Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

Paediatric population

The safety of Prevenar 20 was evaluated in 5,987 participants, 6 weeks of age to less than 18 years of age, in five clinical trials (one Phase 2 and four Phase 3), four randomised, double-blind, active-controlled clinical trials and one single-arm clinical trial; 3,664 participants received at least 1 dose of Prevenar 20, and 2,323 participants received Prevenar 13 (control vaccine).

Participants 6 weeks to less than 15 months of age

Clinical trials were conducted in healthy infants 6 weeks to less than 15 months of age using a 3-dose schedule or a 4-dose schedule (see section 5.1). In these infant trials, 5,156 participants received at least 1 dose of vaccine: 2,833 received Prevenar 20, and 2,323 received Prevenar 13. Overall, approximately 90% of participants in each group received all doses through the study-specified toddler dose. In all studies, local reactions and systemic events were collected after each dose, and adverse events (AEs) were collected in all studies from the first dose through 1 month after the last infant vaccination and from the toddler dose through 1 month after the toddler dose. Serious adverse events were evaluated through 1 month after the last dose in the Phase 3 trial B7471012 (Study 1012) and through 6 months after the last dose in Phase 3 trials (Studies 1011, 1013) and Phase 2 trial (Study 1003).

Prevenar 20 was well tolerated, when administered in a 3-dose and a 4-dose series, in the infant study populations with low rates of severe local reactions and systemic events, and most reactions resolving within 1 to 3 days. The percentages of participants with local reactions and systemic events after Prevenar 20 were generally similar to those after Prevenar 13. The most frequently reported local reactions and systemic events after any dose of Prevenar 20 were irritability, drowsiness, and pain at injection site. In these studies, Prevenar 20 was co-administered or permitted to be administered with certain routine paediatric vaccines (see section 4.5).

Study 1012 was a pivotal, double-blind, randomised, active-controlled Phase 3 trial, in which 601 healthy infants received Prevenar 20 in a 3-dose series. The most frequently reported (> 10%) adverse reactions after any dose of Prevenar 20 were irritability (71.0% to 71.9%), drowsiness/increased sleep (50.9% to 61.2%), pain at injection site (22.8% to 42.4%), decreased appetite (24.7% to 39.3%), redness at the injection site (25.3% to 36.9%), swelling at the injection site (21.4% to 29.8%), and fever ≥ 38.0 ℃ (8.9% to 24.3%). Most adverse reactions occurred within 1 to 2 days following vaccination and were mild or moderate in severity and of short duration (1 to 2 days).

Studies 1011, 1013 and 1003, were double-blind, randomised, active-controlled trials that included 2,232 healthy infants, vaccinated with Prevenar 20 in a 4-dose series. The most frequently reported
(> 10%) adverse reactions observed after any dose of Prevenar 20 in infants were irritability (58.5% to 70.6%), drowsiness/increased sleep (37.7% to 66.2%), pain at injection site (32.8% to 45.5%), decreased appetite (23.0% to 26.4%), redness at the injection site (22.6% to 24.5%), and swelling at the injection site (15.1% to 17.6%). Most adverse reactions were mild or moderate following vaccination and most reactions resolving within 1 to 3 days. Severe reactions were reported infrequently.

In Study 1013, the local reactions and systemic events in the preterm subgroup (111 infants born at 34 to less than 37 weeks of gestation) were similar to or lower than the term infants in the study. In the preterm subgroup, the frequency of any reported local reaction was 31.7% to 55.3% in the Prevenar 20 group, and any systemic event was 65.0% to 85.5% in the Prevenar 20 group.


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Participants aged 15 months to less than 18 years of age

In the Phase 3 trial B7471014 (Study 1014), 831 participants 15 months to less than 18 years of age received a single dose of Prevenar 20 in four age groups (209 participants 15 to less than 24 months of age; 216 participants 2 years to less than 5 years of age; 201 participants 5 years to less than 10 years age; and 205 participants 10 years to less than 18 years of age). The participants less than 5 years of age had received at least 3 prior doses of Prevenar 13.

The most frequently reported (> 10%) adverse reactions observed after any dose of Prevenar 20 in participants less than 2 years of age were irritability (61.8%), pain at the injection site (52.5%), drowsiness/increased sleep (41.7%), redness at the injection site (37.7%), decreased appetite (25.0%), swelling at the injection site (22.1%), and fever ≥ 38.0 °C (11.8%). In participants aged 2 years and older, the most frequently reported adverse reactions were pain at the injection site (66.0% to 82.9%), muscle pain (26.5% to 48.3%), redness at the injection site (15.1% to 39.1%), fatigue (27.8% to 37.2%), headache (5.6% to 29.3%), and swelling at the injection site (15.6% to 27.1%).


Participants 18 years of age and older

The safety of Prevenar 20 was evaluated in 4,552 participants 18 years of age and older in six clinical trials (two Phase 1, one Phase 2, and three Phase 3), and 2,496 participants in the control groups.

