Adverse reactions : תופעות לוואי

6        ADVERSE REACTIONS
6.1   Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The safety of VAQTA has been evaluated in over 10,000 subjects 1 year to 85 years of age. Subjects were given one or two doses of the vaccine. The second (booster dose) was given 6 months or more after the first dose.

The most common local adverse reactions and systemic adverse events (≥15%) reported in different clinical trials across different age groups when VAQTA was administered alone or concomitantly were:
•     Children — 12 through 23 months of age: injection-site pain/tenderness (37.0%), injection-site erythema (21.2%), fever (16.4% when administered alone, and 27.0% when administered concomitantly).
•     Children/Adolescents   — 2 through 18 years of age: injection-site pain (18.7%)
•     Adults — 19 years of age and older: injection-site pain, tenderness, or soreness (67.0%), injection-site warmth (18.2%) and headache (16.1%)

Allergic Reactions
Local and/or systemic allergic reactions that occurred in <1% of over 10,000 children/adolescents or adults in clinical trials regardless of causality included: injection-site pruritus and/or rash; bronchial constriction; asthma; wheezing; edema/swelling; rash; generalized erythema; urticaria; pruritus; eye irritation/itching; dermatitis [see Contraindications (4) and Warnings and Precautions (5.1)].

Children — 12 through 23 Months of Age
In two open-label clinical trials involving 706 healthy children 12 through 23 months of age who received one or two 25U doses of VAQTA, subjects were monitored for local adverse reactions and fever for 5 days and systemic adverse events for 14 days after each vaccination by diary cards. In one trial, 89 children were enrolled and received VAQTA alone. In the other trial, children were randomized to receive the first dose of VAQTA with or without M-M-R II® (Measles, Mumps, and Rubella Virus Vaccine, Live) and VARIVAX® (Varicella Virus Vaccine Live) (N=617) and the second dose of VAQTA with or without Tripedia (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) (DTaP) and optionally either ORIMUNE (Poliovirus vaccine live oral trivalent) (OPV) or IPOL (Poliovirus Vaccine Inactivated) (IPV) (N=555). The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 62.2% Caucasian; 15.3% Hispanic-American; 12.4% African-American; 6.1% Native American; 3.0% other; 0.7% Oriental, 0.1% Asian; and 0.1% Indian. The distribution of subjects by gender was 53.2% male and 46.8% female. Listed below are the solicited local adverse reactions and systemic adverse events (with 95% Confidence Interval (CI)) (Table 1) and unsolicited local adverse reactions and systemic adverse events (Table 2) reported at ≥1.0% in children who received one or two doses of VAQTA alone and for subjects who received VAQTA concomitantly with other vaccines.

Table 1
Incidences of Solicited Local Adverse Reactions and Systemic Adverse Events in Healthy Infants 12 through 23 Months of Age Occurring at ≥1% After Any Dose

VAQTA + vaccines administered
VAQTA administered alone concomitantly*
(N=241)
Adverse Event                                                                              (N=706) Rate (n/total n)
(95% CI)
†
Injection-site
6.8% (16/236)                                 8.6% (59/683)
Pain/tenderness/soreness
(3.9%, 10.8%)                                 (6.6%, 11.0%)
4.2% (10/236)                                 5.1% (35/683)
Swelling
(2.1%, 7.7%)                                  (3.6%, 7.1%)
3.8% (9/236)                                 5.9% (40/683)
Erythema
(1.8%, 7.1%)                                 (4.2%, 7.9%)
2.5% (6/236)                                 3.2% (22/683)
Warmth
(0.9%, 5.5%)                                 (2.0%, 4.8%)
Systemic‡
Fever§
12.3% (29/236)                                14.6% (99/679)
≥100.4°F (≥38.0°C), Oral
(8.4%, 17.2%)                                 (12.0%, 17.5%)
3.4% (8/236)                                 4.9% (33/679)
≥102.0°F (≥38.8°C), Oral
(1.5%, 6.6%)                                 (3.4%, 6.8%)
1.7% (4/236)                                  0.9% (6/679)
Abnormal
(0.5%, 4.3%)                                  (0.3%, 1.9%)
0.0% (0/236)                                 1.8% (12/683)
Rash (measles-like, rubella-like, varicella-like)
(0.0%, 1.5%)                                 (0.9%, 3.1%)
N=Number of subjects enrolled/randomized.
n=Number of subjects in each category.
*VAQTA administered alone or concomitantly with M-M-R II and VARIVAX at Dose 1. VAQTA administered alone or concomitantly with DTaP and poliovirus vaccine optionally at Dose 2.
†
Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination ‡
Systemic Adverse Events reported Days 1-14 after vaccination, regardless of causality.
§
Monitored Days 1-5 after vaccination.


