Adverse Drug Reaction Overview
In clinical studies, the most common solicited adverse reactions were pain at the injection site, fatigue, headache, and muscle pain (see Tables 1 and 2). Nausea was reported in up to 22% of subjects in early phase studies. Most local and systemic reactions were mild or moderate in severity and resolved within 1 to 3 days after vaccination. The frequencies of solicited adverse reactions were highest after the first dose regardless of the schedule. The frequencies of solicited adverse reactions after subsequent doses were similar.
Overall, data for adverse events (AEs) summarized by age, sex, and race were comparable to AEs reported for the overall population.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety of Trumenba was investigated in 11 completed clinical studies (see CLINICAL TRIALS, Table 3) that enrolled a total of 20,803 subjects, of which 15,294 subjects received at least 1 dose of Trumenba (any dose level or vaccination regimen) administered alone or concomitantly with a licensed vaccine and 5509 control subjects received either saline alone, a licensed vaccine alone, or saline and a licensed vaccine. The core safety dataset comprises data derived from the 8 controlled studies for subjects who received at least 1 dose of Trumenba 120 mcg administered alone or concomitantly with a licensed vaccine on a schedule of 0, 2, and 6 months (n=13,284) or control vaccine (n=5509).
The safety evaluation in the clinical studies included an assessment of: (1) solicited local and systemic reactions, and use of antipyretic medication after each vaccination in an electronic diary maintained by the subject or the subject’s parent/legal guardian; and (2) spontaneous reports of adverse events (AEs), including serious adverse events (SAEs) throughout the study (day of vaccination through 1 month or 6 months after the last vaccination, depending on the study and safety parameter).
Solicited Local and Systemic Reactions
Tables 1 and 2 present the percentage of subjects who reported solicited local (Table 1) and systemic (Table 2) reactions, regardless of causality, within 7 days of each dose of Trumenba or control (hepatitis A virus vaccine [HAV]/saline or saline) for pivotal Phase 3 studies 1009 and 1016, which both included Canadian patients.
Study 1009 was a Phase 3, randomized, active-controlled, observer-blinded, global, multicenter trial in which 2,693 subjects 10 to 18 years of age received at least 1 dose of Trumenba on a 0-, 2-, and 6- month schedule. A control group received HAV at 0 and 6 months and received saline at 2 months. Subjects were randomized to receive 1 of 3 lots of Trumenba or HAV/saline.
Study 1016 was a Phase 3, randomized, placebo-controlled, observer-blinded, global, multicenter trial in which 2,471 subjects 18 to 25 years of age received at least 1 dose of Trumenba or saline on a 0-, 2,- and 6- month schedule.
Table 1: Percentage of Subjects 10 to 18 Years of Age (Study 1009) and 18 to 25 Years of Age (Study 1016) Reporting Solicited Local Reactions Within 7 Days After Each Vaccination
- a
- Trumenba, hepatitis A virus vaccine (HAV)/saline, and saline were administered at 0, 2, and 6 months.
- b
- Mild (does not interfere with activity); Moderate (interferes with activity); Severe (prevents daily activity)
- c
- "Any" is defined as the cumulative frequency of subjects who reported a reaction as "mild", "moderate", or "severe" within 7 days of vaccination.
- d
- Mild (2.5-5.0 cm); Moderate (5.5-10.0 cm); Severe (>10.0 cm).