In the Phase 3 trials, 4,263 participants received Prevenar 20. This, included 1,798 participants 18 through 49 years of age, 334 participants 50 through 59 years of age, and 2,131 participants 60 years of age and older (1,138 were 65 years of age and older). Of the participants who received Prevenar 20 in the Phase 3 trials, 3,639 were naïve to pneumococcal vaccines, 253 had previously received Pneumovax 23 (pneumococcal polysaccharide vaccine [23-valent]; PPSV23) (≥ 1 to ≤ 5 years prior to enrollment), 246 had previously received Prevenar 13 only (≥ 6 months prior to enrollment), and 125 had previously received Prevenar 13 followed by PPSV23 (the dose of PPSV23 ≥ 1-year prior to enrollment).

Participants in the Phase 3 trial B7471007 (Pivotal Study 1007) were evaluated for adverse events for 1 month after vaccination, and serious adverse events through 6 months after vaccination. This study included 447 participants 18 to 49 years of age, 445 participants 50 to 59 years of age, 1,985 participants 60 to 64 years of age, 624 participants 65 to 69 years of age, 319 participants 70 to 79 years of age, and 69 participants ≥ 80 years of age.

In participants 18 to 49 years of age in Studies 1007 and a Phase 3 trial B7471008 (Lot Consistency Study 1008), the most frequently reported adverse reactions were pain at injection site (79.2%), muscle pain (62.9%), fatigue (46.7%), headache (36.7%), and joint pain (16.2%). In participants 50 to 59 years of age in Study 1007, the most frequently reported adverse reactions were pain at injection site (72.5%), muscle pain (49.8%), fatigue (39.3%), headache (32.3%), and joint pain (15.4%). In participants ≥ 60 years of age in Study 1007, the most frequently reported adverse reactions were pain at injection site (55.4%), muscle pain (39.1%), fatigue (30.2%), headache (21.5%), and joint pain (12.6%). These were usually mild or moderate in intensity and resolved within a few days after vaccination.

Phase 3 Study B7471006 (Study 1006) evaluated Prevenar 20 in participants ≥ 65 years of age with varying prior pneumococcal status (prior PPSV23, prior Prevenar 13 or prior Prevenar 13 followed by PPSV23). In this study, the most frequently reported adverse reactions for participants were similar in frequency to those described for participants ≥ 60 years of age in Study 1007, with slightly higher injection site pain (61.2%) in participants with prior Prevenar 13, and joint pain (16.8%) in participants with prior Prevenar 13 followed by PPSV23.


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Tabulated list of adverse reactions
Tabulated lists of adverse reactions from the infant Phase 2, Phase 3 clinical trials in paediatric and adult populations and postmarketing experience are presented below.

Adverse reactions from clinical trials

As Prevenar 20 contains the same 13 serotype-specific capsular polysaccharide conjugates and the same vaccine excipients as Prevenar 13, the adverse reactions already identified for Prevenar 13 have been adopted for Prevenar 20. Table 1 presents adverse reactions reported in the Phase 2 infant trial, and the Phase 3 trials in paediatric and adult populations, based on the highest frequency among adverse reactions, local reactions, or systemic events, after vaccination in an Prevenar 20 group or integrated dataset. The data from clinical trials in infants reflect Prevenar 20 administered simultaneously with other routine childhood vaccines.

Adverse reactions are listed by system organ class in decreasing order of frequency and seriousness.
The frequency is defined as follows: 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).

