Adverse reactions : תופעות לוואי

6     ADVERSE REACTIONS
The most common adverse reactions, reported in >10% of subjects vaccinated with PNEUMOVAX 23 for the first time in a clinical trial, were: injection-site pain/soreness/tenderness (60.0%), injection-site swelling/induration (20.3%), headache (17.6%), injection-site erythema (16.4%), asthenia/fatigue (13.2%), and myalgia (11.9%). [See Adverse Reactions (6.1).]

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.
Primary Vaccination and Revaccination with PNEUMOVAX 23 in Adults 50 Years of Age or Older In a randomized, double-blind, placebo-controlled crossover clinical trial, subjects were enrolled in four different cohorts defined by age (50-64 years of age and ≥65 years of age) and vaccination status (no pneumococcal vaccination or receipt of a pneumococcal polysaccharide vaccine 3-5 years prior to the study). Subjects in each cohort were randomized to receive intramuscular injections of PNEUMOVAX 23 followed by placebo (saline containing 0.25% phenol), or placebo followed by PNEUMOVAX 23, at 30-day (±7 days) intervals. The safety of an initial vaccination (first dose) was compared to revaccination (second dose) with PNEUMOVAX 23 for 14 days following each vaccination.
All 1008 subjects (average age, 67 years; 49% male and 51% female; 91% Caucasian, 4.7% African- American, 3.5% Hispanic, and 0.8% Other) received placebo injections.
Initial vaccination was evaluated in a total of 444 subjects (average age 65 years; 32% male and 68% female; 93% Caucasian, 3.2% African-American, 3.4% Hispanic, and 1.1% Other).
Revaccination was evaluated in 564 subjects (average age 69 years; 53% male and 47% female; 90% Caucasian, 3.5% Hispanic, 6.0% African-American, and 0.5% Other).

Serious Adverse Experiences
In this study, 10 subjects had serious adverse experiences within 14 days of vaccination: 6 who received PNEUMOVAX 23 and 4 who received placebo. Serious adverse experiences within 14 days after PNEUMOVAX 23 included angina pectoris, heart failure, chest pain, ulcerative colitis, depression, and headache/tremor/stiffness/sweating. Serious adverse experiences within 14 days after placebo included myocardial infarction complicated with heart failure, alcohol intoxication, angina pectoris, and edema/urinary retention/heart failure/diabetes.
Five subjects reported serious adverse experiences that occurred outside the 14-day follow-up window: 3 who received PNEUMOVAX 23 and 2 who received placebo. Serious adverse experiences after PNEUMOVAX 23 included cerebrovascular accident, lumbar radiculopathy, and pancreatitis/myocardial infarction resulting in death. Serious adverse experiences after placebo included heart failure and motor vehicle accident resulting in death.

Solicited and Unsolicited Reactions
Table 1 presents the adverse event rates for all solicited and unsolicited reactions reported in ≥1% in any group in this study, without regard to causality.
The most common local adverse reactions reported at the injection site after initial vaccination with PNEUMOVAX 23 were pain/tenderness/soreness (60.0%), swelling/induration (20.3%), and erythema (16.4%). The most common systemic adverse experiences were headache (17.6%), asthenia/fatigue (13.2%), and myalgia (11.9%).
The most common local adverse reactions reported at the injection site after revaccination with PNEUMOVAX 23 were pain/soreness/tenderness (77.2%), swelling (39.8%), and erythema (34.5%). The most common systemic adverse reactions with revaccination were headache (18.1%), asthenia/fatigue (17.9%), and myalgia (17.3%). All of these adverse reactions were reported at a rate lower than 10% after receiving a placebo injection.
Table 1: Incidence of Injection-Site and Systemic Complaints in Adults ≥50 Years of Age Receiving Their First (Initial) or Second (Revaccination) Dose of PNEUMOVAX 23 (Pneumococcal Polysaccharide Vaccine, 23 Valent) or Placebo Occurring at ≥1% in Any Group

PNEUMOVAX 23                PNEUMOVAX 23            Placebo Injection† Initial Vaccination          Revaccination*
N=444                    N=564                     N=1008
Number Followed for Safety                             438                          548                     984‡ AE Rate                     AE Rate                   AE Rate
Injection-Site Complaints

Solicited Events

Pain/Soreness/Tenderness                         60.0%                       77.2%                     7.7% 
Swelling/Induration                              20.3%                       39.8%                     2.8% Erythema                                         16.4%                       34.5%                     3.3% Unsolicited Events

