Vaccine Information: ProQuad

PROQUAD- measles virus strain enders’ attenuated edmonston live antigen, mumps virus strain b level jeryl lynn live antigen, rubella virus strain wistar ra 27/3 live antigen and varicella-zoster virus strain oka/merck live antigen injection, powder, lyophilized, for suspension
Merck Sharp & Dohme LLC

1 INDICATIONS AND USAGE

ProQuad is a vaccine indicated for active immunization for the prevention of measles, mumps, rubella, and varicella in children 12 months through 12 years of age.

2 DOSAGE AND ADMINISTRATION

​ INTRAMUSCULAR OR SUBCUTANEOUS ADMINISTRATION ONLY

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

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 only the diluent supplied with the vaccine since it is free of preservatives or other antiviral substances which might inactivate the vaccine.

To reconstitute the vaccine, withdraw the entire volume of the supplied diluent from its vial and inject into lyophilized vaccine vial. 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. Do not use the product if particulates are present or if it appears discolored. 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, inject the entire volume, and discard vial.

To minimize loss of potency, the vaccine should be administered 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.

3 DOSAGE FORMS AND STRENGTHS

ProQuad is a suspension for injection supplied as a single dose vial of lyophilized vaccine to be reconstituted using the accompanying sterile diluent [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)]. A single dose after reconstitution is approximately 0.5 mL.

4 CONTRAINDICATIONS

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 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

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.

Children 12 Through 23 Months of Age Who Received a Single Dose of ProQuad

ProQuad was administered subcutaneously to 4497 children 12 through 23 months of age involved in 4 randomized 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 (N=2038) 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 postvaccination using vaccination report card-aided surveillance. Safety follow-up was obtained for 98% of children in each group. Few subjects (<0.1%) who received ProQuad discontinued the study due to an adverse reaction. The race distribution of the study subjects across these studies following a first dose of ProQuad was as follows: 65.2% White; 13.1% African-American; 11.1% Hispanic; 5.8% Asian/Pacific; 4.5% other; and 0.2% American Indian. The racial distribution of the control group was similar to that of the group who received ProQuad. The gender distribution across the studies following a first dose of ProQuad was 52.5% male and 47.5% female. The gender distribution of the control group was similar to that of the group who received ProQuad. Vaccine-related injection-site and systemic adverse reactions observed among recipients of ProQuad or M-M-R II and VARIVAX at a rate of at least 1% are shown in Table 1. Systemic vaccine-related adverse reactions that were reported at a significantly greater rate in individuals who received a first dose of ProQuad than in individuals who received first doses of 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, risk difference 6.6%, 95% CI: 4.6, 8.5), and measles-like rash (3.0% versus 2.1%, respectively, risk difference 1.0%, 95% CI: 0.1, 1.8). 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 26.8%, respectively, risk difference -4.8%, 95% CI: -7.1, -2.5). The only vaccine-related injection-site adverse reaction that was more frequent among recipients of ProQuad than recipients of M-M-R II and VARIVAX was rash at the injection site (2.4% versus 1.6%, respectively, risk difference 0.9%, 95% CI: 0.1, 1.5).

Table 1: Vaccine-Related Injection-Site and Systemic Adverse Reactions Reported in ≥1% of Children Who Received ProQuad Dose 1 or M-M-R II and VARIVAX at 12 to 23 Months of Age (0 to 42 Days Postvaccination)

	ProQuad(N=4497)	M-M-R II and VARIVAX(N=2038)
Adverse Reactions	(n=4424)%	(n=1997)%
N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* Injection-site adverse reactions for M-M-R II and VARIVAX are based on occurrence with either of the vaccines administered. † Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 0 to 4 postvaccination. ‡ Temperature reported as elevated (≥102°F, oral equivalent) or abnormal.
Injection Site *
Pain/tenderness/soreness †	22.0	26.7
Erythema †	14.4	15.8
Swelling †	8.4	9.8
Ecchymosis	1.5	2.3
Rash	2.3	1.5
Systemic
Fever †, ‡	21.5	14.9
Irritability	6.7	6.7
Measles-like rash †	3.0	2.1
Varicella-like rash †	2.1	2.2
Rash (not otherwise specified)	1.6	1.4
Upper respiratory infection	1.3	1.1
Viral exanthema	1.2	1.1
Diarrhea	1.2	1.3

Rubella-like rashes were observed in <1% of subjects following a first dose of ProQuad.