Table 2
Incidences of Unsolicited Local Adverse Reactions and Systemic Adverse Events in Healthy Infants 12 through 23 Months of Age Occurring at ≥1%

VAQTA + vaccines administered
Body system                                            VAQTA administered alone concomitantly*
(N=241)
(N=706)
Adverse Event
Rate (n/total n)

(95% CI)
Eye disorders†
0.4% (1/236)                                1.3% (9/683)
Conjunctivitis
(0.0%, 2.3%)                                (0.6%, 2.5%)
Respiratory, thoracic and mediastinal disorders †
3.7% (9/236)                                5.7% (39/683)
Rhinorrhea
(1.8%, 7.1%)                                (4.1%, 7.7%)
3.7% (9/236)                                5.1% (35/683)
Cough
(1.8%, 7.1%)                                (3.6%, 7.1%)
1.2% (3/236)                                0.7% (5/683)
Asthma
(0.3%, 3.7%)                                (0.2%, 1.7%)
0.4% (1/236)                                1.6% (11/683)
Respiratory congestion
(0.0%, 2.3%)                                (0.8%, 2.9%)
0.4% (1/236)                                1.2% (8/683)
Nasal congestion
(0.0%, 2.3%)                                (0.5%, 2.3%)
0.4% (1/236)                                1.2% (8/683)
Laryngotracheobronchitis
(0.0%, 2.3%)                                (0.5%, 2.3%)
Gastrointestinal disorders †
3.3% (8/236)                                5.9% (40/683)
Diarrhea
(1.5%, 6.6%)                                (4.2%, 7.9%)
2.9% (7/236)                                4.0% (27/683)
Vomiting
(1.2%, 6.0%)                                (2.6%, 5.7%)
†
Skin and subcutaneous tissue disorders
1.7% (4/236)                                4.5% (31/683)
Rash
(0.5%, 4.3%)                                (3.1%, 6.4%)
Metabolism and nutrition disorders †
1.7% (4/236)                                1.2% (8/683)
Anorexia
(0.5%, 4.3%)                                (0.5%, 2.3%)
Infections and infestations †
10.0% (24/236)                              10.1% (69/683)
Upper respiratory infection
(6.6%, 14.8%)                               (8.0%, 12.6%)
4.1% (10/236)                               7.6% (52/683)
Otitis Media
(2.1%, 7.7%)                                (5.7%, 9.9%)
0.8% (2/236)                                1.8% (12/683)
Otitis
(0.1%, 3.0%)                                (0.9%, 3.1%)
0.4% (1/236)                                1.0% (7/683)
Viral exanthema
(0.0%, 2.3%)                                (0.4%, 2.1%)
General disorders and administration site conditions †
7.1% (17/236)                              10.8% (74/683)
Irritability
(4.3%, 11.3%)                              (8.6%, 13.4%)
0.0% (0/236)                                1.0% (7/683)
Injection-site ecchymosis‡
(0.0%, 1.6%)                                (0.4%, 2.2%)
†
Psychiatric disorders
1.7% (4/236)                                0.7% (5/683)
Insomnia
(0.5%, 4.3%)                                (0.2%, 1.7%)
1.2% (3/236)                                1.8% (12/683)
Crying
(0.3%, 3.7%)                                (0.9%, 3.1%)
N=Number of subjects enrolled/randomized.
n=Number of subjects in each category.
*VAQTA administered alone or concomitantly with M-M-R II and VARIVAX at Dose 1. VAQTA administered alone or concomitantly with DTaP and poliovirus vaccine optionally at Dose 2.
†
Systemic Adverse Events reported Days 1-14 after vaccination, regardless of causality.
‡
Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination.