Ecchymosis                                         0%                          1.1%                    0.3% Pruritus                                          0.2%                         1.6%                    0.0% Systemic Complaints
Solicited Events
Asthenia/Fatigue                                 13.2%                       17.9%                     6.7% Chills                                            2.7%                         7.8%                    1.8% Myalgia                                          11.9%                       17.3%                     3.3% Headache                                         17.6%                       18.1%                     8.9% Unsolicited Events
Fever§                                            1.4%                        2.0%                    0.7% Diarrhea                                          1.1%                        0.7%                    0.5% Dyspepsia                                         1.1%                        1.1%                    0.9% Nausea                                            1.8%                        1.8%                    0.9% Back Pain                                        0.9%                         0.9%                    1.0% Neck Pain                                        0.7%                         1.5%                    0.2% Upper Respiratory                                1.8%                         2.6%                    1.8% Infection
Pharyngitis                                      1.1%                         0.4%                    1.3% *Subjects receiving their second dose of pneumococcal polysaccharide vaccine as PNEUMOVAX 23 approximately 3-5 years after their first dose.
†
Subjects receiving placebo injection from this study combined over periods.
‡
The number of subjects receiving placebo followed for injection-site complaints. The corresponding number of subjects followed for systemic complaints was 981.
§
Fever events include subjects who felt feverish in addition to subjects with elevated temperature.
In this clinical study an increased rate of local reactions was observed with revaccination at 3-5 years following initial vaccination.
For subjects aged 65 years or older, injection-site adverse reaction rate was higher following revaccination (79.3%) than following initial vaccination (52.9%). The proportion of subjects reporting injection site discomfort that interfered with or prevented usual activity or injection site induration ≥4 inches was higher following revaccination (30.6%) than following initial vaccination (10.4%). Injection site reactions typically resolved by 5 days following vaccination.
For subjects aged 50-64 years, the injection-site adverse reaction rate for revaccinees and initial vaccinees was similar (79.6% and 72.8% respectively).
The rate of systemic adverse reactions was similar among both initial vaccinees and revaccinees within each age group. The rate of vaccine-related systemic adverse reactions was higher following revaccination (33.1%) than following initial vaccination (21.7%) in subjects 65 years of age or older, and was similar following revaccination (37.5%) and initial vaccination (35.5%) in subjects 50-64 years of age. The most common systemic adverse reactions reported after PNEUMOVAX 23 were as follows: asthenia/fatigue, myalgia and headache.
Regardless of age, the observed increase in post vaccination use of analgesics (≤13% in the revaccinees and ≤4% in the initial vaccinees) returned to baseline by day 5.

Sequential Administration of Prevnar 13 and PNEUMOVAX 23
In a randomized, double-blind, placebo-controlled, multicenter study, healthy adults, 50 years of age and older, received Prevnar 13 followed by PNEUMOVAX 23 either 8 weeks later (Group 1) or 26 weeks later (Group 2). Placebo was administered instead of PNEUMOVAX 23 at 26 weeks (Group 1) or 8 weeks (Group 2). Solicited injection site adverse reactions were evaluated during Days 1 through 5 postvaccination.
Solicited systemic adverse reactions and any other adverse reactions were evaluated during Days 1 through 14 postvaccination, and any serious adverse events (SAEs) were collected throughout the study period (through Week 30). [See Clinical Studies (14.2).]
Overall, subjects were a mean age of 64.2 years (range: 50 to 97 years). There were more females (n=219, 54.8%) than males (n=181, 45.3%). By race, 84.8% of subjects were White, 9.3% were Black or African-American, and 6.1% were other racial groups; the majority of subjects were not Hispanic or Latino (n=322, 80.5%).
Serious Adverse Reactions
There were 24 SAEs reported in 20 subjects (n=9 [4.5%] Group 1; n=11 [5.5%] Group 2). No SAEs were considered related to vaccination.
Solicited Adverse Reactions
Solicited injection site adverse reactions that occurred during Days 1 through 5 postvaccination with PNEUMOVAX 23, solicited systemic adverse reactions that occurred during Days 1 through 14, and fever that occurred during Days 1 through 5 postvaccination with PNEUMOVAX 23 are presented in Table 2. In this study, 81.4% of subjects in Group 1 and 64.0% of subjects in Group 2 reported at least 1 injection site adverse reaction from Days 1 through 5 postvaccination with PNEUMOVAX 23, and 64.9% of subjects in Group 1 and 54.9% of subjects in Group 2 reported at least 1 systemic adverse reaction from Days 1 through 14 postvaccination with PNEUMOVAX 23.
Table 2: Rates (%) of Solicited Injection Site Reactions Occurring on Days 1 to 5 After PNEUMOVAX 23 and Solicited Systemic Adverse Reactions Occurring on Days 1 to 14 After PNEUMOVAX 23