In these clinical trials, two cases of herpes zoster were reported among 2108 healthy subjects 12 through 23 months of age who were vaccinated with their first dose of ProQuad and followed for 1 year. Both cases were unremarkable and no sequelae were reported.

Children 15 to 31 Months of Age Who Received a Second Dose of ProQuad

In 5 clinical trials, 2780 healthy children were vaccinated subcutaneously with ProQuad (dose 1) at 12 to 23 months of age and then administered a second dose approximately 3 to 9 months later. The race distribution of the study subjects across these studies following a second dose of ProQuad was as follows: 64.4% White; 14.1% African-American; 12.0% Hispanic; 5.9% other; 3.5% Asian/Pacific; and 0.1% American Indian. The gender distribution across the studies following a second dose of ProQuad was 51.5% male and 48.5% female. Children in these open-label studies were monitored for at least 28 days postvaccination using vaccination report card-aided surveillance. Safety follow-up was obtained for approximately 97% of children overall. Vaccine-related injection-site and systemic adverse reactions observed after Dose 1 and 2 of ProQuad at a rate of at least 1% are shown in Table 2. In these trials, the overall rates of systemic adverse reactions after ProQuad (dose 2) were comparable to, or lower than, those seen with the first dose. In the subset of children who received both ProQuad dose 1 and dose 2 in these trials (N=2408) with follow-up for fever, fever ≥102.2°F (≥38.9°C) was observed significantly less frequently days 1 to 28 after the second dose (10.8%) than after the first dose (19.1%) (risk difference 8.3%, 95% CI: 6.4, 10.3). Fevers ≥102.2°F (≥38.9°C) days 5 to 12 after vaccinations were also reported significantly less frequently after dose 2 (3.9%) than after dose 1 (13.6%) (risk difference 9.7%, 95% CI: 8.1, 11.3). In the subset of children who received both doses and for whom injection-site reactions were reported (N=2679), injection-site erythema was noted significantly more frequently after ProQuad (dose 2) as compared to ProQuad (dose 1) (12.6% and 10.8%, respectively, risk difference -1.8, 95% CI: -3.3, -0.3); however, pain and tenderness at the injection site was significantly lower after dose 2 (16.1%) as compared with after dose 1 (21.9%) (risk difference, 5.8%, 95% CI: 4.1, 7.6). Two children had febrile seizures after ProQuad (dose 2); both febrile seizures were thought to be related to a concurrent viral illness [see Adverse Reactions (6.3) and Clinical Studies (14)]. These studies were not designed or statistically powered to detect a difference in rates of febrile seizure between recipients of ProQuad as compared to M-M-R II and VARIVAX. The risk of febrile seizure has not been evaluated in a clinical study comparing the incidence rate after ProQuad (dose 2) with the incidence rate after concomitant M-M-R II (dose 2) and VARIVAX (dose 2) [see Adverse Reactions (6.1), Children 4 to 6 Years of Age Who Received ProQuad After Primary Vaccination with M-M-R II and VARIVAX].

Table 2: Vaccine-Related Injection-Site and Systemic Adverse Reactions Reported in ≥1% of Children Who Received ProQuad Dose 1 at 12 to 23 Months of Age and Dose 2 at 15 to 31 Months of Age (1 to 28 Days Postvaccination)

	ProQuadDose 1	ProQuadDose 2
Adverse Reactions	(N=3112)(n=3019)%	(N=2780)(n=2695)%
N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination. † Temperature reported as elevated or abnormal.
Injection-Site
Pain/tenderness/soreness *	21.4	15.9
Erythema *	10.7	12.4
Swelling *	8.0	8.5
Injection-site bruising	1.1	0.0
Systemic
Fever *, †	20.4	8.3
Irritability	6.0	2.4
Measles-like/Rubella-like rash	4.3	0.9
Varicella-like/Vesicular rash	1.5	0.1
Diarrhea	1.3	0.6
Upper respiratory infection	1.3	1.4
Rash (not otherwise specified)	1.2	0.6
Rhinorrhea	1.1	1.0