Serious Adverse Events: Subjects in an open-label study were randomized to receive VAQTA (Dose 1) alone (N=308) or VAQTA concomitantly with M-M-R II and VARIVAX (N=309). Seven children experienced a total of 9 seizures between 9 days and 81 days following the administration of the vaccines. None of the events was considered to be related to VAQTA by the investigator. Other serious events that occurred during the study included bronchiolitis (N=1), dehydration (N=2), RLL (Right Lower Lobe) pneumonia and asthma (N=1), and asthma exacerbation (N=1), which occurred 9 days to 46 days following the administration of VAQTA and were also considered by the investigator to be unrelated to VAQTA.
In an open-label clinical trial of 1800 subjects, 699 healthy children 12 to 23 months of age were randomized to receive two doses of VAQTA (N=352) or two doses of VAQTA concomitantly with two doses of ProQuad1 (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) (N=347) at least 6 months apart.
An additional 1101 subjects received two doses of VAQTA alone at least 6 months apart (non-randomized), resulting in 1453 subjects receiving two doses of VAQTA alone (1101 non-randomized and 352 randomized) and 347 subjects receiving two doses of VAQTA concomitantly with ProQuad (all randomized).
The race distribution of the study subjects who received VAQTA with or without ProQuad was as follows: 66.4% Caucasian; 19.7% Hispanic-American; 6.7% African-American; 5.0% other; 2.1% Asian; and 0.1% 
Native American. The distribution of subjects by gender was 51.2% male and 48.8% female. Tables 3 and 4 present injection-site adverse reactions and fever ≥100.4°F (≥38.0°C) and ≥102.2°F (≥39.0°C) (Days 1 to 5 postvaccination) and systemic adverse events, including fever or feverish >98.6°F (>37.0°C) (Days 1 to 14 postvaccination) observed among recipients of VAQTA alone or concomitantly with ProQuad at a rate of at least 1% following any dose of VAQTA. Among all subjects, fever (>98.6°F (>37.0°C) or feverish) was the most common systemic adverse event and injection-site pain/tenderness was the most common injection-site adverse reaction. Based on a post-hoc analysis, the rate of fever (>98.6°F (>37.0°C) or feverish) after any dose of VAQTA was increased in subjects who received VAQTA with ProQuad as compared to VAQTA alone in the 14 days after vaccination {risk difference (11.8% [95% CI: 6.8, 17.2]) and relative risk (1.72 [95% CI: 1.40, 2.12])}. The difference in rate of fever (>98.6°F (>37.0°C) or feverish) was higher after Dose 1 (11.5%) as compared to Dose 2 (4.0%). The rates of fever ≥100.4°F (≥38.0°C) and ≥102.2°F (≥39.0°C) in the 5 days after any dose of VAQTA were similar in both treatment groups.

Table 3
Incidences of Unsolicited and Solicited Local Adverse Reactions at the Injection Site for VAQTA Occurring at ≥1%            in Healthy Infants 12 through 23 Months of Age After Any Dose of VAQTA Alone or Concomitantly With ProQuad 
VAQTA administered alone                              VAQTA + ProQuad (N=1453)                                           (N=347)
Adverse Reaction
Rate (n/total n)

Injection-site erythema*                          21.2% (300/1415)                                    17.7% (59/334) Injection-site pain/tenderness*                   42.1% (596/1415)                                    35.9% (120/334) Injection-site swelling*                          12.6% (178/1415)                                    13.5% (45/334) Injection-site bruising*,†                         2.6% (37/1415)                                      3.0% (10/334) N=Number of subjects enrolled/randomized.
n=Number of subjects in each category.
*Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination †
Unsolicited Reaction.


Table 4
Incidences of Unsolicited and Solicited Systemic Adverse Events by Body System Occurring at ≥1% in Healthy              Infants 12 through 23 Months of Age After Any Dose of VAQTA Alone or Concomitantly With ProQuad

VAQTA administered alone                               VAQTA + ProQuad Body System                                                          (N=1453)                                            (N=347) 
Adverse Event                                                                Rate (n/total n) 

