PROQUAD SIDE EFFECTS

Last updated on MDtodate: 10/10/2022

SIDE EFFECTS

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)

Adverse Reactions	ProQuad (N=4497) (n=4424) %	M-M-R II and VARIVAX (N=2038) (n=1997) %
Injection Site*
Pain/tenderness/soreness†	22	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	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
* 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. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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. 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).

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)

Adverse Reactions	Pro Quad Dose 1 (N=3112) (n=3019) %	Pro Quad Dose2 (N=2780) (n=2695) %
Injection-Site
Pain/tenderness/soreness*	21.4	15.9
Erythema*	10.7	12.4
Swelling*	8	8.5
Injection-site bruising	1.1	0
Systemic
Fever*†	20.4	8.3
Irritability	6	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
* Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination. † Temperature reported as elevated or abnormal. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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. 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.

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)  %
Systemic
Fever*†	2.5		2		4.1
Cough	1.3		0.5		0.5
Irritability	1		0.5		1
Headache	0.8		1.5		1.6
Rhinorrhea	0.5		1		0.5
Nasopharyngitis	0.3		1		1
Vomiting	0.3		1		0.5
Upper respiratory infection	0		0		1
	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	0.5	0
Pruritus	1	0.3	0	0	0	1
Nodule	0	0	0	0	0	1
* 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. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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. 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.

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) %
Injection-Site – ProQuad
Pain†	24.9	N/A	24.7
Erythema†	12.4	N/A	11
Swelling†	10.8	N/A	7.5
Bruising	2	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	N/A
Bruising	1.6	1.2	N/A
Systemic
Fever†‡	15.5	10	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	1.2
Diarrhea	0.8	1.2	1.2
Vomiting	0.6	0.8	1.2
Rash	0.4	0	1.2
Somnolence	0	0	1.2
* 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. N/A = Not applicable. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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

Adverse Reactions	Dose 1		Dose 2
	VAQTA (N=1453) (n=1412) %	ProQuad +VAQTA (N=347) (n=328)  %	VAQTA (N=1301) (n=1254) %	Pro Quad + VAQTA (N=292) (n=264) %
Injection-Site – VAQTA
Pain/tenderness*	29.2	27.1	30.1	25
Erythema*	13.5	12.5	14.3	11.7
Swelling*	7.1	9.1	9	8
Injection-site bruising	1.9	2.4	1	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
* Designates a solicited adverse reaction. Injection-site adverse reactions were solicited only from Days 1 to 5 postvaccination. N/A = Not applicable. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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) %
Fever‡,§	5.7	14.9	15.2	4.1	8	8.4
Irritability	5.8	7	7.3	3.5	5.3	5.3
Measles-like rash	0	3.4	3.4	0	1.1	1.1
Rhinorrhea	0.6	2.7	3	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
* 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. 10 ‡ Designates a solicited adverse reaction. § Temperature reported as elevated or abnormal. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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.

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)  %
Injection-Site – ProQuad
Pain/tenderness†	21.2	24.2	18.1	17
Erythema†	13.5	11.9	10.6	13
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	0.4	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
* 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. N/A = Not applicable. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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)  %
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
Varicella-like rash†	1	1.7	0	0
Rash (not otherwise specified)	1.3	1.3	0	0.9
Diarrhea	1.3	1.3	0.4	1.3
Upper respiratory infection	1	1.3	1.1	0.9
Viral infection	1	0.7	0	0
Rhinorrhea	0	0.7	1.1	0
* PCV7 = Pneumococcal 7-valent conjugate vaccine. † Designates a solicited adverse reaction. ‡ Temperature reported as elevated or abnormal. N = number of subjects vaccinated. n = number of subjects with safety follow-up.

 

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

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 in some cases described in the literature or reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Post-Marketing Reports

Adverse events reported with post-marketing use of ProQuad and/or in clinical studies and/or post-marketing use of M-M-R II, the component vaccines, and VARIVAX without regard to causality or frequency are summarized below.

Infections And Infestations

Atypical measles, candidiasis, cellulitis, herpes zoster, infection, influenza, measles, orchitis, parotitis, respiratory infection, skin infection, varicella (vaccine strain).