|
Local Reaction |
Study 1009 |
Study 1016 |
Trumenbaa |
HAV/Salinea |
Trumenbaa |
Salinea |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
N=2681 |
N=2545 |
N=2421 |
N=890 |
N=843 |
N=821 |
N=2425 |
N=2076 |
N=1823 |
N=798 |
N=706 |
N=624 |
Painb |
Anyc |
86.7 |
77.7 |
76.0 |
47.0 |
15.2 |
34.0 |
84.2 |
79.3 |
80.4 |
11.8 |
7.8 |
6.7 |
Mild |
41.1 |
39.4 |
34.1 |
36.5 |
12.3 |
23.8 |
42.3 |
42.2 |
36.1 |
10.7 |
6.8 |
6.4 |
Moderate |
40.7 |
33.2 |
36.5 |
9.9 |
2.7 |
9.9 |
37.1 |
32.7 |
38.9 |
1.1 |
1.0 |
0.3 |
Severe |
5.0 |
5.1 |
5.4 |
0.6 |
0.1 |
0.4 |
4.8 |
4.4 |
5.3 |
0.0 |
0.0 |
0.0 |
Rednessd |
Anyc |
16.2 |
12.5 |
13.9 |
1.3 |
0.6 |
1.1 |
13.8 |
11.8 |
17.1 |
0.6 |
0.3 |
0.2 |
Mild |
5.6 |
5.2 |
4.9 |
1.2 |
0.6 |
1.0 |
5.8 |
4.6 |
6.2 |
0.5 |
0.1 |
0.2 |
Moderate |
8.8 |
6.1 |
6.8 |
0.1 |
0.0 |
0.1 |
7.1 |
6.3 |
8.6 |
0.0 |
0.0 |
0.0 |
Severe |
1.9 |
1.1 |
2.2 |
0.0 |
0.0 |
0.0 |
0.9 |
0.9 |
2.3 |
0.1 |
0.1 |
0.0 |
Swellingd |
Anyc |
18.0 |
13.9 |
15.4 |
2.2 |
0.6 |
0.9 |
15.5 |
14.0 |
16.6 |
0.6 |
0.4 |
0.3 |
Mild |
8.5 |
6.3 |
7.9 |
1.8 |
0.5 |
0.7 |
8.5 |
7.7 |
8.8 |
0.3 |
0.3 |
0.0 |
Moderate |
8.8 |
7.3 |
6.8 |
0.4 |
0.1 |
0.1 |
6.8 |
6.0 |
7.2 |
0.3 |
0.1 |
0.3 |
Severe |
0.7 |
0.2 |
0.7 |
0.0 |
0.0 |
0.0 |
0.2 |
0.3 |
0.5 |
0.1 |
0.0 |
0.0 |
Table 2: Percentage of Subjects 10 to 18 Years of Age (Study 1009) and 18 to 25 Years of Age (Study 1016) Reporting Solicited Systemic Reactions and Use of Antipyretic Medications Within 7 Days After Each Vaccination
- a
- Trumenba, hepatitis A virus vaccine (HAV)/saline, and saline were administered at 0, 2, and 6 months.
- b
- Study 1009: Fever (≥38°C): N=2679, 2540, and 2414 for Trumenba at Dose 1, Dose 2, and Dose 3, respectively; N=890, 840, and 819 for HAV/saline at Dose 1, Dose 2, and Dose 3, respectively.
- c
- Study 1016: Fever (≥38°C): N=2415, 2067, and 1814 for Trumenba at Dose 1, Dose 2, and Dose 3, respectively; N=796, 705, and 621 for saline at Dose 1, Dose 2, and Dose 3, respectively.
- d
- Mild (1-2 times in 24 hours); Moderate (>2 times in 24 hours); Severe (requires intravenous hydration).
- e
- "Any" is defined as the cumulative frequency of subjects who reported a reaction as "mild", "moderate", or "severe" within 7 days of vaccination.
- f
- Mild (2-3 loose stools in 24 hours); Moderate (4-5 loose stools in 24 hours); Severe (6 or more loose stools in 24 hours).