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

In a double-blind clinical trial, 799 healthy 4- to 6-year-old children who received M-M-R II and VARIVAX at least 1 month prior to study entry were randomized to receive ProQuad administered subcutaneously and placebo (N=399), M-M-R II and placebo concomitantly (N=205) at separate injection sites, or M-M-R II and VARIVAX (N=195) concomitantly at separate injection sites [see Clinical Studies (14)]. Children in these studies were monitored for up to 42 days postvaccination using vaccination report card-aided surveillance. Safety follow-up was obtained for >98% of children in each group. The race distribution of the study subjects following a dose of ProQuad was as follows: 78.4% White; 12.3% African-American; 3.8% Hispanic; 3.5% other; and 2.0% Asian/Pacific. The gender distribution following a dose of ProQuad was 52.1% male and 47.9% female. Injection-site and systemic adverse reactions observed after Dose 1 and 2 of ProQuad at a rate of at least 1% are shown in Table 3 [see Clinical Studies (14)].

Table 3: Vaccine-Related Injection-Site and Systemic Adverse Reactions Reported in ≥1% of Children Previously Vaccinated with M-M-R II and VARIVAX Who Received ProQuad + Placebo, M-M-R II + Placebo, or M-M-R II + VARIVAX at 4 to 6 Years of Age (1 to 43 Days Postvaccination)

Adverse Reactions	ProQuad + Placebo(N=399)(n=397)%		M-M-R II + Placebo(N=205)(n=205)%		M-M-R II + VARIVAX(N=195)(n=193)%
N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination. † Temperature reported as elevated (≥102°F, oral equivalent) or abnormal.
Systemic
Fever *, †	2.5		2.0		4.1
Cough	1.3		0.5		0.5
Irritability	1.0		0.5		1.0
Headache	0.8		1.5		1.6
Rhinorrhea	0.5		1.0		0.5
Nasopharyngitis	0.3		1.0		1.0
Vomiting	0.3		1.0		0.5
Upper respiratory infection	0.0		0.0		1.0
	ProQuad%	Placebo%	M-M-R II%	Placebo%	M-M-R II%	VARIVAX%
Injection-Site
Pain *	41.1	34.5	36.6	34.1	35.2	36.8
Erythema *	24.4	13.4	15.6	14.1	14.5	15.5
Swelling *	15.6	8.1	10.2	8.8	7.8	10.9
Bruising	3.5	3.8	2.4	3.4	1.6	2.1
Rash	1.5	1.3	0.0	0.0	0.5	0.0
Pruritus	1.0	0.3	0.0	0.0	0.0	1.0
Nodule	0.0	0.0	0.0	0.0	0.0	1.0

Safety in Trials That Evaluated Concomitant Use with Other Vaccines

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

In an open-label clinical trial, 1434 children were randomized to receive ProQuad administered subcutaneously given 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 concomitantly (N=949) or non-concomitantly with ProQuad given first and the other vaccines 6 weeks later (N=485). No clinically significant differences in adverse events were reported between treatment groups [see Clinical Studies (14)]. The race distribution of the study subjects who received ProQuad was as follows: 70.7% White; 10.9% Asian/Pacific; 10.7% African-American; 4.5% Hispanic; 3.0% other; and 0.2% American Indian. The gender distribution of the study subjects who received ProQuad was 53.6% male and 46.4% female.

ProQuad Administered with Pneumococcal 7-valent Conjugate Vaccine and/or Hepatitis A Vaccine, Inactivated

In an open-label clinical trial, 1027 healthy children 12 to 23 months of age were randomized to receive ProQuad administered subcutaneously (dose 1) and pneumococcal 7-valent conjugate vaccine (dose 4) concomitantly (N=510) or non-concomitantly at different clinic visits (N=517). The race distribution of the study subjects was as follows: 65.2% White; 15.1% African-American; 10.0% Hispanic; 6.6% other; and 3.0% Asian/Pacific. The gender distribution of the study subjects was 54.5% male and 45.5% female. Injection-site and systemic adverse reactions observed among recipients of ProQuad administered concomitantly or non-concomitantly with pneumococcal 7-valent conjugate vaccine at a rate of at least 1% are shown in Table 4. No clinically significant differences in adverse reactions were reported between the concomitant and non-concomitant treatment groups [see Clinical Studies (14)].

