6 ADVERSE REACTIONS
In clinical studies, the most common adverse reactions in subjects 1 through 15 years of age who received TICOVAC were local tenderness (18.1%), local pain (11.2%), headache (11.1%), fever (9.6%), and restlessness (9.1%).
The most common adverse reactions in subjects 16 through 65 years of age who received TICOVAC were local tenderness (29.9%), local pain (13.2%), fatigue (6.6%), headache (6.3%), and muscle pain (5.1%).
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.
Among a total of 10 clinical trials, 3240 healthy children 1 through 15 years of age received at least one dose of TICOVAC. A total of 4427 healthy adults 16 years of age and older received at least one dose of TICOVAC in 10 clinical trials.
Study 209 was a multicenter, open-label study to investigate the safety of TICOVAC in 2,417 healthy children 1 through 15 years of age who received three vaccinations (Day 0, 1 and 6 months after the first vaccination). The incidence rates for local and systemic solicited adverse reactions within 4 days after each dose are presented in Table 2.
| Percentage (%) of Subjects | ||||
|---|---|---|---|---|
| Age Group* | Adverse Reaction | Dose 1 N=2417 | Dose 2 N=2410 | Dose 3 N=2390 |
| Abbreviation: N=total number of subjects who received TICOVAC at each dose for each age group. | ||||
| Clinical trial identifier: NCT 00161863. | ||||
| ||||
| Local Reaction | ||||
| 1–15 Years | Tenderness | 18.1 | 12.9 | 13.3 |
| Local pain | 11.2 | 7.9 | 9.7 | |
| Erythema | 3.0 | 1.5 | 2.8 | |
| Induration | 2.2 | 1.3 | 2.1 | |
| Swelling | 1.9 | 1.1 | 2.5 | |
| Itching | <0.1 | <0.1 | 0 | |
| Ecchymosis | 0 | 0 | <0.1 | |
| Hematoma | <0.1 | 0 | 0 | |
| Systemic Reaction | ||||
| 1–15 Years | Fever | 9.6 | 2.3 | 2.4 |
| Headache | 11.1 | 3.9 | 3.4 | |
| Muscle pain | 3.6 | 2.0 | 1.8 | |
| Loss of appetite | 3.1 | 1.5 | 1.2 | |
| Nausea | 3.3 | 1.0 | 0.8 | |
| Changes in sleeping behavior | 2.8 | 1.0 | 0.8 | |
| Vomiting | 1.7 | 0.7 | 0.3 | |
| Joint pain | 1.2 | 0.6 | 0.5 | |
| Swelling of the axillary /inguinal lymph nodes | 0.2 | 0.3 | 0.2 | |
| N=584 | N=581 | N=576 | ||
| 1–5 Years | Restlessness | 9.1 | 3.6 | 3.5 |
| N=1833 | N=1829 | N=1814 | ||
| 6–15 Years | Fatigue | 6.3 | 2.4 | 2.5 |
| Malaise | 4.8 | 1.6 | 1.8 | |
Incidence rates of fever reported within 4 days after each dose of TICOVAC, by age group, in Study 209 are presented in Table 3.
| Dose Age Group | Percentage (%) of Subjects | |||
|---|---|---|---|---|
| 38.0–38.4°C (100.4–101.1°F) | 38.5–38.9°C (101.2–102.0°F) | 39.0–40.0°C (102.1–104°F) | >40°C (>104°F) | |
| Abbreviation: N=total number of subjects who received TICOVAC at each dose for each age group. | ||||
| Clinical trial identifier: NCT 00161863. | ||||
| Dose 1 | ||||
| 1–2 Years of Age (N=186) | 23.7 | 5.9 | 5.9 | 0 |
| 3–6 Years of Age (N=563) | 4.6 | 5.0 | 3.0 | 0 |
| 7–15 Years of Age (N=1668) | 3.4 | 2.0 | 0.3 | 0 |
| Total (N=2417) | 5.2 | 3.0 | 1.4 | 0 |
| Dose 2 | ||||
| 1–2 Years of Age (N=185) | 9.2 | 2.2 | 0.5 | 0.5 |
| 3–6 Years of Age (N=561) | 1.2 | 0.4 | 0.5 | 0 |
| 7–15 Years of Age (N=1664) | 0.8 | 0.4 | <0.1 | 0 |
| Total (N=2410) | 1.6 | 0.5 | 0.2 | <0.1 |
| Dose 3 | ||||
| 1–2 Years of Age (N=184) | 7.1 | 3.8 | 1.6 | 0 |
| 3–6 Years of Age (N=557) | 1.4 | 0.4 | 0.7 | 0.2 |
| 7–15 Years of Age (N=1649) | 0.6 | 0.3 | 0.2 | 0 |
| Total (N=2390) | 1.3 | 0.6 | 0.5 | <0.1 |
The following additional adverse reactions to the vaccine have been reported in <1% of subjects 1 through 15 years of age who received TICOVAC in clinical trials (N=3240): vertigo, dizziness, sensory abnormalities, abdominal pain, diarrhea, dyspepsia, injection site pruritus, and urticaria.
Study 208 was a randomized, comparative, single-blind study that assessed the safety of TICOVAC. Healthy subjects 16 through <65 years of age (N=3966) were randomized 3:1 to receive two vaccinations with either TICOVAC or a non-US licensed TBE vaccine comparator administered 21 to 35 days apart. Study 213 was an open-label follow-up study to Study 208; all subjects who had received two vaccinations in Study 208 (regardless of which vaccine they had received) were eligible and received a third vaccination with TICOVAC 6 months after the first vaccination in Study 208 (N=3705).
