Adverse reactions : תופעות לוואי

4.8   Undesirable effects
 a. Summary of the safety profile
The most common adverse reactions reported in pivotal clinical trials were injection-site reactions.
Headache and pain in the extremity were the most common systemic adverse reactions. Most of these local and systemic adverse reactions were reported as mild in intensity. Vaccine-related serious adverse reactions were reported for 0.01 % subjects vaccinated with ZOSTAVAX and subjects who received placebo.

Data from a clinical trial (n=368) demonstrated that the current refrigerated formulation has a safety profile comparable to that of the frozen formulation.
 b. Tabulated summary of adverse events

In clinical trials, general safety has been evaluated in more than 57,000 adults vaccinated with ZOSTAVAX.
Table 1 presents vaccine-related injection-site and systemic adverse reactions reported at a significantly greater incidence in the vaccine group versus the placebo group within 42 days postvaccination in the ZOSTAVAX Efficacy and Safety trial (ZEST) study and in the Adverse Event Monitoring Substudy of Shingles Prevention Study (SPS).

Additional adverse reactions, spontaneously reported through post-marketing surveillance, are also included in Table 1. As these events are reported voluntarily from a population of uncertain size, it is not possible to reliably calculate their frequency or establish a causal relationship to vaccine exposure.
Consequently, the frequencies of these adverse reactions have been estimated based on the adverse events reported in SPS and ZEST (regardless of vaccine relationship assigned by the investigator).

The adverse reactions are assigned frequency categories 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)

Table 1: Adverse Reactions from Clinical Trial Experience and Post-Marketing Surveillance 
MedDRA System Organ Class                       Adverse reaction terms                    Frequency 
Infections and infestations        Varicella, Herpes zoster (vaccine strain)               Very rare 
Blood and lymphatic system         Lymphadenopathy (cervical, axillary)                  Uncommon disorders
Immune system disorders            Hypersensitivity reactions including                      Rare 
anaphylactic reactions
Nervous system disorders                     Headache1                                         Common Eye Disorders                                Necrotizing retinitis (patients on                Very rare immunosuppressive therapy)
Gastrointestinal disorders                   Nausea                                           Uncommon Skin and subcutaneous tissue                 Rash                                              Common disorders
Musculoskeletal and connective               Arthralgia, Myalgia, Pain in extremity1           Common tissue disorders
General disorders and                                                   1,2             1,2 Injection site: Erythema , Pain/tenderness ,     Very common administration site conditions                       1,2
Pruritus , Swelling
1,2


Injection site: Induration1, Haematoma1,          Common
Warmth1, Rash, Pyrexia

Injection site urticaria                            Rare
1
Clinical trials experience.
2
Solicited adverse reaction within 5 days postvaccination.
 c. Description of selected adverse reactions
Injection site reactions
Vaccine-related injection-site adverse reactions were significantly greater for subjects vaccinated with ZOSTAVAX versus subjects who received placebo. In SPS, the overall incidence of vaccine-related injection-site adverse reactions were 48 % for ZOSTAVAX and 17 % for placebo in subjects 60 years of age and older.

In ZEST, the overall incidence of vaccine-related injection site adverse reactions were 63.9 % for ZOSTAVAX and 14.4 % for placebo in subjects 50 to 59 years of age. Most of these adverse reactions were reported as mild in intensity.

In other clinical trials evaluating ZOSTAVAX in subjects 50 years of age or older, including a study of concomitantly administered inactivated influenza vaccine, a higher rate of injection-site adverse experiences of mild-to-moderate intensity was reported among subjects 50-59 years of age compared with subjects ≥ 60 years of age (see section 5.1).

Herpes zoster/herpes zoster-like rashes and Varicella/varicella-like rashes in clinical trials In clinical trials the number of herpes zoster/herpes zoster-like rashes within the 42-day post-vaccination was low in both ZOSTAVAX and placebo groups. The majority of rashes have been rated as mild to moderate; no complications from rash have been observed in the clinical setting. Most of the reporting rashes that were VZV positive by PCR analysis were associated with wild-type VZV.

In SPS and ZEST, the number of subjects who reported herpes zoster/herpes zoster-like rashes was less than 0.2 % for ZOSTAVAX and placebo groups, with no significant difference observed between the two groups. The number of subjects who reported varicella/varicella-like rashes was less than 0.7 % for ZOSTAVAX and placebo.

The Oka/Merck strain of VZV was not detected from any specimens in SPS or ZEST. VZV was detected in one (0.01 %) specimen from a ZOSTAVAX recipient reporting a varicella/varicella-like rash; however, the virus strain (wild type or Oka/Merck strain) could not be determined. Across all other clinical trials, the Oka/Merck strain was identified by PCR analysis from the lesion specimens of only two subjects who reported varicella-like rashes (onset on Day 8 and 17).

d. Special populations

Adults with a history of herpes zoster (HZ) prior to vaccination
ZOSTAVAX was administered to subjects 50 years of age or older with a history of herpes zoster (HZ) prior to vaccination (see section 5.1). The safety profile was generally similar to that seen in the Adverse Event Monitoring Substudy of the SPS.

Adults on chronic/maintenance systemic corticosteroids
In subjects 60 years of age or older who were receiving chronic/maintenance systemic corticosteroid therapy at a daily dose equivalent of 5 to 20 mg of prednisone for at least 2 weeks prior to enrollment, and 6 weeks or more following vaccination, the safety profile was generally comparable to that seen in the Adverse Event Monitoring Substudy of the SPS (see sections 4.3 and 5.1).

HIV-infected adults with conserved immune function
In a clinical trial, ZOSTAVAX was administered to HIV-infected adults (18 years of age or older, CD4+ T cell count ≥ 200 cells/µL) (see section 5.1). The safety profile was generally similar to the Adverse Event Monitoring Substudy of the SPS. Adverse events were followed up to Day 42 post vaccination and serious adverse events throughout the entire study period (i.e. through Day 180). Of the 295 ZOSTAVAX recipients, one case of serious vaccine related maculo-papular rash was reported on Day 4 following Dose 1 of ZOSTAVAX (see section 4.3).

VZV-seronegative adults
Based on limited data from 2 clinical trials that enrolled VZV-seronegative or low seropositive subjects (30 years of age or older) receiving live attenuated zoster vaccine, injection site and systemic adverse experiences were generally similar to those reported by other subjects who received ZOSTAVAX in clinical trials, with 2 of the 27 subjects reporting fever. No subjects reported varicella-like or herpes zoster-like rashes. No serious vaccine-related adverse experiences were reported.
 e. Other studies

Adults receiving additional doses/revaccination
In a clinical study, adults 60 years of age or older received a second dose of ZOSTAVAX 42 days following the initial dose (see section 5.1). The frequency of vaccine-related adverse experiences after the second dose of ZOSTAVAX was generally similar to that seen with the first dose.

In another study, ZOSTAVAX was administered as a booster dose to HZ history-negative subjects 70 years of age or older who had received a first dose approximately 10 years previously, and as a first dose to HZ history-negative subjects 70 years of age or older (see section 5.1). The frequency of vaccine- related adverse experiences after the booster dose of ZOSTAVAX was generally similar to that seen with the first dose.

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/