Meningitis vaccine adverse reactions: Difference between revisions
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==Adverse Reactions== | |||
<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dde472-1efb-4630-88bc-41cde216fb3a | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dde472-1efb-4630-88bc-41cde216fb3a | publisher = | date = | accessdate = }}</ref> | ===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 to 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 three randomized multicenter clinical studies 1-3 conducted in the U.S., Australia, Canada, Taiwan and several countries of Latin America in which 8735 infants received at least one 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 2864 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 (SD 7.5 days) at the time of first vaccination. | |||
Safety data for administration of two doses of MENVEO in children between 6 through 23 months of age are available from three randomized studies 1, 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 1985 older infants and toddlers who received two 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 four clinical trials 6-9 conducted in North America (66%), Latin America (28%) and Europe (6%) in which 3181 subjects received MENVEO and 2116 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=1255]). 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 five randomized controlled clinical trials 10-14 in which 6185 participants received MENVEO alone (5286 participants), MENVEO concomitant with other vaccine(s) (899 participants), or a U.S. licensed comparator vaccine (1966 participants). In the concomitant trials 11, 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 (1757 participants). The trials were conducted in North America (46%), Latin America (41%) and Europe (13%). In two 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 MENVEO recipients, 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 Menactra recipients, 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 US infants in the largest multinational MENVEO safety study 2 are presented in Table 1. Among the US participants in the MENVEO with routine vaccines group, 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 four-dose series, common solicited adverse reactions (≥ 10%) were tenderness (24-41%) and[[ erythema]] at injection site (11-15%), [[irritability]] (42-57%), [[sleepiness]] (29-50%), [[persistent crying]] (21-41%), change in eating habits (17-23%), [[vomiting]] (5-11%) and [[diarrhea ]](8-16%). The rates of solicited adverse reactions reported for subjects aged 2 months and above 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. | |||
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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 5 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 two-dose series were tenderness (10-16%) and erythema at injection site (12-15%), irritability (27-40%), sleepiness (17-29%), persistent crying (12-21%), change in eating habits (12-20%) and diarrhea (10-16%). 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. | |||
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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 study 9 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 adults 12 are provided in Tables 4 and 5, respectively. In neither study were concomitant vaccines administered with the study vaccines. | |||
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====Solicited Adverse Reactions following Concomitant Vaccine Administration==== | |||
The safety of 4-dose MENVEO series administered concomitantly with U.S.-licensed routine infant and toddler vaccines was evaluated in one pivotal trial 2. 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 Concomitant Administration with Other Vaccines ] | |||
The safety of MENVEO administered concomitantly with Tdap and HPV was evaluated in a single center study 14 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 one month later by Tdap and then one month later by HPV (N=541), or Tdap followed one month later by MENVEO and then one 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 to the group that first received MENVEO alone (headache 36%, malaise 20%, myalgia 19%, and arthralgia 11%). Among subjects administered MENVEO alone (one month prior to Tdap), 36% reported headache, 20% malaise, and 16% myalgia. Among subjects administered MENVEO one 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 four-dose series of MENVEO at 2, 4, 6 and 12 months were evaluated in three randomized multicenter clinical studies 1-3. In the two controlled studies2, 3, the proportions of infants randomized to receive the four-dose MENVEO series 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 one month following the toddler dose; and d) 1.6% and 2.2%, during the 6 months 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 four 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 one month following the toddler dose. In the same study, 1.9% of infants randomized to receive the four-dose MENVEO series 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 three studies were wheezing, pneumonia, gastroenteritis and convulsions, and most occurred at highest frequency after the infant series. | |||
In a study of older infants 5 randomized to receive the two-dose MENVEO series 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 MENVEO with MMRV and MENVEO-only groups, 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 1597 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, two deaths were reported in the MENVEO treatment groups (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), 3/12049 [0.02%, 95% CI: (0.01% , 0.07%)] MENVEO recipients and 0/2877 [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 co-administered with routine US 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 2883 subjects administered MENVEO. Serious adverse events reported during the safety follow-up periods occurred in 21/2883 (0.7%) of MENVEO subjects, in 7/1255 (0.6%) of Menactra subjects, and 2/861 (0.2%) of Menomune subjects. In the subjects receiving either one or two 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 1255 subjects administered a single dose of Menactra and 861 subjects administered Menomune, there were no events reported to occur in more than one subject. The serious adverse events occurring within the first 30 days after receipt of each vaccine were as follows: MENVEO (6/2883 [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 one or two 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 one subject. During the 30 days post vaccination in this study, one limb injury and one 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 40/6185 (0.6%) of MENVEO subjects, 13/1757 (0.7%) of Menactra subjects, and 5/209 (2.4%) of Menomune subjects. During the 6 months following immunization, serious adverse events reported by more than one 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 6185 (0.1%) subjects in the MENVEO group, 4 of 1757 (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. | |||
===Postmarketing Experience=== | |||
In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for MENVEO in persons 11 through 55 years of age since market introduction of this vaccine are listed below. This list includes serious events or events which have plausible causal connection to MENVEO. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to the vaccine. | |||
====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, fatigue, malaise, pyrexia. | |||
====Immune System Disorders==== | |||
Hypersensitivity. | |||
====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]].<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dde472-1efb-4630-88bc-41cde216fb3a | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dde472-1efb-4630-88bc-41cde216fb3a | publisher = | date = | accessdate = }}</ref> | |||
Latest revision as of 15:24, 9 January 2014
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Adverse Reactions
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 to 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 three randomized multicenter clinical studies 1-3 conducted in the U.S., Australia, Canada, Taiwan and several countries of Latin America in which 8735 infants received at least one 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 2864 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 (SD 7.5 days) at the time of first vaccination.