Table 4: Vaccine-Related Injection-Site and Systemic Adverse Reactions Reported in ≥1% of Children Who Received ProQuad (dose 1) Concomitantly or Non-Concomitantly with PCV7* (dose 4) at the First Visit (1 to 28 Days Postvaccination)

Adverse Reactions	ProQuad + PCV7(N=510)(n=498)%	PCV7(N=258)(n=250)%	ProQuad(N=259)(n=255)%
N/A = Not applicable.N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* PCV7 = Pneumococcal 7-valent conjugate vaccine, dose 4. † Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination. ‡ Temperature reported as elevated (≥102°F, oral equivalent) or abnormal.
Injection-Site — ProQuad
Pain †	24.9	N/A	24.7
Erythema †	12.4	N/A	11.0
Swelling †	10.8	N/A	7.5
Bruising	2.0	N/A	1.6
Injection-Site — PCV7
Pain †	30.5	29.6	N/A
Erythema †	21.1	24.4	N/A
Swelling †	17.9	20.0	N/A
Bruising	1.6	1.2	N/A
Systemic
Fever †, ‡	15.5	10.0	15.3
Measles-like rash	4.4	0.8	5.1
Irritability	3.8	3.6	3.5
Upper respiratory infection	1.6	0.8	1.2
Varicella-like/vesicular rash	1.6	0.0	1.2
Diarrhea	0.8	1.2	1.2
Vomiting	0.6	0.8	1.2
Rash	0.4	0.0	1.2
Somnolence	0.0	0.0	1.2

In an open-label clinical trial, 699 healthy children 12 to 23 months of age were randomized to receive 2 doses of VAQTA (hepatitis A vaccine, inactivated) (N=352) or 2 doses of VAQTA concomitantly with 2 doses of ProQuad administered subcutaneously (N=347) at least 6 months apart. An additional 1101 subjects received 2 doses of VAQTA alone at least 6 months apart (non-randomized), resulting in 1453 subjects receiving 2 doses of VAQTA alone (1101 non-randomized and 352 randomized) and 347 subjects receiving 2 doses of VAQTA concomitantly with ProQuad (all randomized). The race distribution of the study subjects following a dose of ProQuad was as follows: 47.3% White; 42.7% Hispanic; 5.5% other; 2.9% African-American; and 1.7% Asian/Pacific. The gender distribution of the study subjects following a dose of ProQuad was 49.3% male and 50.7% female. Vaccine-related injection-site adverse reactions (days 1 to 5 postvaccination) and systemic adverse events (days 1 to 14 post VAQTA and days 1 to 28 post ProQuad vaccination) observed among recipients of VAQTA and ProQuad administered concomitantly with VAQTA at a rate of at least 1% are shown in Tables 5 and 6, respectively. In addition, among the randomized cohort, in the 14 days after each vaccination, the rates of fever (including all vaccine- and non-vaccine-related reports) were significantly higher in subjects who received ProQuad with VAQTA concomitantly after dose 1 (22.0%) as compared to subjects given dose 1 of VAQTA without ProQuad (10.8%). However, rates of fever were not significantly higher in subjects who received ProQuad with VAQTA concomitantly after dose 2 (12.5%) as compared to subjects given dose 2 of VAQTA without ProQuad (9.4%). In post-hoc analyses, these rates were significantly different for dose 1 (relative risk (RR) 2.03 [95% CI: 1.42, 2.94]), but not dose 2 (RR 1.32 [95% CI: 0.82, 2.13]). Rates of injection-site adverse reactions and other systemic adverse events were lower following a second dose than following the first dose of both vaccines given concomitantly.

Table 5: Vaccine-Related Injection-Site Adverse Reactions Reported in ≥1% of Children Who Received VAQTA or ProQuad Concomitantly with VAQTA 1 to 5 Days After Vaccination with VAQTA or VAQTA and ProQuad

	Dose 1		Dose 2
Adverse Reactions	VAQTA(N=1453)(n=1412)%	ProQuad + VAQTA(N=347)(n=328)%	VAQTA(N=1301)(n=1254)%	ProQuad + VAQTA(N=292)(n=264)%
N/A = Not applicable.N = number of subjects vaccinated. n = number of subjects with safety follow-up.
* Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination.
Injection-Site — VAQTA
Pain/tenderness *	29.2	27.1	30.1	25.0
Erythema *	13.5	12.5	14.3	11.7
Swelling *	7.1	9.1	9.0	8.0
Injection-site bruising	1.9	2.4	1.0	0.8
Injection-Site — ProQuad
Pain/tenderness *	N/A	30.5	N/A	26.2
Erythema *	N/A	13.4	N/A	12.9
Swelling *	N/A	6.7	N/A	6.5
Injection-site bruising	N/A	1.5	N/A	0.4