- g
- Mild (does not interfere with activity); Moderate (interferes with activity); Severe (prevents daily activity).
|
Systemic Reaction |
Study 1009 |
Study 1016 |
Trumenbaa |
HAV/Salinea |
Trumenbaa |
Salinea |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
Dose 1 |
Dose 2 |
Dose 3 |
N=2681 |
N=2545 |
N=2421 |
N=890 |
N=843 |
N=821 |
N=2425 |
N=2076 |
N=1823 |
N=798 |
N=706 |
N=624 |
Fever (≥38°C)b,c |
≥38.0°C |
6.4 |
2.0 |
2.7 |
1.9 |
1.5 |
2.3 |
2.4 |
1.2 |
2.0 |
0.6 |
1.0 |
0.6 |
38.0° to 38.5°C |
4.0 |
1.2 |
1.8 |
1.3 |
0.7 |
1.3 |
1.6 |
0.7 |
1.4 |
0.4 |
0.6 |
0.5 |
38.5° to 39.0°C |
1.9 |
0.7 |
0.6 |
0.3 |
0.7 |
0.4 |
0.7 |
0.4 |
0.4 |
0.0 |
0.3 |
0.2 |
39.0° to ≤40.0°C |
0.5 |
0.1 |
0.3 |
0.2 |
0.1 |
0.5 |
0.0 |
0.1 |
0.1 |
0.3 |
0.1 |
0.0 |
>40.0°C |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.1 |
0.0 |
0.0 |
0.1 |
0.0 |
0.0 |
0.0 |
Vomitingd |
Anye |
3.7 |
2.2 |
1.7 |
1.9 |
1.4 |
2.2 |
2.6 |
2.1 |
2.0 |
2.1 |
1.6 |
1.4 |
Mild |
2.8 |
1.7 |
1.4 |
1.7 |
1.1 |
1.7 |
2.2 |
1.6 |
1.8 |
2.1 |
1.3 |
1.1 |
Moderate |
0.9 |
0.4 |
0.3 |
0.2 |
0.4 |
0.5 |
0.4 |
0.5 |
0.2 |
0.0 |
0.3 |
0.3 |
Severe |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
Diarrheaf |
Anye |
10.6 |
7.6 |
7.7 |
12.1 |
9.1 |
7.6 |
12.7 |
8.6 |
7.5 |
11.8 |
8.1 |
6.9 |
Mild |
9.1 |
6.2 |
6.4 |
10.9 |
7.6 |
6.2 |
10.2 |
6.4 |
6.1 |
9.8 |
4.7 |
5.3 |
Moderate |
0.3 |
1.3 |
1.0 |
1.1 |
1.2 |
1.1 |
2.4 |
1.7 |
1.2 |
1.9 |
2.8 |
1.3 |
Severe |
0.3 |
0.1 |
0.3 |
0.1 |
0.4 |
0.2 |
0.2 |
0.5 |
0.2 |
0.1 |
0.6 |
0.3 |
Headacheg |
Anye |
51.8 |
37.8 |
35.4 |
37.2 |
28.1 |
24.8 |
43.9 |
33.1 |
32.5 |
36.2 |
24.9 |
21.6 |
Mild |
28.7 |
20.2 |
18.9 |
24.0 |
15.7 |
13.5 |
24.3 |
18.4 |
17.6 |
22.1 |
13.6 |
12.5 |
Moderate |
21.0 |
16.0 |
15.2 |
12.5 |
10.9 |
10.4 |
17.9 |
13.3 |
13.3 |
13.5 |
10.1 |
8.3 |
Severe |
2.2 |
1.7 |
1.3 |
0.7 |
1.5 |
1.0 |
1.6 |
1.4 |
1.6 |
0.6 |
1.3 |
0.8 |
Fatigueg |
Anye |
54.0 |
38.3 |
35.9 |
40.3 |
26.3 |
24.4 |
50.9 |
39.2 |
39.3 |
39.8 |
27.3 |
24.5 |
Mild |
27.8 |
20.6 |
18.4 |
23.5 |
13.2 |
13.5 |
25.4 |
20.6 |
18.9 |
23.2 |
13.9 |
13.1 |
Moderate |
23.2 |
15.8 |
15.2 |
15.2 |
11.7 |
10.0 |
22.1 |
16.4 |
18.8 |
15.8 |
11.5 |
9.6 |
Severe |
3.0 |
1.9 |
2.3 |
1.7 |
1.4 |
0.9 |
3.4 |
2.2 |
1.6 |
0.9 |
2.0 |
1.8 |
Chillsg |
Anye |
25.3 |
16.0 |
13.1 |
17.2 |
10.3 |
8.3 |
18.1 |
12.4 |
12.6 |
9.8 |
8.5 |
6.4 |
Mild |
16.2 |
10.6 |
8.7 |
13.3 |
8.1 |
6.5 |
12.0 |