Group 1*                               Group 2†
(Prevnar 13 ->                    (Prevnar 13 -> Placebo ->
PNEUMOVAX 23 -> Placebo)                   PNEUMOVAX 23) n          (%)                          n          (%)
Injection Site Adverse Reactions
Subjects in population with follow-up                                           188                                   164 Any injection site reaction                                                     153          (81.4)                   105       (64.0) Any Injection site pain‡                                                     149          (79.3)                   105       (64.0) Mild                                                                          72         (38.3)                     65      (39.6) Moderate                                                                      65         (34.6)                     36      (22.0) Severe§                                                                       12          (6.4)                      4       (2.4) Any Injection site swelling                                                    95         (50.5)                     48      (29.3) 0 to <2.5 cm                                                                  28         (14.9)                     19      (11.6) ≥2.5 to <5.1 cm                                                               20         (10.6)                      9       (5.5) ≥5.1 to <7.6 cm                                                               20         (10.6)                     10       (6.1) ≥7.6 to <10.2 cm                                                              15          (8.0)                      2       (1.2) ≥10.2 cm§                                                                     12          (6.4)                      8       (4.9) Any Injection site erythema                                                    78         (41.5)                     48      (29.3) 0 to <2.5 cm                                                                  26         (13.8)                     20      (12.2) ≥2.5 to <5.1 cm                                                               12          (6.4)                     13       (7.9) ≥5.1 to <7.6 cm                                                               12          (6.4)                      6       (3.7) ≥7.6 to <10.2 cm                                                               7          (3.7)                      3       (1.8) ≥10.2 cm                                                                      19         (10.1)                      6       (3.7) Unknown [missing data]                                                         2          (1.1)                      0       (0.0) Systemic Adverse Reactions
Subjects in population with follow-up                                           188                                   164 Any systemic adverse reaction                                                   122          (64.9)                     90      (54.9) Myalgia                                                                        93         (49.5)                     70      (42.7) Fatigue                                                                        59         (31.4)                     45      (27.4) Headache                                                                       46         (24.5)                     30      (18.3) Arthralgia                                                                     37         (19.7)                     25      (15.2) Subjects with temperature data¶                                                 185                                   161 Temperature ≥ 100.4°F                                                           1         (0.5)                       0       (0.0) Every subject is counted a single time for each applicable row and column.
A specific adverse reaction appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding.
*Group 1: 8-week interval between Prevnar 13 and PNEUMOVAX 23.
†
Group 2: 26-week interval between Prevnar 13 and PNEUMOVAX 23.
‡
Pain was characterized as mild, moderate or severe. (Mild: awareness of sign or symptom, but easily tolerated. Moderate: discomfort enough to cause interference with usual activity. Severe: incapacitating with inability to work or do usual activity).
§
One Group 1 subject with severe pain and swelling greater than 10.2 cm after receipt of PNEUMOVAX 23, went to the Emergency Room for medical attention.
¶
Percentages are calculated based on number of subjects with temperature data. Oral temperature was solicited on Days 1 to 5 after PNEUMOVAX 23 vaccination.
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

6.2 Post-Marketing Experience
The following list of adverse reactions includes those identified during post approval use of PNEUMOVAX 23. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or their causal relationship to product exposure.
General disorders and administration site conditions
Cellulitis
Malaise
Fever (>38.9°C)
Warmth at the injection site
Decreased limb mobility
Peripheral edema in the injected extremity
Injection-site necrosis
Digestive System
Nausea
Vomiting
Hematologic/ Lymphatic
Lymphadenitis
Lymphadenopathy
Thrombocytopenia in patients with stabilized idiopathic thrombocytopenic purpura Hemolytic anemia in patients who have had other hematologic disorders Leukocytosis
Hypersensitivity reactions including
Anaphylactoid reactions
Serum Sickness
Angioneurotic edema
Musculoskeletal System
Arthralgia
Arthritis
Nervous System
Paresthesia
Radiculoneuropathy
Guillain-Barré syndrome
Febrile convulsion
Skin
Rash
Urticaria
Cellulitis-like reactions
Erythema multiforme
Investigations
Increased serum C-reactive protein