Eye disorders*
Conjunctivitis                                                     0.9% (13/1415)                                     1.5% (5/334) Gastrointestinal disorders*
Constipation                                                       1.1% (15/1415)                                     0.3% (1/334) Diarrhea                                                          10.1% (143/1415)                                   6.9% (23/334) Vomiting                                                           6.4% (90/1415)                                    4.8% (16/334) General disorders and administration site conditions*
Irritability                                                      11.2% (158/1415)                                   10.8% (36/334) Fever ≥102.2°F (≥39.0°C) (Days 1-5
4.0% (56/1383)                                    4.1% (13/320) postvaccination)†
Fever ≥100.4°F (≥38.0°C) (Days 1-5
16.3% (226/1383)                                   15.9% (51/320) postvaccination)†
Fever >98.6°F or feverish (>37.0°C) (Days 1-14
16.3% (231/1415)                                   28.1% (94/334) postvaccination)‡
Infections and infestations*
Ear infection                                                      1.1% (15/1415)                                     0.0% (0/334) Gastroenteritis                                                    1.1% (16/1415)                                     0.6% (2/334) Gastroenteritis viral                                              0.8% (11/1415)                                     1.8% (6/334) Nasopharyngitis                                                    4.7% (66/1415)                                    4.8% (16/334) Otitis media                                                       4.0% (56/1415)                                    3.3% (11/334) Rhinitis                                                           3.2% (45/1415)                                     0.3% (1/334) Upper respiratory tract infection                                  6.6% (93/1415)                                    9.0% (30/334) Viral infection                                                    1.1% (16/1415)                                     0.9% (3/334) Metabolism and nutrition disorders*
Anorexia                                                           1.1% (15/1415)                                     0.9% (3/334) Respiratory, thoracic and mediastinal disorders*

VAQTA administered alone                              VAQTA + ProQuad Body System                                                             (N=1453)                                           (N=347) 
Adverse Event                                                                        Rate (n/total n) 

Cough                                                                7.8% (111/1415)                                   6.0% (20/334) Nasal congestion                                                      2.6% (37/1415)                                   2.1% (7/334) Rhinorrhea                                                           7.6% (107/1415)                                   6.6% (22/334) Skin and subcutaneous tissue disorders*
Dermatitis diaper                                                     1.7% (24/1415)                                   5.7% (19/334) Rash                                                                  2.0% (29/1415)                                   5.7% (19/334) Rash morbilliform                                                     0.0% (0/1415)                                    4.8% (16/334) N=Number of subjects enrolled/randomized.
n=Number of subjects in each category.
*Systemic Adverse Events reported Days 1-14 after vaccination, regardless of causality.
†
T≥100.4°F (≥38.0°C) and T≥102.2°F (≥39.0°C), recorded Days 1-5 after vaccination.
‡
Risk Difference (11.8% [95% CI: 6.8, 17.2]) and relative risk (1.72 [95% CI: 1.40, 2.12]) in post-hoc analysis.


In an open-label clinical trial, 653 children 12 to 23 months of age were randomized to receive a first dose of VAQTA with ProQuad and Prevnar4 (Pneumococcal 7-valent Conjugate Vaccine) concomitantly (N=330) or a first dose of ProQuad and pneumococcal 7-valent conjugate vaccine concomitantly, followed by a first dose of VAQTA 6 weeks later (N=323). Approximately 6 months later, subjects received either the second doses of ProQuad and VAQTA concomitantly or the second doses of ProQuad and VAQTA separately. The race distribution of the study subjects was as follows: 60.3% Caucasian; 21.6% African- American; 9.5% Hispanic-American; 7.2% other; 1.1% Asian; and 0.3% Native American. The distribution of subjects by gender was 50.7% male and 49.3% female.
Table 5 presents rates of solicited local reactions at the VAQTA injection site and rates of elevated temperatures (≥100.4°F (≥38.0°C) and ≥102.2°F (≥39.0°C)) that occurred within 5 days following each dose of VAQTA and elevated temperatures >98.6°F (>37.0°C) for a total of 14 days after vaccination; occurrences of these events were recorded daily on diary cards. Table 6 presents rates of unsolicited systemic adverse events that occurred within 14 days at ≥5% in any group following each dose of VAQTA.

