Menveo Dailymed

6 Adverse Reactions

• •Common solicited adverse reactions (≥10%) among children initiating vaccination at 2 months of age and receiving the 4-dose series were tenderness (24% to 41%) and erythema at injection site (11% to 15%), irritability (42% to 57%), sleepiness (29% to 50%), persistent crying (21% to 41%), change in eating habits (17% to 23%), vomiting (5% to 11%), and diarrhea (8% to 16%). (6.1)
• •Common solicited adverse reactions (≥10%) among children initiating vaccination at 7 months through 23 months of age and receiving the 2-dose series were tenderness (10% to 16%) and erythema at injection site (12% to 15%), irritability (27% to 40%), sleepiness (17% to 29%), persistent crying (12-21%), change in eating habits (12% to 20%), and diarrhea (10% to 16%). (6.1)
• •Common solicited adverse reactions (≥10%) among children aged 2 through 10 years who received MENVEO were injection site pain (31%), erythema (23%), irritability (18%), induration (16%), sleepiness (14%), malaise (12%), and headache (11%). (6.1)
• •Common solicited adverse reactions (≥10%) among adolescents and adults who received a single dose of MENVEO were pain at the injection site (41%), headache (30%), myalgia (18%), malaise (16%), and nausea (10%). Similar rates of solicited adverse reactions were observed following a single booster dose. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Overall, in clinical studies, 36,146 individuals 2 months through 55 years of age were administered at least one dose of MENVEO supplied in the two-vial presentation and 1,337 individuals 10 through 44 years of age were administered one dose of MENVEO supplied in the one-vial presentation. The safety data for the two-vial presentation are relevant to the safety of the one-vial presentation because each presentation contains the same meningococcal conjugated oligosaccharides. [See Description (11).]

Primary Vaccination Studies

Children Aged 2 through 23 Months: The safety of MENVEO in infants vaccinated at 2, 4, 6, and 12 months of age was evaluated in 3 randomized multicenter clinical studies (NCT00474526, NCT00806195, NCT01000311) conducted in the U.S., Australia, Canada, Taiwan, and several countries of Latin America in which 8,735 infants received at least 1 dose of MENVEO and routine infant vaccines (diphtheria toxoid; acellular pertussis; tetanus toxoid [DTaP]; inactivated polio types 1, 2, and 3 [IPV]; hepatitis B; Haemophilus influenzae type b (Hib) antigens; pentavalent rotavirus; and 7-valent pneumococcal conjugate [PCV7]). With Dose 4 of MENVEO, toddlers received concomitantly the following vaccines: 7-valent pneumococcal conjugate; measles, mumps, rubella, and varicella (MMRV); and inactivated hepatitis A. A total of 2,864 infants in these studies received the routine infant/toddler vaccines only. The infants who received MENVEO were Caucasian (33%), Hispanic (44%), African American (8%), Asian (8%), and other racial/ethnic groups (7%); 51% were male, with a mean age of 65.1 days (Standard Deviation [SD]: 7.5 days) at the time of first vaccination.

Safety data for administration of 2 doses of MENVEO in children aged 6 through 23 months are available from 3 randomized studies (NCT00474526, NCT00310856, NCT00626327) conducted in the U.S., Latin America, and Canada, of which one U.S. study specifically addressed the safety of MENVEO administered concomitantly with MMRV vaccine. The 1,985 older infants and toddlers who received 2 doses of MENVEO were Caucasian (49%), Hispanic (32%), African American (11%), and other racial/ethnic groups (8%), 51% male, with a mean age of 10.1 months (SD: 2.0 months).

Children Aged 2 through 10 Years: The safety of MENVEO in children aged 2 through 10 years was evaluated in 4 clinical trials (NCT00310817, NCT00262028, NCT00329849, NCT00616421) conducted in North America (66%), Latin America (28%), and Europe (6%) in which 3,181 subjects received MENVEO and 2,116 subjects received comparator vaccines (either Meningococcal Polysaccharide Vaccine, Groups A, C, Y, and W-135 Combined - MENOMUNE, Sanofi Pasteur [n = 861], or Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine - MENACTRA, Sanofi Pasteur [n = 1,255]). The subjects aged 2 through 10 years who received MENVEO were Caucasian (69%), Hispanic (13%), African American (7%), and other racial/ethnic groups (6%), 51% male, with a mean age of 5.2 years. The safety of a second dose of MENVEO administered 2 months following a first dose was studied in 351 children aged 2 through 5 years.

