulbar neuritis, ocular palsies, edema of the eyelid, irritation eye.

Ear and labyrinth disorders

Nerve deafness, ear pain.

Vascular disorders

Extravasation blood.

Respiratory, thoracic and mediastinal disorders

Pneumonitis, pulmonary congestion, wheezing, bronchial spasm, epistaxis, sore throat.

Gastrointestinal disorders

Hematochezia, abdominal pain, mouth ulcer.

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome, Henoch-Schönlein purpura, erythema multiforme, acute hemorrhagic edema of infancy, purpura, skin induration, panniculitis, pruritus.

Musculoskeletal, connective tissue and bone disorders

Arthritis, arthralgia, pain of the hip, leg, or neck; myalgia; musculoskeletal pain.

General disorders and administration site conditions

Injection-site complaints including wheal and flare, warm to touch, stiffness, warm sensation, inflammation, injection-site hemorrhage, injection-site injury.

Herpes Zoster

The vaccine virus (Oka/Merck strain) contained in ProQuad may establish latency of varicella zoster virus in immunocompetent individuals, with the potential for later development of herpes zoster.

6.3 Post-Marketing Observational Safety Surveillance Study

Safety was evaluated in an observational study that included 69,237 children vaccinated with ProQuad 12 months to 12 years old. A historical comparison group included 69,237 age-, gender-, and date-of-vaccination- (day and month) matched subjects who were given M-M-R II and VARIVAX concomitantly. The primary objective was to assess the incidence of febrile seizures occurring within various time intervals after vaccination in 12- to 60-month-old children who had neither been vaccinated against measles, mumps, rubella, or varicella, nor had a history of the wild-type infections (N=31,298 vaccinated with ProQuad, including 31,043 who were 12 to 23 months old). The incidence of febrile seizures was also assessed in a historical control group of children who had received their first vaccination with M-M-R II and VARIVAX concomitantly (N=31,298, including 31,019 who were 12 to 23 months old). The secondary objective was to assess the general safety of ProQuad in the 30-day period after vaccination in children 12 months to 12 years old.

In pre-licensure clinical studies, an increase in fever was observed 5 to 12 days after vaccination with ProQuad (dose 1) compared to M-M-R II and VARIVAX (dose 1) given concomitantly. In the post-marketing observational surveillance study, results from the primary safety analysis revealed an approximate two-fold increase in the risk of febrile seizures in the same 5 to 12 day timeframe after vaccination with ProQuad (dose 1). The incidence of febrile seizures 5 to 12 days after ProQuad (dose 1) (0.70 per 1000 children) was higher than that in children receiving M-M-R II and VARIVAX concomitantly (0.32 per 1000 children) [RR 2.20, 95% confidence interval (CI): 1.04, 4.65]. The incidence of febrile seizures 0 to 30 days after ProQuad (dose 1) (1.41 per 1000 children) was similar to that observed in children receiving M-M-R II and VARIVAX concomitantly [RR 1.10 (95% CI: 0.72, 1.69)]. See Table 11. General safety analyses revealed that the risks of fever (RR=1.89; 95% CI: 1.67, 2.15) and skin eruption (RR=1.68; 95% CI: 1.07, 2.64) were significantly higher after ProQuad (dose 1) compared with those who received concomitant first doses of M-M-R II and VARIVAX, respectively. All medical events that resulted in hospitalization or emergency room visits were compared between the group given ProQuad and the historical comparison group, and no other safety concerns were identified in this study.

In this observational post-marketing study, no case of febrile seizure was observed during the 5 to 12 day postvaccination time period among 26,455 children who received ProQuad as a second dose of M-M-R II and VARIVAX. In addition, detailed general safety data were available from more than 25,000 children who received ProQuad as a second dose of M-M-R II and VARIVAX, most of them (95%) between 4 and 6 years of age, and an analysis of these data by an independent, external safety monitoring committee did not identify any specific safety concern.

7.1 Immune Globulins and Transfusions

Administration of immune globulins and other blood products concurrently with ProQuad vaccine may interfere with the expected immune response [see Warnings and Precautions (5.7)] {9-11}. The ACIP has specific recommendations for intervals between administration of antibody containing products and live virus vaccines.

7.2 Salicylates

Reye 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 [see Warnings and Precautions (5.8) and Patient Counseling Information (17)].

7.3 Corticosteroids and Immunosuppressive Drugs

ProQuad vaccine should not be administered to individuals receiving immunosuppressive therapy, including high dose corticosteroids. Vaccination with ProQuad vaccine can result in disseminated disease and extensive vaccine-associated rash in individuals on immunosuppressive drugs [see Contraindications (4.2)].