Table 1.    Tabulated Adverse Reactions From Prevenar 20 Clinical Trials System Organ    Adverse Reactions                        Frequency
Class
Infants/Children/Adolescents                     Adults
6 weeks to less    5 years to less than 5 years of     than 18 years age              of age a
Immune System Hypersensitivity               Rare                 -                      Uncommon Disorders       reaction including face oedema,
dyspnoea,
bronchospasm
Metabolism and Decreased appetite        Very common       Very commona                     Very Nutrition                                                                                 commona Disorders
Psychiatric     Irritability             Very common       Very commona                       - a
Disorders       Crying                    Uncommon                -                           - Nervous         Drowsiness/increased     Very common       Very commona                       - System          sleep
Disorders       Seizures (including       Uncommon                -                           - febrile seizures)
Hypotonic-                   Rarea                -                           - hyporesponsive episode
Restless                Very commona       Very commona                       - sleep/decreased sleep
Headache                       -           Very common                     Very common
Gastrointestinal   Diarrhoea                      Common               Commona          Uncommonb Disorders          Nausea                            -                    -             Uncommon Vomiting                       Common               Commona          Uncommonb Skin and           Rash                           Common               Commona          Uncommonb Subcutaneous       Angioedema                        -                    -             Uncommon Tissue             Urticaria or urticaria-       Uncommon             Uncommon              - Disorders          like rash
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Table 1.     Tabulated Adverse Reactions From Prevenar 20 Clinical Trials System Organ     Adverse Reactions                        Frequency
Class
Infants/Children/Adolescents                                      Adults 6 weeks to less    5 years to less than 5 years of     than 18 years age              of age
Musculoskeletal Muscle pain                     -           Very common                                      Very and connective                                                                                             common tissue Disorders Joint pain                     -              Common                                        Very common
General                Fever (pyrexia)                  Very common                 Uncommon               Common Disorders and          Fever greater than                 Common                        -                     - Administration         38.9 °C
Site Conditions        Fatigue                                   -                Very common                Very common
Vaccination-site                 Very common               Very common              Commonb erythema
Vaccination-site                 Very common               Very common              Commonb induration/swelling
Vaccination-site                 Very common                       -                      - erythema or                    (after toddler dose induration/swelling                and in older
(> 2.0-7.0 cm)                 children [age 2 to
< 5 years])
Common (after                     -                      - infant series)
Vaccination-site                   Uncommon                        -                      - erythema or induration/swelling
(> 7.0 cm)
Vaccination-site                 Very common               Very common                Very pain/tenderness                                                                     common Vaccination-site                    Common                    Common                  Very pain/tenderness                                                                     commona causing limitation of limb movement
Vaccination-site                          -                        -               Uncommon pruritus
Lymphadenopathy                           -                        -               Uncommon Vaccination-site                          -                        -               Uncommon urticaria
Chills                                   -                         -              Uncommonb Vaccination-site                       Rarec                       -                  - hypersensitivity a. These frequencies are based on adverse reactions (ARs) reported in clinical trials with Prevenar 13 as these ARs were not reported in Prevenar 20 trials of infants (Phase 2 and 3), children and adolescents less than 18 years of age, and adults 18 years and older (Phase 3); therefore, the frequency is not known.
b. Event reported from clinical trials in adults with Prevenar 13 with very common frequency (≥ 1/10).
c. AR not reported for Prevenar 13, although injection-site urticaria, injection-site pruritus, and injection-site dermatitis were reported in Prevenar 13 postmarketing experience.



Safety with concomitant vaccine administration in adults
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When Prevenar 20 was administered to adults aged ≥ 65 years together with the third (booster) dose of a COVID-19 mRNA vaccine (nucleoside modified), the tolerability profile generally resembled that of the COVID-19 mRNA vaccine (nucleoside modified) administered alone. There were a few differences in the safety profile when compared to administration of Prevenar 20 alone. In the phase 3 trial B7471026 (Study 1026), pyrexia (13.0%) and chills (26.5%) were reported as “very common” with co-administration. There was also one report of dizziness (0.5%) in the co-administration group.

Adverse reactions from postmarketing experience

Table 2 includes adverse experiences that have been spontaneously reported during the postmarketing use of Prevenar 13 in paediatric and adult populations , which may also occur with Prevenar 20. The postmarketing safety experience with Prevenar 13 is relevant to Prevenar 20, as Prevenar 20 contains all components (polysaccharide conjugates and excipients) of Prevenar 13. These events were reported voluntarily from a population of uncertain size. Therefore, it is not possible to reliably estimate their frequency or to establish, for all events, a causal relationship to vaccine exposure.

Table 2. Adverse Reactions From Prevenar 13 Postmarketing Experience
System Organ Class                                  Frequency Not Known 
Blood and lymphatic system disorders                     Lymphadenopathy localised to the region of the vaccination -site
Immune system disorders                                  Anaphylactic/anaphylactoid reaction, including shock
Skin and subcutaneous tissue disorders                   Angioedema, Erythema multiforme General disorders and administration site                Vaccination-site dermatitis, Vaccination-site conditions                                               urticaria, Vaccination-site pruritus Events reported spontaneously in Prevenar 13 postmarketing experience; therefore, the frequencies could not be estimated from the available Prevenar 20 data and are considered as not known.

Additional information in special populations in studies with Prevenar 13 
Participants 6 to < 18 years of age with HIV infection have similar frequencies of adverse reactions in Table 1, except fever (11% to 19%), joint pain (24% to 42%), and vomiting (8% to 18%), which were very common. Participants ≥ 18 years of age with HIV infection have similar frequencies of adverse reactions in Table 1, except for pyrexia (5% to 18%) and vomiting (8% to 12%) which were very common and nausea (< 1% to 3%) which was common.

Participants 2 to < 18 years of age with HSCT have similar frequencies of adverse reactions in Table 1, except vaccination-site pain causing limitation of limb movement (5% to 15%), vomiting (6% to 21%), diarrhoea (15% to 32%), and joint pain (25% to 32%), which were very common.
Participants ≥ 18 years of age with an HSCT have similar frequencies of adverse reactions in Table 1, except for pyrexia (4% to 15%), vomiting (6% to 21%), and diarrhoea (25% to 36%) which were very common.

Participants 6 to < 18 years of age with SCD have similar frequencies of adverse reactions in Table 1, except vaccination-site pain causing limitation of limb movement (11% to 16%), fever (21% to 22%), vomiting (13% to 15%), diarrhoea (13% to 25%), and joint pain (40% to 45%), which were very common.


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.

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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/