Adolescents and Adults: The safety of MENVEO in individuals aged 11 through 55 years was evaluated in 5 randomized controlled clinical trials (NCT01018732, NCT00329901, NCT00450437, NCT00474487, NCT00518180) in which 6,185 participants received MENVEO alone (5,286 participants), MENVEO concomitant with other vaccine(s) (899 participants), or a U.S.-licensed comparator vaccine (1,966 participants). In the concomitant trials (NCT00329901, NCT00518180) MENVEO was given with vaccines containing: tetanus toxoid, diphtheria toxoid, and pertussis (Tdap), or Tdap with human papillomavirus (HPV). The comparator vaccine was either MENOMUNE (209 participants) or MENACTRA (1,757 participants). The trials were conducted in North America (46%), Latin America (41%), and Europe (13%). In 2 of the studies, subjects received concomitant vaccination with Tdap or with Tdap plus HPV. Overall, in these studies, subjects were Caucasian (50%), followed by Hispanic (40%), African American (7%), and other racial/ethnic groups (3%). Among recipients of MENVEO, 61%, 17%, and 22% were in the 11- through 18-year, 19- through 34-year, and 35- through 55-year age groups, respectively, with a mean age of 23.5 years (SD: 12.9 years). Among recipients of MENACTRA, 31%, 32%, and 37% were in the 11- through 18-year, 19- through 34-year, and 35- through 55-year age groups, respectively, with a mean age of 29.2 years (SD: 13.4 years). Among MENOMUNE recipients, 100% were in the 11- through 18-year age group, and the mean age was 14.2 years (SD: 1.8 years).

The safety of MENVEO one-vial presentation was evaluated in 2 randomized clinical trials (NCT03652610, NCT03433482). In these studies, 1,337 subjects aged 10 through 44 years were administered a single dose of MENVEO supplied in the one‑vial presentation and contributed to study analyses and 1,332 subjects 10 through 40 years of age were administered MENVEO supplied in the two-vial presentation. The studies were conducted in Australia, Belgium, Canada, Germany, and Italy (NCT03652610), and in Brazil, Estonia, Finland, France, Mexico, Russian Federation, South Africa, Spain, and Turkey (NCT03433482). Overall, in these studies, subjects were White (80.8%), followed by Hispanic or Latino ethnicity (12.8%), other racial groups (11.4%), African American (4.3%), Asian (3.0%), American Indian or Alaskan Native (0.3%), and Native Hawaiian or other Pacific Islander (0.1%). Overall, 25.6% of individuals were aged 10 through 17 years, and 74.4% were aged 18 through 44 years.

Booster Vaccination Study

In a multicenter, open-label trial (NCT02986854) conducted in the U.S., 601 subjects aged 15 to 51 years received a single booster dose of MENVEO 4 to 6 years after prior vaccination with MENVEO (n = 301; median age: 16 years) or MENACTRA (n = 300; median age: 16 years). Across booster groups of MENVEO, 81% of subjects were White and 50% were female.

In most trials, solicited local and systemic adverse reactions were monitored daily for 7 days following each (one or more) vaccination and recorded on a diary card. Participants were monitored for unsolicited adverse events which included adverse events requiring a physician visit or Emergency Department visit (i.e., medically-attended) or which led to a subject’s withdrawal from the study. Among children, adolescents, and adults aged 2 to 55 years, medically significant adverse events and serious adverse events (SAEs) were monitored for 6 months after vaccination. Across the studies of infants and toddlers aged 2 through 23 months, either all medically-attended or all medically-significant adverse events were collected in the period between the infant dose(s) and the toddler doses and during the 6-month period after the toddler dose.

Solicited Adverse Reactions in the Primary Vaccination Studies

The reported frequencies of solicited local and systemic adverse reactions from U.S. infants in the largest multinational safety study of MENVEO (NCT00806195) are presented in Table 2. Among the U.S. participants in the group receiving MENVEO with routine vaccines, 51% were female; 64% were Caucasian, 12% were African American, 15% were Hispanic, 2% were Asian, and 7% were of other racial/ethnic groups.