Table 6: Vaccine-Related Systemic Adverse Reactions Reported in ≥1% of Children Who Received VAQTA * or ProQuad Concomitantly with VAQTA 1 to 14 Days After VAQTA or Vaccination with ProQuad and VAQTA and 1 to 28 Days After Vaccination with ProQuad and VAQTA

Adverse Reactions	Dose 1			Dose 2
	Days 1 to 14		Days 1 to 28	Days 1 to 14		Days 1 to 28
	VAQTA †(N=1453)(n=1412)%	ProQuad + VAQTA †(N=347)(n=328)%	ProQuad + VAQTA(N=347)(n=328)%	VAQTA(N=1301)(n=1254)%	ProQuad + VAQTA †(N=292)(n=264)%	ProQuad + VAQTA †(N=291)(n=263)%
N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* Systemic adverse events for subjects given VAQTA alone were collected for 14 days postvaccination. † Safety follow-up for systemic adverse reactions was 14 days for VAQTA and 28 days for ProQuad + VAQTA. ‡ Designates a solicited adverse reaction. § Temperature reported as elevated or abnormal.
Fever ‡, §	5.7	14.9	15.2	4.1	8.0	8.4
Irritability	5.8	7.0	7.3	3.5	5.3	5.3
Measles-like rash	0.0	3.4	3.4	0.0	1.1	1.1
Rhinorrhea	0.6	2.7	3.0	0.6	1.1	2.7
Diarrhea	1.5	1.8	2.4	1.7	0.4	0.8
Cough	0.6	2.1	2.1	0.2	0.8	1.5
Vomiting	1.1	0.3	0.9	0.6	0.8	1.1

In an open-label clinical trial, 653 children 12 to 23 months of age were randomized to receive a first dose of ProQuad administered subcutaneously with VAQTA and pneumococcal 7-valent conjugate vaccine concomitantly (N=330) or a first dose of ProQuad administered subcutaneously and pneumococcal 7-valent conjugate vaccine concomitantly and then vaccinated with VAQTA 6 weeks later (N=323). Approximately 6 months later, subjects received either the second doses of ProQuad and VAQTA concomitantly or the second doses of ProQuad and VAQTA separately. The race distribution of the study subjects was as follows: 60.3% White; 21.6% African-American; 9.5% Hispanic; 7.2% other; 1.1% Asian/Pacific; and 0.3% American Indian. The gender distribution of the study subjects was 50.7% male and 49.3% female. Vaccine-related injection-site and systemic adverse reactions observed among recipients of concomitant ProQuad, VAQTA, and pneumococcal 7-valent conjugate vaccine and ProQuad and pneumococcal 7-valent conjugate vaccine at a rate of at least 1% are shown in Tables 7 and 8. In the 28 days after vaccination with the first dose of ProQuad, the rates of fever (including all vaccine- and non-vaccine-related reports) were comparable in subjects who received the 3 vaccines together (38.6%) as compared with subjects given ProQuad and pneumococcal 7-valent conjugate vaccine (42.7%). The rates of fever in the 28 days following the second dose of ProQuad were also comparable in subjects who received ProQuad and VAQTA together (17.4%) as compared with subjects given ProQuad separately from VAQTA (17.0%). In a post-hoc analysis, these differences were not statistically significant after ProQuad (dose 1) (RR 0.90 [95% CI: 0.75, 1.09]) nor after dose 2 (RR 1.02 [95% CI: 0.70, 1.51]). No clinically significant differences in adverse reactions were reported among treatment groups [see Clinical Studies (14)].

Table 7: Vaccine-Related Injection-Site Adverse Reactions Reported in ≥1% of Children Who Received ProQuad + VAQTA + PCV7* Concomitantly or VAQTA Alone Followed by ProQuad + PCV7 Concomitantly (1 to 5 Days After a Dose of ProQuad)

