Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
The safety of Vaxigrip Tetra was assessed in six clinical trials in which 3,040 adults from 18 to 60 years of age, 1,392 elderly over 60 years of age and 429 children from 9 to 17 years of age received one dose of Vaxigrip Tetra and 884 children from 3 to 8 years of age received one or two doses of Vaxigrip Tetra depending on their influenza vaccination history and 1,614 children from 6 to 35 months of age received two doses (0.5 mL) of Vaxigrip Tetra.
Most reactions usually occurred within the first 3 days following vaccination, resolved spontaneously within 1 to 3 days after onset. The intensity of these reactions was mild.
The most frequently reported adverse reaction after vaccination, in all populations including the whole group of children from 6 to 35 months of age, was injection site pain (between 52.8% and 56.5% in children from 3 to 17 years of age and in adults, 26.8% in children from 6 to 35 months of age and 25.8% in elderly). In subpopulation of children less than 24 months of age, irritability (32.3%) was the most frequently reported adverse reaction.
In subpopulation children from 24 to 35 months of age, malaise (26.8%) is the most frequently reported adverse reaction.
The other most frequently reported adverse reactions after vaccination were: - In adults: headache (27.8%), myalgia (23%) and malaise (19.2%),
- In elderly: headache (15.6%) and myalgia (13.9%),
- In children from 9 to 17 years of age: myalgia (29.1%), headache (24.7%), malaise (20.3%) and injection site swelling (10.7%),
- In children from 3 to 8 years of age: malaise (30.7%), myalgia (28.5%), headache (25.7%), injection site swelling (20.5%), injection site erythema (20.4%), injection site induration (16.4%), shivering (11.2%),
- In all children from 6 to 35 months of age: fever (20.4%) and injection site erythema (17.2%),
- In children less than 24 months of age: appetite lost (28.9%), crying abnormal (27.1%), vomiting (16.1%) and drowsiness (13.9%),
- In children from 24 to 35 months of age: headache (11.9%) and myalgia (11.6%).
Overall, adverse reactions were generally less frequent in the elderly than in adults and children.
Tabulated summary of adverse reactions
The data below summarize the frequencies of the adverse reactions that were recorded following vaccination with Vaxigrip Tetra during clinical trials and worldwide post-marketing surveillance.
Adverse events are ranked under headings of frequency using the following convention:
Very common (≥1/10);
Common (≥1/100 to <1/10);
Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000);
Very rare (<1/10,000);
Not known (cannot be estimated from available data): adverse reactions have been reported following commercial use of Vaxigrip Tetra based on spontaneous reporting. Because these reactions are reported voluntarily from populations of uncertain size, it is not possible to reliably estimate their frequency.
Within each frequency grouping the adverse reactions are presented in the order of decreasing seriousness.

Adult and elderly
The safety profile presented below is based on:
- data from 3,040 adults from 18 to 60 years of age and 1,392 elderly over 60 years of age
- data from worldwide post-marketing surveillance (*).
ADVERSE REACTIONS                                         FREQUENCY
Blood and Lymphatic System Disorders
Lymphadenopathy (1)                                                                      Uncommon Immune System Disorders
Hypersensitivity (1), allergic reactions such as angioedema (1), dermatitis              Rare allergic (1), pruritus generalised (1), urticaria (1), pruritus (2), erythema Anaphylactic reactions                                                                   Not known* Nervous System Disorders
Headache                                                                                 Very common Dizziness (3)                                                                            Uncommon Paraesthesia, somnolence                                                                 Rare Vascular disorders
Hot flush (4)                                                                            Uncommon Respiratory, thoracic and mediastinal disorders
Dyspnoea (1)                                                                             Rare Gastrointestinal Disorders
Diarrhoea, nausea (5)                                                                    Uncommon Skin and Subcutaneous Tissue Disorders
Hyperhidrosis                                                                            Rare Musculoskeletal and Connective Tissue Disorders
Myalgia                                                                                  Very common Arthralgia (1)                                                                           Rare General Disorders and Administration Site Conditions
Malaise (6)                                                                              Very common Injection site pain
Shivering, fever (2)                                                                     Common Injection site erythema, injection site swelling, injection site induration Fatigue                                                                                  Uncommon Injection site ecchymosis, injection site pruritus, injection site warmth Asthenia, flu-like illness                                                               Rare Injection site discomfort (1)
(1)
In adults (2) Uncommon in elderly (3) Rare in adults (4) In elderly (5) Rare in elderly (6) Common in elderly