In infants initiating vaccination at 2 months of age and receiving the 4-dose series, common solicited adverse reactions (>10%) were tenderness (24% to 41%) and erythema at injection site (11% to 15%), irritability (42% to 57%), sleepiness (29% to 50%), persistent crying (21% to 41%), change in eating habits (17% to 23%), vomiting (5% to 11%), and diarrhea (8% to 16%). The rates of solicited adverse reactions reported for subjects aged 2 months and older receiving MENVEO with routine vaccines at 2, 4, 6, and 12 months of age were comparable to rates among subjects who only received routine vaccines.

Table 2. Rates of Solicited Adverse Reactions Reported in U.S. Infants, Aged 2 Months and Older, during the 7 Days following Each Vaccination of MENVEO Administered with Routine Infant/Toddler Vaccines, or Routine Infant/Toddler Vaccines Alone at 2, 4, 6, and 12 Months of Age^a

Adverse Reactions	Dose 1		Dose 2		Dose 3		Dose 4
	MENVEO with Routineb %	Routine Vaccinesb %	MENVEO with Routineb %	Routine Vaccinesb %	MENVEO with Routineb %	Routine Vaccinesb %	MENVEO with Routineb %	Routine Vaccinesb %
Clinicaltrials.gov Identifier NCT00806195.n = Number of subjects who completed the diary card for a given symptom at the specified vaccination. a As-Treated Safety Subpopulation = U.S. children who received at least 1 dose of study vaccine and whose diary cards were completed per protocol and returned to the site. b Routine infant/toddler vaccines include DTaP-IPV-Hib and PCV7 at Doses 1, 2, 3, and PCV7, MMRV, and Hepatitis A vaccines at Dose 4. HBV and rotavirus vaccines were allowed according to Advisory Committee on Immunization Practices (ACIP) recommendations. c Local reactogenicity of MENVEO and PCV7 was assessed. d Tenderness, severe = Cried when injected limb moved. e Irritability, severe = Unable to console. f Sleepiness, severe = Sleeps most of the time, hard to arouse. g Change in eating habits, severe = Missed >2 feeds. h Vomiting, severe = Little/no intake for more prolonged time. i Diarrhea, severe = ≥6 liquid stools, no solid consistency. j Rash was assessed only as present or not present, without a grading for severity. k Axillary temperature.
Local Adverse Reactionsc	n = 1,250-1,252	n = 428	n = 1,205-1,207	n = 399	n = 1,056-1,058	n = 351-352	n = 1,054-1,055	n = 334-337
Tenderness, any	41	45	31	36	24	32	29	39
Tenderness, severed	3	5	2	2	1	3	1	1
Erythema, any	11	14	12	21	14	23	15	25
Erythema, >50 mm	<1	<1	0	0	0	0	0	0
Induration, any	8	16	9	17	8	19	8	21
Induration, >50 mm	0	<1	0	0	0	0	0	0
Systemic Adverse Reactions	n = 1,246-1,251	n = 427-428	n = 1,119-1,202	n = 396-398	n = 1,050-1,057	n = 349-350	n = 1,054-1,056	n = 333-337
Irritability, any	57	59	48	46	42	38	43	42
Irritability, severee	2	2	1	3	1	1	2	1
Sleepiness, any	50	50	37	36	30	30	29	27
Sleepiness, severef	2	1	1	1	<1	<1	1	0
Persistent crying, any	41	38	28	24	22	17	21	18
Persistent crying, ≥3 hours	2	2	2	2	1	1	1	1
Change in eating habits, any	23	24	18	17	17	13	19	16
Change in eating habits, severeg	1	1	1	1	1	<1	1	0
Vomiting, any	11	9	7	6	6	4	5	4
Vomiting, severeh	<1	0	<1	0	<1	0	<1	0
Diarrhea, any	16	11	11	8	8	6	13	9
Diarrhea, severei	<1	<1	<1	<1	1	<1	1	1
Rashj	3	3	3	4	3	3	4	3
Fever ≥38.0°Ck	3	2	4	6	7	6	9	7
Fever 38.0-38.9°C	3	2	4	5	7	6	6	5
Fever 39.0-39.9°C	0	0	1	1	<1	0	2	2
Fever ≥40.0°C	0	<1	0	<1	0	0	<1	0