Table 5
Incidences of Solicited Local Adverse Reactions at the VAQTA Injection Site and Elevated Temperatures Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PCV7* Dose 1                                     Dose 2
Adverse reaction: Days                        VAQTA alone                      VAQTA + ProQuad +                         VAQTA alone             VAQTA + 1-5 unless noted                                                               PCV7 concomitantly                                                ProQuad concomitantl y
Injection site adverse                            N=274                                 N=311                              N=251                  N=263 reactions
Injection site erythema                        11.7%                                  9.6%                               12.7%                 9.5% Injection site                             15.3%                                 20.9%                               20.3%                 17.5% pain/tenderness
Injection site swelling                         9.5%                                  6.8%                               7.6%                  6.1% Temperature > 98.6°F or                         12.4%                                 35.7%                               10.8%                 10.3% feverish (>37.0°C) (Days 1-
14)
N=243                                 N=285                              N=221                  N=237 Temperature ≥ 100.4°F                           10.3%                                 16.8%                               10%                   4.2% (≥38.0°C)
Temperature ≥ 102.2 °F                           2.1%                                  3.5%                               2.3%                  2.5% (≥39.0°C)
*Pneumococcal 7-valent Conjugate Vaccine
N=number of subjects for whom data are available.



Table 6
Incidences of Unsolicited Systemic Adverse Events ≥5% in Any Group Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PCV7*
Dose 1                     Dose 2
Adverse Event:                  VAQTA alone              VAQTA + ProQuad +                VAQTA alone              VAQTA + ProQuad Days 1-14                                                PCV7 concomitantly                                          concomitantly 
Dose 1              Dose 2
N=274                N=311               N=251             N=263
General Disorders and Administration Site Conditions
Irritability             3.6%                 6.1%                2.8%               2.7% Infections and Infestations
Upper respiratory            3.3%                 6.1%                4.8%               5.7% tract infection
Skin and Subcutaneous Tissue Disorders
Dermatitis diaper           1.1%                 6.1%                2.4%               3.4% 
*Pneumococcal 7-valent Conjugate Vaccine



Data presented in Tables 5 through 6 on solicited local reactions, and solicited and unsolicited systemic adverse events with incidence ≥5% following each dose of VAQTA are representative of other clinical trials of VAQTA in children 12 through 23 months of age.

The following additional unsolicited local adverse reactions and systemic adverse events were observed at a common frequency of ≥1% to <10% in any individual clinical study. This listing includes only the adverse reactions not reported elsewhere in the label. These local adverse reactions and systemic adverse events occurred among recipients of VAQTA alone or VAQTA given concomitantly within 14 days following any dose of VAQTA across four clinical studies.
Eye disorders: Conjunctivitis

Gastrointestinal disorders: Constipation; vomiting

General disorders and administration site conditions: Injection-site            bruising;   injection-site ecchymosis

Infections and infestations: Otitis media; nasopharyngitis; rhinitis; viral infection; croup; pharyngitis streptococcal; laryngotracheobronchitis; viral exanthema; gastroenteritis viral; roseola 
Metabolism and nutrition disorders: Anorexia

Psychiatric disorders: Insomnia; crying
Respiratory, thoracic and mediastinal disorders: Cough; nasal congestion; respiratory congestion 
Skin and subcutaneous tissue disorders: Rash vesicular; measles-like/rubella-like rash; varicella- like rash; rash morbilliform

Children/Adolescents — 2 Years through 18 Years of Age
In 11 clinical trials, 2615 healthy children 2 years through 18 years of age received at least one dose of VAQTA. These studies included administration of VAQTA in varying doses and regimens (1377 children received one or more 25U doses). The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 84.7% Caucasian; 10.6% American Indian; 2.3% African- American; 1.5% Hispanic-American; 0.6% other; 0.2% Oriental. The distribution of subjects by gender was 51.2% male and 48.8% female.
In a double-blind, placebo-controlled efficacy trial (i.e. The Monroe Efficacy Study), 1037 healthy children and adolescents 2 through 16 years of age were randomized to receive a primary dose of 25U of VAQTA and a booster dose of VAQTA 6, 12, or 18 months later, or placebo (alum diluent). All study subjects were Caucasian: 51.5% were male and 48.5% were female. Subjects were followed days 1 to 5 postvaccination for fever and local adverse reactions and days 1 to 14 for systemic adverse events. The most common adverse events/reactions were injection-site reactions, reported by 6.4% of subjects. Table 7 summarizes local adverse reactions and systemic adverse events reported in 1% of subjects. There were no significant differences in the rates of any adverse events or adverse reactions between vaccine and placebo recipients after Dose 1.
Table 7
Local Adverse Reactions and Systemic Adverse Events (1%) in Healthy Children and Adolescents from the Monroe Efficacy Study