8.1 |
7.7 |
8.1 |
6.9 |
4.3 |
Moderate |
8.0 |
4.8 |
3.8 |
3.5 |
1.8 |
1.7 |
4.9 |
3.5 |
4.2 |
1.6 |
1.6 |
2.1 |
Severe |
1.2 |
0.6 |
0.5 |
0.4 |
0.5 |
0.1 |
1.1 |
0.8 |
0.8 |
0.0 |
0.0 |
0.0 |
Muscle paing (other than muscle pain at injection site) |
Anye |
24.4 |
17.8 |
17.6 |
19.2 |
10.3 |
11.1 |
25.9 |
15.6 |
16.9 |
14.5 |
8.5 |
7.5 |
Mild |
13.2 |
8.7 |
9.5 |
13.5 |
5.2 |
6.6 |
13.0 |
7.6 |
8.9 |
9.6 |
5.8 |
4.5 |
Moderate |
10.1 |
7.9 |
7.2 |
5.4 |
4.5 |
4.3 |
11.3 |
7.1 |
6.8 |
4.4 |
2.3 |
2.9 |
Severe |
1.2 |
1.2 |
0.8 |
0.3 |
0.6 |
0.2 |
1.6 |
0.8 |
1.2 |
0.5 |
0.4 |
0.2 |
Joint paing |
Anye |
21.9 |
16.7 |
16.0 |
13.6 |
9.1 |
8.9 |
19.6 |
15.1 |
12.6 |
10.9 |
6.5 |
5.3 |
Mild |
11.8 |
8.4 |
8.9 |
8.3 |
5.0 |
5.5 |
10.3 |
8.1 |
6.6 |
6.9 |
3.7 |
2.9 |
Moderate |
8.7 |
7.5 |
5.9 |
4.6 |
3.4 |
3.0 |
7.9 |
6.2 |
5.4 |
3.5 |
2.5 |
2.4 |
Severe |
1.4 |
0.8 |
1.2 |
0.7 |
0.7 |
0.4 |
1.4 |
0.9 |
0.6 |
0.5 |
0.3 |
0.0 |
Use of antipyretic medication |
20.7 |
13.6 |
12.7 |
10.4 |
8.9 |
6.8 |
13.4 |
12.3 |
12.8 |
8.9 |
7.6 |
6.6 |
Study 10421 was a Phase 2 safety and immunogenicity study in US microbiology laboratory workers (n = 13, 24 to 62 years of age; 8 subjects >40 years of age) who received Trumenba 120 mcg on a 0, 2, 6-month schedule. No new safety signal was identified with the limited number of subjects.
Adverse Events
Overall, in the 8 controlled studies (as described above) adverse events within 30 days after any dose were reported in 30.95% of subjects receiving Trumenba (n=13,284) and 28.37% of subjects in the control group (n=5509). Adverse events that occurred at a frequency of at least 2% and were more frequently observed in subjects who received Trumenba than subjects in the control group were injection site pain (6.84% vs 3.59%), headache (3.78% vs 3.47%), and fever (2.61% vs 1.43%).
Serious Adverse Events
In the 8 controlled studies, serious adverse events (SAEs) were reported by 1.6% and 1.9% of subjects who received at least one dose of Trumenba or control, respectively.
Post-Market Adverse Reactions
The following are considered adverse reactions for Trumenba and were reported in the post-marketing experience. Because these reactions were derived from spontaneous reports, the frequency could not be determined.
Immune system disorders: Allergic reactions
Nervous system disorders: Syncope (fainting)
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