The safety of a second dose of MENVEO administered at 12 months of age concomitantly with MMRV was investigated in a randomized, controlled, multicenter study (NCT00626327) conducted in the U.S. The rates of solicited adverse reactions reported were comparable between the concomitantly administered group (MENVEO with MMRV) and the group which received MMRV alone or MENVEO alone. The frequency and severity of solicited local and systemic reactions occurring within 7 days following vaccination at 12 months of age are shown in Table 3. In subjects who received both MENVEO and MMRV at 12 months of age local reactions at both injection sites were evaluated separately. Body temperature measurements were collected for 28 days following the 12-months-of-age visit, when MMRV was administered to the vaccinees. Common solicited adverse reactions (≥10%) among children initiating vaccination at 7 months through 23 months of age and receiving the 2-dose series were tenderness (10% to 16%) and erythema at injection site (12% to 15%), irritability (27% to 40%), sleepiness (17% to 29%), persistent crying (12% to 21%), change in eating habits (12% to 20%), and diarrhea (10% to 16%). An examination of the fever profile during this period showed that MENVEO administered with MMRV did not increase the frequency or intensity of fever above that observed for the MMRV-only group.

Table 3. Rates of Solicited Adverse Reactions Reported in U.S. Toddlers during the 7 Days following Vaccination with MENVEO Administered at 7-9 Months and 12 Months of Age, MENVEO Administered Alone at 7-9 Months and with MMRV at 12 Months of Age, and MMRV Administered Alone at 12 Months of Age^a

Adverse Reactions	MENVEO		MENVEO + MMRV		MMRV
	MENVEO 7-9 Months %	MENVEO 12 Months %	MENVEO 7-9 Months %	MENVEO with MMRV 12 Months %	MMRV 12 Months %
Clinicaltrials.gov Identifier NCT00626327.MMRV = Measles, mumps, rubella, and varicella; n = Number of subjects who completed the diary card for a given symptom at the specified vaccination. a As-Treated Safety Subpopulation = U.S. children who received at least 1 dose of study vaccine and whose diary cards were completed per protocol and returned to the site. b Tenderness, severe = Cried when injected limb moved. c Irritability, severe = Unable to console. d Sleepiness, severe = Sleeps most of the time, hard to arouse. e Change in eating habits, severe = Missed >2 feeds. f Vomiting, severe = Little/no intake for more prolonged time. g Diarrhea, severe = ≥6 liquid stools, no solid consistency. h Rash was assessed only as present or not present, without a grading for severity. i Axillary temperature.
Local Adverse Reactions– MENVEO	n = 460-462	n = 381-384	n = 430-434	n = 386-387
Tenderness, any	11	10	11	16	N/A
Tenderness, severeb	<1	<1	<1	0	N/A
Erythema, any	15	13	13	12	N/A
Erythema, >50 mm	<1	<1	0	1	N/A
Induration, any	8	8	7	8	N/A
Induration, >50 mm	<1	<1	0	1	N/A
Local Adverse Reactions– MMRV				n = 382-383	n = 518-520
Tenderness, any	N/A	N/A	N/A	16	19
Tenderness, severeb	N/A	N/A	N/A	0	<1
Erythema, any	N/A	N/A	N/A	15	14
Erythema, >50 mm	N/A	N/A	N/A	1	<1
Induration, any	N/A	N/A	N/A	13	8
Induration, >50 mm	N/A	N/A	N/A	<1	0
Systemic Adverse Reactions	n = 461-463	n = 385-386	n = 430-434	n = 387-389	n = 522-524
Irritability, any	40	27	37	37	44
Irritability, severec	2	2	2	1	3
Sleepiness, any	26	17	29	26	32
Sleepiness, severed	2	1	1	1	2
Persistent crying, any	21	12	20	19	20
Persistent crying, ≥3 hours	2	1	1	1	2
Change in eating habits, any	17	12	17	20	20
Change in eating habits, severee	<1	1	1	2	1
Vomiting, any	9	6	9	6	6
Vomiting, severef	<1	<1	<1	<1	<1
Diarrhea, any	16	10	15	15	20
Diarrhea, severeg	2	1	<1	1	2
Rashh	3	5	6	6	8
Fever ≥38.0°Ci	5	5	6	9	7
Fever 38.0-38.9°C	3	3	5	7	7
Fever 39.0-39.9°C	2	2	1	1	1
Fever ≥40.0°C	<1	1	<1	<1	0