Blood And The Lymphatic System Disorders

Aplastic anemia, lymphadenitis, regional lymphadenopathy, thrombocytopenia.

Immune System Disorders

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

Psychiatric Disorders

Agitation, apathy, nervousness.

Nervous System Disorders

Acute disseminated encephalomyelitis (ADEM), afebrile convulsions or seizures, aseptic meningitis, ataxia, Bell’s palsy, cerebrovascular accident, convulsion, dizziness, dream abnormality, encephalitis, encephalopathy, febrile seizure, Guillain-Barré syndrome, headache, hypersomnia, measles inclusion body encephalitis, ocular palsies, paraesthesia, polyneuritis, polyneuropathy, subacute sclerosing panencephalitis, syncope, transverse myelitis, tremor.

Eye Disorders

Edema of the eyelid, irritation, necrotizing retinitis (in immunocompromised individuals), optic neuritis, retinitis, retrobulbar neuritis.

Ear And Labyrinth Disorders

Ear pain, nerve deafness.

Vascular Disorders

Extravasation.

Respiratory, Thoracic And Mediastinal Disorders

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

Gastrointestinal Disorders

Abdominal pain, flatulence, hematochezia, mouth ulcer.

Skin And Subcutaneous Tissue Disorders

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

Musculoskeletal, Connective Tissue And Bone Disorders

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

Reproductive System And Breast Disorders

Epididymitis.

General Disorders And Administration Site Conditions

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

Deaths have been reported following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals. Death as a direct consequence of disseminated measles vaccine virus infection has been reported in severely immunocompromised individuals in whom a measles-containing vaccine is contraindicated and who were inadvertently vaccinated. However, there were no deaths or permanent sequelae reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982 to 1993³.

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

Recipients of rubella vaccine may develop chronic joint symptoms. Arthralgia and/or arthritis, and polyneuritis after wild-type rubella virus infection vary in frequency and severity with age and gender, being greatest in adult females and least in pre-pubertal children. Following vaccination in children, reactions in joints are uncommon (0 to 3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are higher than those seen in children (12 to 26%), and the reactions tend to be more marked and of longer duration (e.g., months or years). In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and adult women.

Chronic arthritis has been associated with wild-type rubella infection and has been related to persistent virus and/or viral antigen isolated from body tissues. Chronic joint symptoms have been reported following administration of rubella-containing vaccine.

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

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

Cases of thrombocytopenia have been reported after use of measles vaccine; measles, mumps, and rubella vaccine; and after varicella vaccination. Post-marketing experience with live measles, mumps, and rubella vaccine indicates that individuals with current thrombocytopenia may develop more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia following the first dose of a live measles, mumps, and rubella vaccine may develop thrombocytopenia with repeat doses. Serologic testing for antibody to measles, mumps, or rubella should be considered in order to determine if additional doses of vaccine are needed.

The reported rate of zoster in recipients of VARIVAX appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella⁴. In clinical trials, 8 cases of herpes zoster were reported in 9454 vaccinated individuals 12 months to 12 years of age during 42,556 person-years of follow-up. This resulted in a calculated incidence of at least 18.8 cases per 100,000 person-years. All 8 cases reported after VARIVAX were mild and no sequelae were reported. The long-term effect of VARIVAX on the incidence of herpes zoster is unknown at present.

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 9. 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.

Table 9: Confirmed Febrile Seizures Days 5 to 12 and 0 to 30 After Vaccination with ProQuad (dose 1) Compared to Concomitant Vaccination with M-M-R II and VARIVAX (dose 1) in Children 12 to 60 Months of Age

Time Period	ProQuad cohort (N=31,298)		MMR+V cohort (N=31,298)		Relative risk (95% CI)
	n	Incidence per 1000	n	Incidence per 1000
5 to 12 Days	22	0.7	10	0.32	2.20 (1.04, 4.65)
0 to 30 Days	44	1.41	40	1.28	1.10 (0.72, 1.69)

 

In this observational post-marketing study, no case of febrile seizure was observed during the 5 to 12 day post-vaccination 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.