ProQuad: Package Insert and Label Information

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 Corp.

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

2.1 Recommended Dose and Schedule

FOR SUBCUTANEOUS ADMINISTRATION ONLY

Each 0.5-mL dose of ProQuad is administered subcutaneously.

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

If a second dose of measles, mumps, rubella, and varicella vaccine is needed, ProQuad may be used. This dose is usually administered at 4 to 6 years of age. At least 1 month should elapse between a dose of a measles-containing vaccine such as M-M-R® II (measles, mumps, and rubella virus vaccine live) 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

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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. 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.

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 Method of Administration

Inject the vaccine subcutaneously into the outer aspect of the deltoid region of the upper arm or into the higher anterolateral area of the thigh.

Use With Other Vaccines

Use different injection sites to administer each vaccine if other vaccines are administered concomitantly. [See Drug Interactions (7.5).]

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Do not administer ProQuad to individuals with a history of anaphylactic reactions to neomycin. If vaccination with ProQuad is medically necessary for such individuals, they are advised to consult an allergist or immunologist and should receive ProQuad only in settings where anaphylactic reactions can be appropriately managed.

Do not administer ProQuad to individuals with a history of hypersensitivity to gelatin or any other component of the vaccine or following previous vaccination with ProQuad, VARIVAX® (varicella virus vaccine live), or any measles-, mumps-, or rubella-containing vaccine [see Description (11) and Warnings and Precautions (5) for exceptions].

4.2 Immunosuppression

Do not administer ProQuad to individuals with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or to individuals on immunosuppressive therapy (including high-dose systemic corticosteroids) [see Drug Interactions (7.3)]. 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. ProQuad may be used by individuals who are receiving topical corticosteroids or low-dose corticosteroids, as are commonly used for asthma prophylaxis or in patients who are receiving corticosteroids as replacement therapy, e.g. , for Addison’s disease.

Do not administer ProQuad to individuals with primary and acquired immunodeficiency states, including AIDS or other clinical manifestations of infection with human immunodeficiency viruses; cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. Measles inclusion body encephalitis, pneumonitis, and death as a direct consequence of disseminated measles vaccine virus infection have been reported in severely immunocompromised individuals inadvertently vaccinated with measles-containing vaccine. In addition, disseminated varicella vaccine virus infection has been reported in children with underlying immunodeficiency disorders who were inadvertently vaccinated with a varicella-containing vaccine {1}.

Do not administer ProQuad to individuals with a family history of congenital or hereditary immunodeficiency, unless the immune competence of the potential vaccine recipient is demonstrated.

4.3 Concurrent Illness

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

4.4 Pregnancy

Do not administer ProQuad to individuals who are pregnant because the effects of the vaccine on fetal development are unknown. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for three months following administration of ProQuad [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 dose 1 of both M-M-R II and VARIVAX administered separately [see Adverse Reactions (6.3)].

5.2 History of Cerebral Injury or Seizures

Exercise caution when 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. Healthcare providers should be alert to the temperature elevations that may occur following vaccination.

5.3 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. Carefully evaluate the potential risk-to-benefit ratio 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 Contraindications (4.1)] {2}.

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 {2}.

5.4 Contact 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.

5.5 Thrombocytopenia

Carefully evaluate the potential risk-to-benefit ratio before considering vaccination with ProQuad in children with thrombocytopenia or in those who experienced thrombocytopenia after vaccination with a previous dose of measles, mumps, rubella, and/or varicella vaccine. No clinical data are available regarding the development or worsening of thrombocytopenia in individuals vaccinated with ProQuad. Cases of thrombocytopenia have been reported after primary vaccination with measles vaccine; measles, mumps, and rubella vaccine; after varicella vaccination; and following re-vaccination with measles vaccine or M-M-R II [see Adverse Reactions (6.2)].

5.6 Use for Post-Exposure Prophylaxis

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

5.7 Use in HIV-Infected Children

The safety and efficacy of ProQuad for use in children known to be infected with human immunodeficiency viruses have not been established.

5.8 Risk of Vaccine Virus Transmission

Post-licensing experience with VARIVAX suggests that transmission of varicella vaccine virus may occur between healthy vaccine recipients (who develop or do not 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:

  • 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.

5.9 Immune Globulins and Transfusions

Immune globulins (IG) administered concomitantly with ProQuad contain antibodies that may interfere with vaccine virus replication and decrease the expected immune response. Vaccination should be deferred for at least 3 months following blood or plasma transfusions, or administration of 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]) {2}. Following administration of ProQuad, any IG including VZIG should not be given for 1 month thereafter unless its use outweighs the benefits of vaccination {2}. [See Drug Interactions (7.1).]

5.10 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 aspirin 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 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 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 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 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 (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 (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 with VAQTA and pneumococcal 7-valent conjugate vaccine concomitantly (N=330) or a first dose of ProQuad 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
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