VAQTA                                                               ,†,‡ Adverse Event                                          (N=519)                                   Placebo (Alum Diluent)* (N=518)
Dose 1*                          Booster
Rate (Percent)
Rate (Percent)                   Rate (Percent)
§
Injection-Site                                  n=515                             n=475                              n=510 Pain                           6.4%                              3.4%                               6.3% Tenderness                            4.9%                              1.7%                               6.1% Erythema                            1.9%                              0.8%                               1.8% Swelling                           1.7%                              1.5%                               1.6% Warmth                             1.7%                              0.6%                               1.6% 

Systemic¶                                       n=519                             n=475                              n=518 Abdominal pain                          1.2%                              1.1%                               1.0% Pharyngitis                         1.2%                               0%                                0.8% Headache                            0.4%                              0.8%                               1.0% N=Number of subjects enrolled/randomized.
Percent=percentage of subjects for whom data are available with adverse event n=number of subjects for whom adverse events available
* No statistically significant differences between the two groups.
†
Second injection of placebo not administered because code for the trial was broken.
‡
Placebo (Alum diluent) = amorphous aluminum hydroxyphosphate sulfate.
§
Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination with VAQTA ¶
Systemic adverse events reported Days 1-15 after vaccination, regardless of causality.


Adults — 19 Years of Age and Older
In an open-label clinical trial, 240 healthy adults 18 to 54 years of age were randomized to receive either VAQTA (50U/1.0 mL) with Typhim Vi (Typhoid Vi polysaccharide vaccine) and YF-Vax (yellow fever vaccine) concomitantly (N=80), typhoid Vi polysaccharide and yellow fever vaccines concomitantly (N=80), or VAQTA alone (N=80). Approximately 6 months later, subjects who received VAQTA were administered a second dose of VAQTA. The race distribution of the study subjects who received VAQTA with or without typhoid Vi polysaccharide and yellow fever vaccine was as follows: 78.3% Caucasian; 14.2% Oriental; 3.3% other; 2.1% African-American; 1.7% Indian; 0.4% Hispanic-American. The distribution of subjects by gender was 40.8% male and 59.2% female. Subjects were monitored for local adverse reactions and fever for 5 days and systemic adverse events for 14 days after each vaccination. In the 14 days after the first dose of VAQTA, the proportion of subjects with adverse events was similar between recipients of VAQTA given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines compared to recipients of typhoid Vi polysaccharide and yellow fever vaccines without VAQTA. Table 8 summarizes solicited local adverse reactions and Table 9 summarizes unsolicited systemic adverse events reported in ≥5% in adults who received one or two doses of VAQTA alone and for subjects who received VAQTA concomitantly with typhoid Vi polysaccharide and yellow fever vaccines. There were no solicited systemic complaints reported at a rate ≥5%. Fever ≥101°F (≥38.3°C) occurred in 1.3% of subjects in each group.

Table 8
Incidences of Solicited Local Adverse Reactions in Healthy Adults      ≥19 Years of Age Occurring at ≥5% After Any Dose 
VAQTA + ViCPS* and
VAQTA administered          Yellow Fever vaccines alone                      administered
Adverse Event
(N=80)                     concomitantly†
(N=80)
Rate (Percent)
Injection-site‡
Pain/tenderness/soreness           78.8%                         70.3% Warmth                   23.7%                         23.7%
Swelling                  16.2%                         8.8%
Erythema                  17.5%                         6.3%
N=Number of subjects enrolled/randomized.
Percent=percentage of subjects with adverse event.
*ViCPS=Typhoid Vi polysaccharide vaccine.
†
VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines.
‡
Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination 
Table 9
Incidences of Unsolicited Systemic   Adverse Events in Adults ≥19 Years of Age Occurring at ≥ 5% After Any Dose 
VAQTA + ViCPS* and
Body System                         VAQTA administered          Yellow Fever vaccines alone                      administered
(N=80)                     concomitantly†
Adverse Event                                                     (N=80) Rate (Percent)
General disorders and administration site reactions
Asthenia/fatigue                     7.5%                         11.3% Chills                          1.3%                         7.5%
Gastrointestinal disorders
Nausea                           7.5%                         12.5%
Musculoskeletal and connective tissue disorders
Myalgia                          5.0%                         10.0%
Arm pain                         0.0%                         6.3%
Nervous system disorders
Headache                         23.8%                         26.3%
Infections and infestations
Upper respiratory infection               7.5%                         3.8% Pharyngitis                        2.5%                         6.3%
N=Number of subjects enrolled/randomized with data available.
Percent=percentage of subjects with adverse event for whom data are available.
*ViCPS=Typhoid Vi polysaccharide vaccine.
†
VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines.
‡
Systemic Adverse Events reported Days 1-15 after vaccination, regardless of causality.