Incidence rates of solicited local and systemic adverse reactions reported in Study 208 (Doses 1 and 2) and Study 213 (Dose 3) are presented in Table 4.
| Percentage (%) of Subjects | |||
|---|---|---|---|
| Adverse Reaction | Dose 1 N=2977* | Dose 2 N=2950† | Dose 3‡ N=2790‡ |
| Clinical trial identifiers: NCT00161824 and NCT00161876. | |||
| Local Reaction | |||
| Tenderness | 29.9 | 27.4 | 25.7 |
| Local pain | 13.2 | 13.5 | 12.0 |
| Erythema | 3.6 | 2.3 | 3.4 |
| Induration | 2.0 | 1.5 | 2.6 |
| Swelling | 1.6 | 1.4 | 2.0 |
| Hematoma | <0.1 | <0.1 | 0.1 |
| Ecchymosis | <0.1 | 0 | <0.1 |
| Systemic Reaction | |||
| Fever | 0.8 | 0.5 | 0.5 |
| Fatigue | 6.6 | 4.1 | 5.3 |
| Headache | 6.3 | 4.4 | 4.9 |
| Muscle pain | 5.1 | 3.7 | 3.8 |
| Malaise | 4.9 | 3.3 | 3.7 |
| Joint pain | 1.4 | 1.1 | 1.4 |
| Nausea | 2.1 | 0.9 | 1.0 |
| Swelling of the lymph nodes | 0.6 | 0.3 | 0.7 |
| Vomiting | 0.2 | 0.1 | <0.1 |
The following additional adverse reactions have been reported in <1% of subjects 16 through <65 years of age who received TICOVAC in clinical trials (N=4427): hypersensitivity, somnolence, vertigo, diarrhea, abdominal pain, injection site pruritus, and injection site warmth.
Subjects who were seropositive either by ELISA or NT 1 month after the third dose in Studies 209 and 208/213, were invited to participate in follow-up Studies 700401 and 223 (studies assessing antibody persistence and response to a booster dose at 3 years), respectively. A total of 156 subjects received a fourth dose of TICOVAC (0.25 mL), and 240 subjects received a fourth dose of TICOVAC (0.5 mL) in these clinical trials.
Incidence rates of solicited local and systemic adverse reactions reported in Study 223 and 70401 after the booster are presented in Table 5.
| Percentage (%) of Subjects | |||
|---|---|---|---|
| Study 223 (N*=240) TICOVAC (0.5 mL) | Study 700401 (N†=156) TICOVAC (0.25 mL) | ||
| Abbreviation: NA=not applicable. | |||
| Note: Solicited symptoms with onset date between Day 0 (vacciantion day) and Day 4 were included in the analysis. | |||
| Local Reaction | Tenderness | 4.6 | 10.3 |
| Injection Site Pain | 3.8 | 14.7 | |
| Erythema | 0.4 | 1.3 | |
| Induration | 0.4 | 3.2 | |
| Swelling | 0.8 | 3.2 | |
| Hematoma | 0 | 0 | |
| Ecchymosis | 0 | 0 | |
| Systemic Reaction | Fever | 0 | 0 |
| Fatigue | 0 | 0.6 | |
| Headache | 0.4 | 3.2 | |
| Muscle Pain | 0.4 | 3.2 | |
| Malaise | 0.4 | 1.3 | |
| Joint Pain | 0 | 1.3 | |
| Nausea | 0 | 0.6 | |
| Swelling of the Lymphnodes | 0 | 0 | |
| Vomiting | 0 | 0 | |
| Loss of Appetite | NA | 1.9 | |
| Changes in sleeping behavior | NA | 0 | |
Among 3240 subjects who received TICOVAC (0.25 mL) in clinical trials, serious adverse events (SAEs) and death were reported in 62 subjects and 1 subject, respectively. Among 4427 subjects who received TICOVAC (0.5 mL) in clinical trials, SAEs and deaths were reported in 54 subjects and 2 subjects, respectively. None of these events was considered related to the vaccine. Only one SAE in TICOVAC (0.25 mL) was considered possibly related to vaccine (febrile convulsion reported in a 12-month old male two days after vaccination in Study 197, a postmarketing safety surveillance study).
6.2 Postmarketing Experience
The following adverse reactions have been reported spontaneously (postmarketing) with the use of TICOVAC in the European Union (EU). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
- Infections and infestations: herpes zoster (triggered in pre-exposed individuals)
- Immune system disorders: anaphylactic reaction, hypersensitivity, precipitation or aggravation of autoimmune disorders (e.g., multiple sclerosis)
- Nervous system disorders: convulsion, convulsion (including febrile), demyelinating disorders (acute disseminated encephalomyelitis, Guillain-Barré syndrome, myelitis, transverse myelitis), encephalitis, sensory abnormalities and motor dysfunction (hemiparesis, hemiplegia, VIIth nerve paralysis/facial paresis, paralysis, paresis, neuritis, neuralgia, optic neuritis), polyneuropathy, meningism, dizziness, aseptic meningitis
- Eye disorders: visual impairment, photophobia, eye pain
- Ear and labyrinth disorders: tinnitus
- Cardiac disorders: tachycardia
- Respiratory, thoracic and mediastinal disorders: dyspnea
- Skin and subcutaneous tissue disorders: urticaria, rash (erythematous, maculo-papular, vesicular), pruritus, dermatitis, erythema, hyperhidrosis
- Musculoskeletal and connective tissue disorders: back pain, joint swelling, neck pain, musculoskeletal stiffness (including neck stiffness), pain in extremity
- General disorders and administration site conditions: injection site joint movement impairment, injection site joint pain, injection site nodule, injection site inflammation, influenza-like illness, chills, gait disturbance, asthenia, edema