Paediatric population
The safety profile presented below is based on:
- data from 429 children from 9 to 17 years of age who received one dose of Vaxigrip Tetra and from 884 children from 3 to 8 years of age who received one or two doses of Vaxigrip Tetra depending on their influenza vaccination history - data from worldwide post-marketing surveillance (*).
ADVERSE REACTIONS                                       FREQUENCY
Blood and Lymphatic System Disorders
Thrombocytopenia (1)                                                                      Uncommon Immune System Disorders
Allergic including anaphylactic reactions                                                 Not known* Psychiatric disorders
Moaning (2), restlessness (2)                                                             Uncommon Nervous System Disorders
Headache                                                                                  Very common Dizziness (2)                                                                             Uncommon Gastrointestinal Disorders
Diarrhoea, vomiting (2), abdominal pain upper (2)                                         Uncommon Musculoskeletal and Connective Tissue Disorders
Myalgia                                                                                   Very common (2)
Arthralgia                                                                                Uncommon General Disorders and Administration Site Conditions
Malaise, shivering (3)                                                                    Very common Injection site pain, injection site swelling, injection site erythema (3), injection site induration (3)
Fever                                                                                     Common Injection site ecchymosis
Fatigue (2),                                                                              Uncommon Injection site warmth (2), injection site pruritus (4)


(1)                                       (2)
Reported in one child of 3 years of       Reported in children from 3 to 8 age                                       years of age
(3)                                       (4)
Common in children from 9 to 17           Reported in children from 9 to 17 years of age                              years of age

The safety profile presented below is based on:
- data from 1,614 children from 6 to 35 months of age who received two doses of Vaxigrip Tetra.
- data from worldwide post-marketing surveillance (*).
ADVERSE REACTIONS                                FREQUENCY
Immune System Disorders
Hypersensitivity                                                         Uncommon Allergic reactions such as pruritus generalised, rash papular                   Rare Anaphylactic reactions                                                          Not known* Nervous System Disorders
Headache (1)                                                                    Very common Gastrointestinal Disorders
Vomiting (2)                                                                    Very common Diarrhoea                                                                       Uncommon Musculoskeletal and Connective Tissue Disorders
Myalgia (3)                                                                     Very common General Disorders and Administration Site Conditions
Irritability (4), appetite lost (4), crying abnormal (5), malaise (3), fever,   Very common drowsiness (5)
Injection site pain/tenderness, injection site erythema
Shivering (1)                                                                   Common Injection site induration, injection site swelling, injection site ecchymosis Influenza like illness                                                          Rare Injection site rash, injection site pruritus


(1)
Reported in children ≥24 months of     (2)
Uncommon in children ≥24 months of age                                        age
(3)
Rare in children <24 months of age     (4)
Rare in children ≥24 months of age
(5)
Reported in children <24 months of age
In children from 6 months to 8 years of age, the safety profile of Vaxigrip Tetra was similar after the first and the second injections with a trend of lower incidence of adverse reactions after the second injection compared to the first one in children from 6 to 35 months.

Adverse events
The following adverse events were reported following commercial use of Inactivated Influenza Vaccine (Split Virion) BP. A causal relationship with Vaxigrip Tetra has not been established.
• Blood and lymphatic system disorders
Transient thrombocytopenia (1), lymphadenopathy (1)
• Nervous system disorders
Paraesthesia (1), Guillain-Barré Syndrome (GBS), neuritis, neuralgia, convulsions, encephalomyelitis
• Vascular disorders
Vasculitis, such as Henoch-Schönlein purpura, with transient renal involvement in certain cases
(1)
These adverse events were reported during clinical trials only in some age groups (see Tabulated summary of adverse reactions).

Other special populations
The safety profile of Vaxigrip Tetra observed in a limited number of subjects with co-morbidities enrolled in the clinical studies does not differ from the one observed in the overall population. In addition, studies conducted with Vaxigrip in renal transplant patients, and asthmatic patients showed no major differences in terms of safety profile of Vaxigrip in these populations.
- Pregnant women
In clinical studies conducted in pregnant women in South Africa and Mali with Inactivated Influenza Vaccine (Split Virion) BP (see Sections 4.6 and 5.1), frequencies of local and systemic solicited reactions reported within 7 days following administration of the vaccine, were consistent with those reported for the adult population during clinical studies conducted with Inactivated Influenza Vaccine (Split Virion) BP. In the South Africa study, local reactions were more frequent in the Inactivated Influenza Vaccine (Split Virion) BP group than in the placebo group in both HIV-negative and HIV-positive cohorts. There were no other significant differences in solicited reactions between Inactivated Influenza Vaccine (Split Virion) BP and placebo groups in both cohorts.
In one clinical study conducted in pregnant women in Finland with Vaxigrip Tetra (see sections 4.6 and 5.1), frequencies of local and systemic solicited reactions reported within 7 days following administration of Vaxigrip Tetra were consistent with those reported for the non-pregnant adult population during clinical studies conducted with Vaxigrip Tetra even though higher for some adverse reactions (injection site pain, malaise, shivering, headache, myalgia).

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 (www.health.gov.il) according to the National Regulation by using an online form https://sideeffects.health.gov.il