Menveo: Package Insert and Label Information

MENVEO- meningococcal (groups a, c, y and w-135) oligosaccharide diphtheria crm197 conjugate vaccine
GlaxoSmithKline Biologicals SA

1 INDICATIONS AND USAGE

MENVEO is a vaccine indicated for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135. MENVEO is approved for use in persons 2 months through 55 years of age.

MENVEO does not prevent N. meningitidis serogroup B infections.

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Reconstitution

MENVEO is supplied in 2 vials that must be combined prior to administration. Use the MenCYW-135 liquid conjugate vaccine component (Vial 1) to reconstitute the MenA lyophilized conjugate vaccine component (Vial 2) to form MENVEO. Invert the vial and shake well until the vaccine is dissolved and then withdraw 0.5 mL of reconstituted product. Following reconstitution, the vaccine is a clear, colorless solution, free from visible foreign particles. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If any of these conditions exist, MENVEO should not be administered.

Menveo Figure 1Menveo Figure 2Menveo Figure 3Menveo Figure 4

Figure 1. Cleanse both vial stoppers. Using a sterile needle and sterile graduated syringe, withdraw the entire contents of Vial 1 containing the MenCYW-135 liquid conjugate component while slightly tilting the vial.

Figure 2. Slowly transfer entire contents of the syringe into Vial 2 containing the MenA lyophilized conjugate component (powder).

Figure 3. Invert the vial and shake well until powder is completely dissolved.

Figure 4. After reconstitution, withdraw 0.5 mL from the vial containing the reconstituted vaccine. Administer intramuscularly.

Please note that it is normal for a small amount of liquid to remain in the vial following withdrawal of the dose. Discard unused portion.

2.2 Administration Instructions

For intramuscular injection only.

After reconstitution, administer MENVEO immediately or store between 36°F and 77°F (2°C and 25°C) for up to 8 hours. Shake well before using. Do not freeze. Discard reconstituted vaccine if it has been frozen or not used within 8 hours.

Use a separate sterile needle and sterile syringe for each individual. Each dose of MENVEO should be administered as a single 0.5-mL intramuscular injection, preferably into the anterolateral aspect of the thigh in infants or into the deltoid muscle (upper arm) in toddlers, adolescents, and adults. Do not administer MENVEO intravenously, subcutaneously, or intradermally.

2.3 Dosing Schedule

The dosing schedule for individuals initiating vaccination is as follows:

Infants 2 Months of Age

MENVEO is to be administered as a 4-dose series at 2, 4, 6, and 12 months of age.

Children 7 Months through 23 Months of Age

MENVEO is to be administered as a 2-dose series with the second dose administered in the second year of life and at least 3 months after the first dose.

Children 2 Years through 10 Years of Age

MENVEO is to be administered as a single dose. For children 2 years through 5 years of age at continued high risk of meningococcal disease, a second dose may be administered 2 months after the first dose.

Adolescents and Adults 11 Years through 55 Years of Age

MENVEO is to be administered as a single dose.

3 DOSAGE FORMS AND STRENGTHS

MENVEO is a solution for intramuscular injection supplied as a lyophilized MenA conjugate vaccine component to be reconstituted with the accompanying MenCYW-135 liquid conjugate vaccine component. A single dose, after reconstitution, is 0.5 mL. [See Dosage and Administration (2), How Supplied/Storage and Handling (16).]

4 CONTRAINDICATIONS

Severe allergic reaction (e.g., anaphylaxis) after a previous dose of MENVEO, any component of this vaccine, or any other CRM197 -, diphtheria toxoid-, or meningococcal-containing vaccine is a contraindication to administration of MENVEO. [See Description (11).]

5 WARNINGS AND PRECAUTIONS

5.1 Management of Acute Allergic Reactions

Appropriate medical treatment must be available should an acute allergic reaction, including an anaphylactic reaction, occur following administration of MENVEO.

5.2 Syncope

Syncope, sometimes resulting in falling injury associated with seizure-like movements, has been reported following vaccination with MENVEO. Vaccinees should be observed for at least 15 minutes after vaccine administration to prevent and manage syncopal reactions.

5.3 Altered Immunocompetence

Reduced Immune Response

Some individuals with altered immunocompetence, including some individuals receiving immunosuppressant therapy, may have reduced immune responses to MENVEO.

Complement Deficiency

Persons with certain complement deficiencies and persons receiving treatment that inhibits terminal complement activation (for example, eculizumab) are at increased risk for invasive disease caused by N. meningitidis, including invasive disease caused by serogroups A, C, Y, and W, even if they develop antibodies following vaccination with MENVEO. [See Clinical Pharmacology (12.1).]

5.4 Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) has been reported in temporal relationship following administration of another U.S.-licensed meningococcal quadrivalent polysaccharide conjugate vaccine. The decision to administer MENVEO to subjects with a known history of Guillain-Barré Syndrome should take into account the potential benefits and risks.

5.5 Apnea in Premature Infants

Apnea following intramuscular vaccination has been observed in some infants born prematurely. The decision about when to administer an intramuscular vaccine, including MENVEO, to an infant born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination.

6 ADVERSE REACTIONS

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.