Adverse Reactions	Dose 1		Dose 2
	VAQTA + ProQuad + PCV7(N=330)(n=311)%	VAQTA Alone Followed by ProQuad + PCV7(N=323)(n=302)%	VAQTA + ProQuad(N=273)(n=265)%	VAQTA Alone Followed by ProQuad(N=240)(n=230)%
N/A = Not applicable.N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* PCV7 = Pneumococcal 7-valent conjugate vaccine. † Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination at each vaccine injection site.
Injection-Site — ProQuad
Pain/tenderness †	21.2	24.2	18.1	17.0
Erythema †	13.5	11.9	10.6	13.0
Swelling †	7.4	10.9	8.3	11.7
Bruising	1.9	1.3	0.8	0.4
Injection-Site — VAQTA
Pain/tenderness †	20.6	15.3	17.5	20.3
Erythema †	9.6	11.7	9.1	12.7
Swelling †	6.8	9.5	6.1	7.6
Bruising	1.3	1.1	1.1	1.6
Rash	1.0	0.0	0.4	0.4
Injection-Site — PCV7
Pain/tenderness †	25.4	27.6	N/A	N/A
Erythema †	16.4	16.6	N/A	N/A
Swelling †	13.2	14.3	N/A	N/A
Bruising	0.6	1.7	N/A	N/A

Table 8: Vaccine-Related Systemic Adverse Reactions Reported in ≥1% of Children Who Received ProQuad + VAQTA + PCV7* Concomitantly, or VAQTA Alone Followed by ProQuad + PCV7 Concomitantly (1 to 28 Days After a Dose of ProQuad)

Adverse Reactions	Dose 1		Dose 2
	VAQTA + ProQuad + PCV7(N=330)(n=311)%	VAQTA Alone Followed by ProQuad + PCV7(N=323)(n=302)%	VAQTA + ProQuad(N=273)(n=265)%	VAQTA Alone Followed by ProQuad(N=240)(n=230)%
N = number of subjects vaccinated.n = number of subjects with safety follow-up.
* PCV7 = Pneumococcal 7-valent conjugate vaccine. † Designates a solicited adverse reaction. ‡ Temperature reported as elevated or abnormal.
Fever †, ‡	26.4	27.2	9.1	9.6
Irritability	4.8	6.3	1.9	1.3
Measles-like rash †	2.3	4.0	0.0	0.0
Varicella-like rash †	1.0	1.7	0.0	0.0
Rash (not otherwise specified)	1.3	1.3	0.0	0.9
Diarrhea	1.3	1.3	0.4	1.3
Upper respiratory infection	1.0	1.3	1.1	0.9
Viral infection	1.0	0.7	0.0	0.0
Rhinorrhea	0.0	0.7	1.1	0.0

In a randomized open-label clinical trial (NCT00402831), conducted in France, 405 children 12 months through 18 months of age received 2 doses ProQuad, administered 30 days apart (a non-US licensed interval), by either the intramuscular (n=202) or subcutaneous (n=203) route. In the overall population, 50.9% were male and the median age was 13.3 months. Local and systemic solicited adverse reactions were recorded by parents or guardians using standardized diary cards. Local solicited reactions were recorded for 4 days after vaccination, and systemic solicited adverse reactions were recorded for 28 days after vaccination. In the event that a participant experienced a rash or a mumps-like illness, parents and/or guardians were instructed to contact the investigator for an examination as soon as possible and no later than 72 hours following onset of symptoms. The nature of any rash was characterized by principal investigator either as a measles-like, rubella-like, varicella-like or “other”. Study investigators reviewed the diary card with the participant or participant’s legal guardian 30 days and 42 days after dose 1 and dose 2, respectively to ensure consistency with protocol definitions. Tables 9 and 10 below present the frequency of solicited adverse reactions based on the final assessment by the study investigators.

Table 9. Proportion of Participants Reporting Solicited Adverse Reactions Following First Vaccination with ProQuad, by the Intramuscular or Subcutaneous Route