7.4 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.

7.5 Use with Other Vaccines

At least 1 month should elapse between a dose of a measles-containing vaccine and a dose of ProQuad, and at least 3 months should elapse between administration of 2 doses of ProQuad or varicella-containing vaccines.

ProQuad may be administered concomitantly with Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant). Additionally, ProQuad may be administered concomitantly with pneumococcal 7-valent conjugate vaccine, and/or hepatitis A (inactivated) vaccines [see Clinical Studies (14)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Do not administer ProQuad to infants younger than 12 months of age or to children 13 years and older. Safety and effectiveness of ProQuad in infants younger than 12 months of age and in children 13 years and older have not been established [see Clinical Studies (14)].

8.5 Geriatric Use

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

12.1 Mechanism of Action

ProQuad has been shown to induce measles-, mumps-, rubella-, and varicella-specific immunity, which is thought to be the mechanism by which it protects against these four childhood diseases.

The efficacy of ProQuad was established through the use of immunological correlates for protection against measles, mumps, rubella, and varicella. Results from efficacy studies or field effectiveness studies that were previously conducted for the component vaccines were used to define levels of serum antibodies that correlated with protection against measles, mumps, and rubella. Also, in previous studies with varicella vaccine, antibody responses against varicella virus ≥5 gpELISA units/mL in a glycoprotein enzyme-linked immunosorbent assay (gpELISA) (not commercially available) similarly correlated with long-term protection. In these efficacy studies, the clinical endpoint for measles and mumps was a clinical diagnosis of either disease confirmed by a 4-fold or greater rise in serum antibody titers between either postvaccination or acute and convalescent titers; for rubella, a 4-fold or greater rise in antibody titers with or without clinical symptoms of rubella; and for varicella, varicella-like rash that occurred >42 days postvaccination and for which varicella was not excluded by either viral cultures of the lesion or serological tests. Specific laboratory evidence of varicella either by serology or culture was not required to confirm the diagnosis of varicella. 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 (14)] and seroresponse rates for varicella virus were similar to those observed after vaccination with a single dose of VARIVAX [see Clinical Studies (14)]. The duration of protection from measles, mumps, rubella, and varicella infections after vaccination with ProQuad is unknown.

12.6 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 neutralizing and ELISA antibodies to measles, mumps, and rubella viruses are still detectable in 95-100%, 74-91%, and 90-100% of individuals respectively, 11 to 13 years after primary vaccination series {18-24}. Varicella antibodies were present for up to ten years postvaccination in most of the individuals tested who received 1 dose of VARIVAX.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Immunogenicity in Children 12 Months to 6 Years of Age

Prior to licensure, immunogenicity was studied in 5845 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 administered subcutaneously was similar to that of its individual component vaccines (M-M-R II and VARIVAX), which are currently used in routine vaccination.

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.

Immunogenicity in Children 12 to 23 Months of Age After a Single Dose

In 4 randomized clinical trials, 5446 healthy children 12 to 23 months of age were administered ProQuad subcutaneously, 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 ProQuad Administered with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine below], no concomitant vaccines were permitted during study participation. The race distribution of the study subjects across these studies following a first dose of ProQuad was as follows: 66.3% White; 12.7% African-American; 9.9% Hispanic; 6.7% Asian/Pacific; 4.2% other; and 0.2% American Indian. The gender distribution of the study subjects across these studies following a first dose of ProQuad was 52.6% male and 47.4% female. A summary of combined immunogenicity results 6 weeks following administration of a single dose of ProQuad or M-M-R II and VARIVAX is shown in Table 12. 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 (lower bound of the 95% CI for the risk difference in measles, mumps, and rubella seroconversion rates were >-5.0 percentage points and the lower bound of the 95% CI for the risk difference in varicella seroprotection rates was either >-15 percentage points [one study] or >-10.0 percentage points [three studies]).

Immunogenicity in Children 15 to 31 Months of Age After 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 subcutaneously were administered a second dose of ProQuad subcutaneously, approximately 3 to 9 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 race distribution across these studies following a second dose of ProQuad was as follows: 67.3% White; 14.3% African-American; 8.3% Hispanic; 5.4% Asian/Pacific; 4.4% other; 0.2% American Indian; and 0.10% mixed. The gender distribution of the study subjects across these studies following a second dose of ProQuad was 50.4% male and 49.6% female. A summary of immune responses following a second dose of ProQuad is presented in Table 13. Results from this study showed that 2 doses of ProQuad administered at least 3 months apart elicited a positive antibody response to all four antigens in greater than 98% of subjects. 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.