Safety data for administration of two doses of MENVEO in children between 6 through 23 months of age are available from three randomized studies 1, 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 1985 older infants and toddlers who received two 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 four clinical trials 6-9 conducted in North America (66%), Latin America (28%) and Europe (6%) in which 3181 subjects received MENVEO and 2116 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=1255]). 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 five randomized controlled clinical trials 10-14 in which 6185 participants received MENVEO alone (5286 participants), MENVEO concomitant with other vaccine(s) (899 participants), or a U.S. licensed comparator vaccine (1966 participants). In the concomitant trials 11, 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 (1757 participants). The trials were conducted in North America (46%), Latin America (41%) and Europe (13%). In two 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 MENVEO recipients, 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 Menactra recipients, 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 US infants in the largest multinational MENVEO safety study 2 are presented in Table 1. Among the US participants in the MENVEO with routine vaccines group, 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 four-dose series, common solicited adverse reactions (≥ 10%) were tenderness (24-41%) anderythema at injection site (11-15%), irritability (42-57%), sleepiness (29-50%), persistent crying (21-41%), change in eating habits (17-23%), vomiting (5-11%) and diarrhea (8-16%). The rates of solicited adverse reactions reported for subjects aged 2 months and above 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.
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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 5 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 two-dose series were tenderness (10-16%) and erythema at injection site (12-15%), irritability (27-40%), sleepiness (17-29%), persistent crying (12-21%), change in eating habits (12-20%) and diarrhea (10-16%). 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.
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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 study 9 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 adults 12 are provided in Tables 4 and 5, respectively. In neither study were concomitant vaccines administered with the study vaccines.
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Solicited Adverse Reactions following Concomitant Vaccine Administration
The safety of 4-dose MENVEO series administered concomitantly with U.S.-licensed routine infant and toddler vaccines was evaluated in one pivotal trial 2. 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 Concomitant Administration with Other Vaccines ]
The safety of MENVEO administered concomitantly with Tdap and HPV was evaluated in a single center study 14 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 one month later by Tdap and then one month later by HPV (N=541), or Tdap followed one month later by MENVEO and then one 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 to the group that first received MENVEO alone (headache 36%, malaise 20%, myalgia 19%, and arthralgia 11%). Among subjects administered MENVEO alone (one month prior to Tdap), 36% reported headache, 20% malaise, and 16% myalgia. Among subjects administered MENVEO one 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 four-dose series of MENVEO at 2, 4, 6 and 12 months were evaluated in three randomized multicenter clinical studies 1-3. In the two controlled studies2, 3, the proportions of infants randomized to receive the four-dose MENVEO series 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 one month following the toddler dose; and d) 1.6% and 2.2%, during the 6 months 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 four 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 one month following the toddler dose. In the same study, 1.9% of infants randomized to receive the four-dose MENVEO series 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 three studies were wheezing, pneumonia, gastroenteritis and convulsions, and most occurred at highest frequency after the infant series.
In a study of older infants 5 randomized to receive the two-dose MENVEO series 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 MENVEO with MMRV and MENVEO-only groups, 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 1597 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, two deaths were reported in the MENVEO treatment groups (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), 3/12049 [0.02%, 95% CI: (0.01% , 0.07%)] MENVEO recipients and 0/2877 [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 co-administered with routine US 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 2883 subjects administered MENVEO. Serious adverse events reported during the safety follow-up periods occurred in 21/2883 (0.7%) of MENVEO subjects, in 7/1255 (0.6%) of Menactra subjects, and 2/861 (0.2%) of Menomune subjects. In the subjects receiving either one or two 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 1255 subjects administered a single dose of Menactra and 861 subjects administered Menomune, there were no events reported to occur in more than one subject. The serious adverse events occurring within the first 30 days after receipt of each vaccine were as follows: MENVEO (6/2883 [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 one or two 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 one subject. During the 30 days post vaccination in this study, one limb injury and one 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 40/6185 (0.6%) of MENVEO subjects, 13/1757 (0.7%) of Menactra subjects, and 5/209 (2.4%) of Menomune subjects. During the 6 months following immunization, serious adverse events reported by more than one 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 6185 (0.1%) subjects in the MENVEO group, 4 of 1757 (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.
Postmarketing Experience
In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for MENVEO in persons 11 through 55 years of age since market introduction of this vaccine are listed below. This list includes serious events or events which have plausible causal connection to MENVEO. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to the vaccine.
Ear and Labyrinth Disorders
Hearing impaired, ear pain, vertigo, vestibular disorder.
Eye Disorders
General Disorders and Administration Site Conditions
Injection site pruritus, pain, erythema, inflammation and swelling, fatigue, malaise, pyrexia.
Immune System Disorders
Hypersensitivity.
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
References
- ↑ "http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dde472-1efb-4630-88bc-41cde216fb3a". External link in
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Adapted from the FDA Package Insert.