In clinical trials of children aged 2 through 10 years (NCT00310817, NCT00262028, NCT00329849, NCT00616421), the most frequently occurring adverse reactions (>10%) among all subjects who received MENVEO were injection site pain (31%), erythema (23%), irritability (18%), induration (16%), sleepiness (14%), malaise (12%), and headache (11%). Among subjects aged 11 through 55 years, the most frequently occurring adverse reactions (>10%) among all subjects who received MENVEO were pain at the injection site (41%), headache (30%), myalgia (18%), malaise (16%), and nausea (10%).

The rates of solicited adverse reactions reported for subjects aged 2 through 5 years and 6 through 10 years who received a single dose of MENVEO or MENACTRA in a randomized, controlled, multicenter study (NCT00616421) conducted in the U.S. and Canada are shown in Table 4. Following a second dose of MENVEO administered to children aged 2 through 5 years, the most common solicited adverse reactions (≥10%) were pain at injection site (28%), erythema (22%), irritability (16%), induration (13%), and sleepiness (12%). The solicited adverse reactions from a separate randomized, controlled, multicenter study conducted in the U.S. in adolescents and adults (NCT00450437) are provided in Tables 5 and 6, respectively. In neither study were concomitant vaccines administered with the study vaccines.

Table 4. Rates of Solicited Adverse Reactions within 7 Days following a Single Vaccination in Children Aged 2 through 5 Years and 6 through 10 Years

Adverse Reactions	Participants Aged 2 through 5 Years
	MENVEO n = 693 %			MENACTRA n = 684 %
	Any	Moderate	Severe	Any	Moderate	Severe
Clinicaltrials.gov Identifier NCT00616421. a Moderate: Some limitation in normal daily activity, Severe: Unable to perform normal daily activity. b Moderate: ≥50-100 mm, Severe: >100 mm. c Different systemic reactions were solicited in different age groups. d Rash was assessed only as present or not present, without a grading for severity. e Fever grading: Any: ≥38°C, Moderate: 39-39.9°C, Severe: ≥40°C. Parents reported the use of antipyretic medication to treat or prevent symptoms in 11% and 13% of subjects aged 2 through 5 years, 9% and 10% of subjects aged 6 through 10 years for MENVEO and MENACTRA, respectively.
Local Adverse Reactions
Injection site paina	33	6	1	35	8	0.4
Erythemab	27	5	1	25	3	0.3
Indurationb	18	2	0.4	18	2	0.3
Systemic Adverse Reactionsc
Irritabilitya	21	6	1	22	7	1
Sleepinessa	16	3	1	18	5	1
Change in eatinga	9	2	1	10	2	0.3
Diarrheaa	7	1	0.1	8	1	0
Headachea	5	1	0	6	1	0.3
Rashd	4	-	-	5	-	-
Arthralgiaa	3	1	0.1	4	1	0
Vomitinga	3	1	0.1	3	1	0
Fevere	2	0.4	0	2	0.3	0
	Participants Aged 6 through 10 Years
Adverse Reactions	MENVEO n = 582 %			MENACTRA n = 571 %
	Any	Moderate	Severe	Any	Moderate	Severe
Local Adverse Reactions
Injection site paina	39	8	1	45	10	2
Erythemab	28	5	1	22	2	0.2
Indurationb	17	2	0.3	13	2	0
Systemic Adverse Reactionsc
Headachea	18	3	1	13	2	1
Malaisea	14	3	1	11	3	1
Myalgiaa	10	2	1	10	2	1
Nauseaa	8	2	1	6	2	0.4
Arthralgiaa	6	1	0	4	1	0.4
Chillsa	5	1	0	5	1	0.4
Rashd	5	-	-	3	-	-
Fevere	2	1	0	2	0	0.4

Table 5. Rates of Solicited Adverse Reactions within 7 Days following Vaccination in Individuals Aged 11 through 18 Years