In four clinical trials involving 1645 healthy adults 19 years of age and older who received one or more 50U doses of hepatitis A vaccine, subjects were followed for fever and local adverse reactions 1 to 5 days postvaccination and for systemic adverse events 1 to 14 days postvaccination. One single-blind study evaluated doses of VAQTA with varying amounts of viral antigen and/or alum content in healthy adults ≥170 pounds and ≥30 years of age (N=210 adults administered 50U/1.0 mL dose). One open-label study evaluated VAQTA given with immune globulin (IG) or alone (N=164 adults who received VAQTA alone). A third study was single-blind and evaluated 3 different lots of VAQTA (N=1112). The fourth study that was also single-blind evaluated doses of VAQTA with varying amounts of viral antigen in heal thy adults ≥170 pounds and ≥30 years of age (N=159 adults administered the 50U/1.0 mL dose). Overall, the race distribution of the study subjects who received at least one dose of VAQTA was as follows: 94.2% Caucasian; 2.2% Black; 1.5% Hispanic; 1.5% Oriental; 0.4% other; 0.2% American Indian. 47.6% of subjects were male and 52.4% were female. The most common adverse event/reaction was injection-site pain/soreness/tenderness reported by 67.0% of subjects. Of all reported injection-site reactions 99.8% were mild (i.e., easily tolerated with no medical intervention) or moderate (i.e., minimally interfered with usual activity possibly requiring little medical intervention). Listed below in Table 10 are the local adverse reactions and systemic adverse events reported by 5% of subjects, in decreasing order of frequency within each body system.

Table 10
Incidences of Local Adverse Reactions and Systemic Adverse Events       ≥5% in Adults 19 Years of Age and Older 
Body System                                          VAQTA (Any Dose) (N=1645)

Adverse Events                               Rate (n/total n)

Nervous system disorders*                                   n=1641
16.1%
Headache

General disorders and n=1640 administration site reactions †
Injection-site                                    67.0% pain/tenderness/soreness
18.2%
Injection-site warmth

14.7%
Injection-site swelling
13.7%
Injection-site erythema

N=Number of subjects enrolled/randomized.
n=Number of subjects in each category with data available.

Percent=percentage of subjects for whom data are available with adverse event.
*Systemic Adverse Events reported Days 1 to 14 after vaccination, regardless of causality.
†
Adverse Reactions at the injection site (VAQTA) and measured fever Days 1 to 5 after vaccination.


The following additional unsolicited systemic adverse events were observed among recipients of VAQTA that occurred within 14 days at a common frequency of ≥1% to <10% following any dose not reported elsewhere in the label. These adverse reactions have been reported across 4 clinical studies.
Musculoskeletal and connective tissue disorders: Back pain; stiffness 
Reproductive system and breast disorders: Menstruation disorders

6.2  Post-Marketing Experience
The following additional adverse events have been reported with use of the marketed vaccine. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to a vaccine exposure.

Blood and lymphatic disorders: Thrombocytopenia.
Nervous system disorders: Guillain-Barré syndrome; cerebellar ataxia; encephalitis.

Post-Marketing Observational Safety Study
In a post-marketing, 60-day safety surveillance study, conducted at a large health maintenance organization in the United States, a total of 42,110 individuals ≥2 years of age received 1 or 2 doses of VAQTA (13,735 children/adolescents and 28,375 adult subjects). Safety was passively monitored by electronic search of the automated medical records database for emergency room and outpatient visits, hospitalizations, and deaths. Medical charts were reviewed when an event was considered to be possibly vaccine-related by the investigator. None of the serious adverse events identified were assessed as being related to vaccine by the investigator. Diarrhea/gastroenteritis, resulting in outpatient visits, was determined by the investigator to be the only vaccine-related nonserious adverse reaction in the study. There was no vaccine-related adverse reaction identified that had not been reported in earlier clinical trials with VAQTA.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il /