Immunogenicity in Children 4 to 6 Years of Age Who Received a First Dose of ProQuad After Primary Vaccination With M-M-R II and VARIVAX

In a clinical trial, 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 were randomized to receive ProQuad subcutaneously and placebo (N=399), M-M-R II and placebo concomitantly at separate injection sites (N=205), or M-M-R II and VARIVAX concomitantly at separate injection sites (N=195). 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 [see Adverse Reactions (6.1) for ethnicity and gender information].

A summary of antibody responses to measles, mumps, rubella, and varicella at 6 weeks postvaccination in subjects who had previously received M-M-R II and VARIVAX is shown in Table 14. Results from this study showed that a first dose of ProQuad after primary vaccination with M-M-R II and VARIVAX elicited a positive antibody response to all four antigens in greater than 98% of subjects. Postvaccination 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 (the lower bound of the 95% CI around the fold difference in measles, mumps, rubella, and varicella GMTs excluded 0.5). 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 lower bound of the 95% CI around the fold difference for the comparison of measles, mumps, and rubella GMTs excluded 0.5).

Immunogenicity Following 2 Doses of ProQuad Administered Intramuscularly or Subcutaneously

In an open label clinical trial (NCT00402831) 405 children 12 through 18 months of age received two doses of ProQuad, administered 30 days apart (a non-US licensed interval), either intramuscularly (n=202) or subcutaneously (n=203). Antibody responses to measles, mumps, rubella and varicella viruses were measured by ELISAs using sera obtained 30 days post-dose 1, and 6-weeks post-dose 2. For anti-measles virus, anti-mumps virus, anti-rubella virus and anti-varicella virus, seroresponse rates were defined as the percentage of children seronegative at baseline who achieved antibody titers above the respective seroresponse threshold for each assay 30 days post-dose 1 and 6 weeks post-dose 2. Seroresponse thresholds were defined as 255 mIU/mL, 10 EU/mL, 10 IU/mL and 5 gpELISA units for anti-measles virus, anti-mumps virus, anti-rubella virus and anti-varicella virus antibodies, respectively after each dose. For each vaccine antigen at least 87% of enrolled children were seronegative at baseline.

The seroresponse rates to measles, mumps, and varicella viruses after dose 1 were noninferior in the intramuscular group compared to the subcutaneous group in a post hoc analysis (lower bound of the 95% confidence interval for the difference in seroresponse rates [intramuscular group minus subcutaneous group] ≥-5%). The seroresponse rate to rubella virus narrowly missed meeting the criterion for noninferiority (lower bounds of the 95% CI for the difference in seroresponse rate -5.5%). For measles, mumps, rubella, and varicella antigens, the lower bound of the 95% CI of the seroresponse rate was ˃90% after intramuscular administration. The proportions of children achieving antibody titers above the seroresponse thresholds for measles, mumps, rubella and varicella viruses after dose 1 were as follows: 100%, 97.4%, 98.4%, and 98.6%, respectively, in the intramuscular group and 97.3%, 91.3%, 100%, and 98.5%, respectively, in the subcutaneous group.

Storage

Vaccine Vial

To maintain potency, ProQuad must be stored frozen between -58°F and +5°F (-50°C to -15°C). Use of dry ice may subject ProQuad to temperatures colder than -58°F (-50°C).

Before reconstitution, store the lyophilized vaccine in a freezer at a temperature between −58°F and +5°F (−50°C and −15°C) for up to 18 months. Any freezer (e.g., chest, frost-free) that reliably maintains an average temperature between −58°F and +5°F (−50°C and −15°C) and has a separate sealed freezer door is acceptable for storing ProQuad. Routine defrost cycling of a frost-free freezer is acceptable.

ProQuad may be stored at refrigerator temperature (36° to 46°F, 2° to 8°C) for up to 72 hours prior to reconstitution. Discard any ProQuad vaccine stored at 36° to 46°F which is not used within 72 hours of removal from 5°F (-15°C) storage.

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

Sterile Diluent

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

IF NOT USED IMMEDIATELY, THE RECONSTITUTED VACCINE MAY BE STORED AT ROOM TEMPERATURE, PROTECTED FROM LIGHT, FOR UP TO 30 MINUTES.

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

DO NOT FREEZE RECONSTITUTED VACCINE.

For information regarding the product or questions regarding storage conditions, call 1-800-637-2590.