Adverse Reactions	MENVEO n = 1,631 %			MENACTRA n = 539 %
	Any	Moderate	Severe	Any	Moderate	Severe
Clinicaltrials.gov Identifier NCT00450437. a Moderate: Some limitation in normal daily activity, Severe: Unable to perform normal daily activity. b Moderate: ≥50-100 mm, Severe: >100 mm. c Rash was assessed only as present or not present, without a grading for severity. d Fever grading: Any: ≥38°C, Moderate: 39-39.9°C, Severe: ≥40°C.
Local Adverse Reactions
Injection site paina	44	9	1	53	11	1
Erythemab	15	2	0.4	16	1	0
Indurationb	12	2	0.2	11	1	0
Systemic Adverse Reactions
Headachea	29	8	2	28	7	1
Myalgiaa	19	4	1	18	5	0.4
Nauseaa	12	3	1	9	2	1
Malaisea	11	3	1	12	5	1
Chillsa	8	2	1	7	1	0.2
Arthralgiaa	8	2	0.4	6	1	0
Rashc	3	-	-	3	-	-
Feverd	1	0.4	0	1	0	0

Table 6. Rates of Solicited Adverse Reactions within 7 Days following Vaccination in Individuals Aged 19 through 55 Years

Adverse Reactions	MENVEO n = 1,018 %			MENACTRA n = 336 %
	Any	Moderate	Severe	Any	Moderate	Severe
Clinicaltrials.gov Identifier NCT00450437. a Moderate: Some limitation in normal daily activity, Severe: Unable to perform normal daily activity. b Moderate: ≥50-100 mm, Severe: >100 mm. c Rash was assessed only as present or not present, without a grading for severity. d Fever grading: Any: ≥38°C, Moderate: 39-39.9°C, Severe: ≥40°C.
Local Adverse Reactions
Injection site paina	38	7	0.3	41	6	0
Erythemab	16	2	1	12	1	0
Indurationb	13	1	0.4	9	0.3	0
Systemic Adverse Reactions
Headachea	25	7	2	25	7	1
Myalgiaa	14	4	0.5	15	3	1
Malaisea	10	3	1	10	2	1
Nauseaa	7	2	0.4	5	1	0.3
Arthralgiaa	6	2	0.4	6	1	1
Chillsa	4	1	0.1	4	1	0
Rashc	2	-	-	1	-	-
Feverd	1	0.3	0	1	0.3	0

In studies NCT03652610 and NCT03433482, there were no notable differences in frequency and severity of solicited adverse reactions within 7 days following vaccination in individuals who received the one-vial presentation compared to individuals who received the two-vial presentation.

Solicited Adverse Reactions in the Booster Vaccination Study (Adolescents and Adults)

A multicenter, open-label clinical trial (NCT02986854) was conducted in the U.S. in subjects aged 15 through 55 years [see Clinical Studies (14.1)]. The methodology for evaluating solicited adverse reactions, unsolicited adverse events, and SAEs after a booster dose of MENVEO was similar to the primary vaccination studies. The most common solicited local and systemic adverse reactions within 7 days of vaccination were pain at injection site (36%) and fatigue (38%), respectively.

Solicited Adverse Reactions following Concomitant Vaccine Administration

The safety of 4-dose series of MENVEO administered concomitantly with U.S.-licensed routine infant and toddler vaccines was evaluated in one pivotal trial (NCT00806195). The safety of a 2-dose series of MENVEO initiated at 7-9 months of age, with the second dose administered concomitantly with U.S.-licensed MMRV vaccine at 12 months of age, was evaluated in one pivotal trial (NCT00626327). Rates of solicited adverse reactions which occurred 7 days following vaccination are shown in Tables 2 and 3, respectively. There was no significant increase in the rates of solicited systemic or local reactions observed in recipients of routine childhood vaccines when concomitantly vaccinated with MENVEO. [See Drug Interactions (7.1).]

The safety of MENVEO administered concomitantly with Tdap and HPV was evaluated in a single-center study (NCT00518180) conducted in Costa Rica. Solicited local and systemic adverse reactions were reported as noted above. In this study, subjects aged 11 through 18 years received MENVEO concomitantly with Tdap and HPV (n = 540), or MENVEO followed 1 month later by Tdap and then 1 month later by HPV (n = 541), or Tdap followed 1 month later by MENVEO and then 1 month later by HPV (n = 539). Some solicited systemic adverse reactions were more frequently reported in the group that received MENVEO, Tdap, and HPV concomitantly, (headache 40%, malaise 25%, myalgia 27%, and arthralgia 17%) compared with the group that first received MENVEO alone (headache 36%, malaise 20%, myalgia 19%, and arthralgia 11%). Among subjects administered MENVEO alone (1 month prior to Tdap), 36% reported headache, 20% malaise, and 16% myalgia. Among subjects administered MENVEO 1 month after Tdap, 27% reported headache, 18% malaise, and 16% myalgia.