Children 2 Months through 23 Months of Age

The safety of MENVEO in infants vaccinated at 2, 4, 6, and 12 months of age was evaluated in 3 randomized multicenter clinical studies1-3 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; inactivated polio types 1, 2, and 3; hepatitis B; Haemophilus influenzae type b (Hib) antigens; pentavalent rotavirus; and 7-valent pneumococcal conjugate). With Dose 4 of MENVEO, toddlers received concomitantly the following vaccines: 7-valent pneumococcal conjugate; measles, mumps, rubella, and varicella; 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 between 6 through 23 months of age are available from 3 randomized studies1,4,5 conducted in the U.S., Latin America, and Canada, of which one U.S. study specifically addressed the safety of MENVEO administered concomitantly with measles, mumps, rubella, and varicella vaccine (MMRV). 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 2 Years through 10 Years of Age

The safety of MENVEO in children 2 years through 10 years of age was evaluated in 4 clinical trials6-9 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 2 years through 10 years of age 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 2 years through 5 years of age.

Adolescents and Adults

The safety of MENVEO in individuals 11 through 55 years of age was evaluated in 5 randomized controlled clinical trials10-14 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 trials11,14 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, 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).

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 years to 55 years, medically significant adverse events and serious adverse events (SAE) were monitored for 6 months after vaccination. Across the studies of infants and toddlers aged 2 months 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

The reported frequencies of solicited local and systemic adverse reactions from U.S. infants in the largest multinational safety study of MENVEO2 are presented in Table 1. 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 1: Rates of Solicited Adverse Reactions Reported in U.S. Infants, 2 Months of Age and Older, during the 7 Days following Each Vaccination with MENVEO Administered with Routine Infant/Toddler Vaccines, or Routine Infant/Toddler Vaccines Alone at 2, 4, 6, and 12 Months of Agea
Clinicaltrials.gov Identifier NCT00806195.2 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.

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

%

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 study5 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 2. 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 2: 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 Agea
Clinicaltrials.gov Identifier NCT00626327.5 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.

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

%

Local Adverse Reactions– MENVEO Site

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 Site

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 2 years through 10 years of age,6-9 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 11 years through 55 years of age, 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 2 years through 5 years and 6 years through 10 years of age who received a single dose of MENVEO or MENACTRA in a randomized controlled, multicenter study9 conducted in the U.S. and Canada are shown in Table 3. Following a second dose of MENVEO administered to children 2 years through 5 years of age, 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 events from a separate randomized, controlled, multicenter study conducted in the U.S. in adolescents and adults12 are provided in Tables 4 and 5, respectively. In neither study were concomitant vaccines administered with the study vaccines.

Table 3: Rates of Solicited Adverse Reactions within 7 Days following a Single Vaccination in Children 2 Years through 5 Years and 6 Years through 10 Years of Age
Clinicaltrials.gov Identifier NCT00616421.9 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. Parents reported the use of antipyretic medication to treat or prevent symptoms in 11% and 13% of subjects 2 through 5 years of age, 9% and 10% of subjects 6 through 10 years of age for MENVEO and MENACTRA, respectively.e Different systemic reactions were solicited in different age groups.

Adverse Reactions

Participants 2 through 5 Years of Age

MENVEO

n = 693

%

MENACTRA

n = 684

%

Any

Moderate

Severe

Any

Moderate

Severe

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 Reactionse

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

Rashc

4

-

-

5

-

-

Arthralgiaa

3

1

0.1

4

1

0

Vomitinga

3

1

0.1

3

1

0

Feverd

2

0.4

0

2

0.3

0

Participants 6 through 10 Years of Age

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 Reactionse

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

Rashc

5

-

-

3

-

-

Feverd

2

1

0

2

0

0.4

Table 4: Rates of Solicited Adverse Reactions within 7 Days following Vaccination in Individuals 11 Years through 18 Years of Age
Clinicaltrials.gov Identifier NCT00450437.12 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.

Adverse Reactions

MENVEO

n = 1,631

%

MENACTRA

n = 539

%

Any

Moderate

Severe

Any

Moderate

Severe

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 5: Rates of Solicited Adverse Reactions within 7 Days following Vaccination in Individuals 19 Years through 55 Years of Age
Clinicaltrials.gov Identifier NCT00450437.12 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.

Adverse Reactions

MENVEO n = 1,018

%

MENACTRA n = 336

%

Any

Moderate

Severe

Any

Moderate

Severe

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

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 trial2. 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 MMR and V vaccine at 12 months of age, was evaluated in one pivotal trial.5 Rates of solicited adverse reactions which occurred 7 days following vaccination are shown in Tables 1 and 2, 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 study14 conducted in Costa Rica. Solicited local and systemic adverse reactions were reported as noted above. In this study, subjects 11 through 18 years of age 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

Serious adverse events in subjects receiving a 4-dose series of MENVEO at 2, 4, 6, and 12 months were evaluated in 3 randomized multicenter clinical studies.1-3 In the 2 controlled studies,2,3 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 serious adverse events 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,1 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 serious adverse events 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 serious adverse events during the 6-month follow-up period after the toddler dose. The most common serious adverse events 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 infants5 randomized to receive the 2-dose series of MENVEO concomitantly with MMRV at 12 months of age, the rates of serious adverse events 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 serious adverse events (1.5%). Among 1,597 study subjects included in the safety population, the most commonly reported serious adverse events in all study arms combined were dehydration (0.4%) and gastroenteritis (0.3%). Across the submitted studies of individuals 2 through 23 months of age, 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 MMR and varicella vaccines).

The information regarding serious adverse events in subjects 2 years through 10 years of age was derived from 3 randomized, controlled clinical trials.7-9 Safety follow-up ranged from 6 months through 12 months and included 2,883 subjects administered MENVEO. Serious adverse events 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 serious adverse events 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,6 298 subjects received 1 or 2 doses of MENVEO and 22 (7%) had serious adverse events 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 serious adverse events in subjects 11 years through 55 years of age was derived from 5 randomized, controlled clinical trials.10-14 Serious adverse events 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, serious adverse events 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. Serious adverse events 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.

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