	INTRAMUSCULAR N=202%	SUBCUTANEOUS N=203%
N=total number of participants in the group
* Post-dose 1 (0-28 days), there was one episode of an injection-site rubella-like rash and one injection-site varicella-like rash. They were both reported in the subcutaneous group. † Intensity of injection site reaction: mild or ≤2.5 cm; moderate or >2.5 to ≤5.0 cm; severe or >5.0 cm. ‡ Intensity of pain: mild: awareness of symptom but easily tolerated; moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities. § The percentage of fever is defined within the population who had valid temperature measurements. Three participants in IM group and four participants in SC group do not have temperature measurements and were excluded from the denominator; resulting in N=199 and N=199, respectively. ¶ In the IM Group 96.0% of fevers were documented using the rectal route of measurement and 4.0% of fevers were documented only by the axillary route of measurement. In the SC Group 99.3% of fevers were documented using the rectal route of measurement and 0.7% of fevers were documented only by the axillary route of measurement.
Solicited local injection-site adverse reactions (Days 0 to 4)*
Erythema †	5.0	14.3
Mild	4.5	12.8
Moderate	0	1.5
Severe	0	0
Missing	0.5	0
Pain ‡	10.9	5.9
Mild	8.9	3.9
Moderate	2.0	2.0
Severe	0	0
Swelling †	1.0	3.9
Mild	1.0	3.9
Moderate	0	0
Severe	0	0
Solicited systemic adverse reactions (Days 0 to 28)
Measles/Measles-like rash	0.5	2.0
Rubella/Rubella-like rash	3.0	3.0
Varicella/Varicella-like rash	1.0	0.5
Zoster/Zoster-like rash	0	0
Mumps-like illness	0.5	0
Fever (temperature ≥38.0°C)§, ¶	62.8	68.3
38.0-38.5°C	21.1	17.6
>38.5-39.0°C	18.1	21.6
>39.0-39.5°C	14.1	18.1
>39.5-40.0°C	7.0	9.0
>40.0°C	2.5	2.0

Table 10. Proportion of Participants Reporting Solicited Adverse Reactions Following Second Vaccination with ProQuad, by the Intramuscular or Subcutaneous Route

	INTRAMUSCULAR N=201%	SUBCUTANEOUS N=200%
N=total number of participants in the group
* Post-dose 2 (0-28 days), there was only 1 episode of an injection-site measle-like rash and this was reported in the subcutaneous group. † Intensity of injection site reaction: mild or ≤2.5 cm; moderate or >2.5 to ≤5.0 cm; severe or >5.0 cm. ‡ Intensity of pain: mild: awareness of symptom but easily tolerated; moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities. § The percentage of fever is defined within the population who had valid temperature measurements. Five participants in IM group and five participants in SC group did not have temperature measurements and were excluded from the denominator; resulting in N=196 and N=195, respectively. ¶ In the IM Group 95.9% of fevers were documented using the rectal route of measurement and 4.1% of fevers were documented only by the axillary route of measurement. In the SC Group 98.9% of fevers were documented using the rectal route of measurement and 1.1% of fevers were documented only by the axillary route of measurement.
Solicited local injection-site adverse reactions (Days 0 to 4)*
Erythema †	15.4	27.0
Mild	13.9	22.5
Moderate	1.0	4.5
Severe	0	0
Missing	0.5	0
Pain ‡	10.0	10.0
Mild	9.0	7.0
Moderate	0.5	3.0
Severe	0.5	0
Swelling †	6.0	12.5
Mild	5.0	11.0
Moderate	1.0	1.0
Severe	0	0
Missing	0	0.5% (1/200)
Solicited systemic adverse reactions (Days 0 to 28)
Measles-like rash	0	1.0
Rubella-like rash	2.0	1.0
Varicella-like rash	0	2.0
Zoster-like rash	0	0
Mumps-like illness	0.5	0
Fever (temperature ≥38.0°C)§, ¶	50.0	47.2
38.0-38.5°C	13.8	16.4
>38.5-39.0°C	18.4	10.8
>39.0-39.5°C	11.2	11.3
>39.5-40.0°C	5.6	7.2
>40.0°C	1.0	1.5

Unsolicited adverse events (0-28 days post-vaccination 1 and 2) and serious adverse events (day 0 to last visit) were recorded using diary cards supplemented by medical review. Data on unsolicited adverse events were transcribed into the study database during an on-site visit at day 30 and day 42. Serious adverse events occurred at a rate of 1% and 0.5% in each group post-dose 1 and 2, respectively. None of the serious adverse events that occurred were considered related to the study vaccination.

Herpes Zoster

ProQuad and VARIVAX each contain the Oka/Merck varicella virus vaccine strain. Clinical trial data with VARIVAX are therefore, relevant to ProQuad. 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 VARIVAX 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. All 9 cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type VZV as confirmed by restriction endonuclease analysis {11}. The long-term effect of VARIVAX on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type varicella, is unknown at present.

In children, the reported rate of herpes zoster in VARIVAX recipients appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella {12}. The incidence of herpes zoster in adults who have had wild-type varicella infection is higher than that in children.