Serious Adverse Events in All Safety Studies

SAEs in subjects receiving a 4-dose series of MENVEO at 2, 4, 6, and 12 months were evaluated in 3 randomized, multicenter clinical studies (NCT00474526, NCT00806195, NCT01000311). In the 2 controlled studies (NCT00806195, NCT01000311), the proportions of infants randomized to receive the 4-dose series of MENVEO concomitantly with routine vaccinations and infants who received routine vaccinations alone that reported SAEs during different study periods were, respectively: a) 2.7% and 2.2% during the infant series, b) 2.5% and 2.5% between the infant series and the toddler dose, c) 0.3% and 0.3% in the 1 month following the toddler dose, and d) 1.6% and 2.2% during the 6-month follow-up period after the last dose. In the third study (NCT00474526), which was controlled up to the toddler dose, the proportions of infants randomized to dosing regimens that included receiving 4 doses of MENVEO concomitantly with routine vaccinations at 2, 4, 6, and 12 months and infants who received routine vaccinations alone that reported SAEs during different study periods were, respectively: a) 3.5% and 3.6% during the infant series, and b) 2.8% and 3.3% between the infant series and the toddler dose, and c) 0.5% and 0.7% in the 1 month following the toddler dose. In the same study, 1.9% of infants randomized to receive the 4-dose series of MENVEO concomitantly with routine vaccinations reported SAEs during the 6-month follow-up period after the toddler dose. The most common SAEs reported in these 3 studies were wheezing, pneumonia, gastroenteritis, and convulsions, and most occurred at highest frequency after the infant series.

In a study of older infants (NCT00626327) randomized to receive the 2-dose series of MENVEO concomitantly with MMRV at 12 months of age, the rates of SAEs during the study, including the 6-month follow-up period after the last dose, were 3.6% and 3.8% for the groups receiving MENVEO with MMRV and MENVEO only, respectively. Infants receiving MMRV alone, who had a shorter period of study participation as they were enrolled at 12 months of age, had a lower rate of SAEs (1.5%). Among 1,597 study subjects included in the safety population, the most commonly reported SAEs in all study arms combined were dehydration (0.4%) and gastroenteritis (0.3%). Across the submitted studies of individuals aged 2 through 23 months within 28 days of vaccination, 2 deaths were reported in the groups receiving MENVEO (one case of sudden death and one case of sepsis), while no deaths were reported in the control group. None of the deaths was assessed as related to vaccination. Among subjects with symptom onset within 42 days of vaccination (Days 12, 25, 29), 3/12,049 (0.02%, 95% CI: [0.01%, 0.07%]) recipients of MENVEO and 0/2,877 (0%, 95% CI: [0%, 0.13%]) control recipients were diagnosed with Kawasaki Disease. One case of acute disseminated encephalomyelitis with symptom onset 29 days post Dose 4 was observed in a participant given MENVEO coadministered with routine U.S. childhood vaccines at 12 months of age (including measles, mumps, and rubella vaccine [MMR] and varicella vaccine).

The information regarding SAEs in subjects aged 2 through 10 years was derived from 3 randomized, controlled clinical trials (NCT00262028, NCT00329849, NCT00616421). Safety follow-up ranged from 6 through 12 months and included 2,883 subjects administered MENVEO. SAEs reported during the safety follow-up periods occurred in 21/2,883 (0.7%) subjects receiving MENVEO, in 7/1,255 (0.6%) MENACTRA subjects, and 2/861 (0.2%) MENOMUNE subjects. In the subjects receiving either 1 or 2 doses of MENVEO, there were 6 subjects with pneumonia, 3 subjects with appendicitis, and 2 subjects with dehydration; all other events were reported to occur in one subject. Among 1,255 subjects administered a single dose of MENACTRA and 861 subjects administered MENOMUNE, there were no events reported to occur in more than 1 subject. The SAEs occurring within the first 30 days after receipt of each vaccine were as follows: MENVEO (6/2,883 [0.2%]) — appendicitis, pneumonia, staphylococcal infection, dehydration, febrile convulsion, and tonic convulsion; MENACTRA (1/1255 [0.1%]) — inguinal hernia; MENOMUNE (2/861 [0.2%]) — abdominal pain, lobar pneumonia. In a supportive study (NCT00310817), 298 subjects received 1 or 2 doses of MENVEO and 22 (7%) had SAEs over a 13-month follow-up period including 13 subjects with varicella and 2 subjects with laryngitis. All other events were reported to occur in 1 subject. During the 30 days post vaccination in this study, 1 limb injury and 1 case of varicella were reported.

The information regarding SAEs in subjects aged 11 through 55 years was derived from 5 randomized, controlled clinical trials (NCT01018732, NCT00329901, NCT00450437, NCT00474487, NCT00518180). SAEs reported within 6 months of vaccination occurred in 40/6,185 (0.6%) subjects receiving MENVEO, 13/1,757 (0.7%) MENACTRA subjects, and 5/209 (2.4%) MENOMUNE subjects. During the 6 months following immunization, SAEs reported by more than 1 subject were as follows: MENVEO - appendicitis (3 subjects), road traffic accident (3 subjects), and suicide attempt (5 subjects); MENACTRA - intervertebral disc protrusion (2 subjects); MENOMUNE - none. SAEs that occurred within 30 days of vaccination were reported by 7 of 6,185 (0.1%) subjects in the group receiving MENVEO, 4 of 1,757 (0.2%) subjects in the MENACTRA group, and by none of 209 subjects in the MENOMUNE group. The events that occurred during the first 30 days post immunization with MENVEO were: vitello-intestinal duct remnant, Cushing’s syndrome, viral hepatitis, pelvic inflammatory disease, intentional multiple-drug overdose, simple partial seizure, and suicidal depression. The events that occurred during the first 30 days post immunization with MENACTRA were: herpes zoster, fall, intervertebral disc protrusion, and angioedema.

In the 2 clinical studies (NCT03652610, NCT03433482) which evaluated the safety of the one-vial presentation of MENVEO, SAEs were reported by 14 subjects (1.0%) who received the one-vial presentation of MENVEO and 14 subjects (1.1%) who received the two-vial presentation of MENVEO within the 6-month follow-up period after vaccination. No deaths were reported. None of the SAEs were related to the study vaccines.

6.2 Postmarketing Experience

In addition to reports in clinical trials, the following adverse reactions have been identified during postapproval use of MENVEO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Blood and Lymphatic System Disorders

Local lymphadenopathy.

Ear and Labyrinth Disorders

Hearing impaired, ear pain, vertigo, vestibular disorder.

Eye Disorders

Eyelid ptosis.

General Disorders and Administration Site Conditions

Injection site pruritus; pain; erythema; inflammation; and swelling, including extensive swelling of the vaccinated limb; fatigue; malaise; pyrexia.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis.

Infections and Infestations

Vaccination site cellulitis.

Injury, Poisoning, and Procedural Complications

Fall, head injury.

Investigation

Alanine aminotransferase increased, body temperature increased.

Musculoskeletal and Connective Tissue Disorders

Arthralgia, bone pain.

Nervous System Disorders

Dizziness, syncope, tonic convulsion, headache, facial paresis, balance disorder.

Respiratory, Thoracic, and Mediastinal Disorders

Oropharyngeal pain.

Skin and Subcutaneous Tissue Disorders

Skin exfoliation.

Postmarketing Observational Safety Study

In a postmarketing observational safety study conducted in a U.S. health maintenance organization, data from electronic health records of 48,899 persons aged 11 through 21 years were used to evaluate pre-specified events of interest following vaccination with MENVEO. Using a self-controlled case series method, Bell’s palsy showed a statistically significant increased risk in the period 1 to 84 days post vaccination compared with the control period, with an overall adjusted relative incidence of 2.9 (95% CI: 1.1-7.5). Among the 8 reported cases of Bell’s palsy, 6 cases occurred in persons who received MENVEO concomitantly with one or more of the following vaccines: Tdap, HPV, and Influenza vaccine. All reported Bell’s palsy cases resolved.