ZOSTAVAX Powder and solvent for suspension for injection Ref.[9861] Active ingredients: Attenuated varicella-zoster virus

Traceability

In order to improve the traceability ofbiological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic/anaphylactoid reaction following the administration of the vaccine, as there is a possibility of hypersensitivity reactions, not only to the active substances, but also to the excipients and trace residuals (e.g. neomycin) present in the vaccine (see sections 4.3, 4.8 and 6.1).

Neomycin allergy generally manifests as a contact dermatitis. However, a history of contact dermatitis due to neomycin is not a contraindication to receiving live virus vaccines.

ZOSTAVAX is a live, attenuated varicella-zoster vaccine and administration to individuals who are immunosuppressed or immunodeficient may result in disseminated varicella-zoster virus disease, including fatal outcomes. Patients who previously received immune suppressive therapy should be carefully evaluated for the reconstitution of the immune system prior to receiving Zostavax (see section 4.3).

The safety and efficacy of ZOSTAVAX have not been established in adults who are known to be infected with HIV with or without evidence of immunosuppression (see section 4.3) however, a phase II safety and immunogenicity study in HIV-infected adults with conserved immune function (CD 4+T cell count ≥200 cells/µL) has been completed (see sections 4.8 and 5.1).

This vaccine should be given subcutaneously to individuals with severe thrombocytopenia or any coagulation disorder, because these individuals may bleed following intramuscular injections.

ZOSTAVAX is not indicated for treatment of zoster or PHN.

Immunisation should be postponed in individuals suffering from moderate to severe acute febrile illness or infection.

As for any vaccine, vaccination with ZOSTAVAX may not result in protection in all vaccine recipients. See section 5.1.

Transmission

In clinical trials with ZOSTAVAX, transmission of the vaccine virus has not been reported. However, post-marketing experience with varicella vaccines suggests that transmission of vaccine virus may occur rarely between vaccinees who develop a varicella-like rash and susceptible contacts [for example, varicella-zoster virus (VZV) susceptible infant grandchildren]. Transmission of vaccine virus from varicella vaccine recipients who do not develop a varicella-like rash has also been reported. This is a theoretical risk for vaccination with ZOSTAVAX. The risk of transmitting the attenuated vaccine virus from a vaccinee to a susceptible contact should be weighed against the risk of developing natural zoster and potentially transmitting wild-type VZV to a susceptible contact.

Sodium

This medicinal product contains less than 1 mmol sodium (23 milligrams) per dose, that is to say essentially ‘sodium-free’.

Potassium

This medicinal product contains less than 1 mmol potassium (39 milligrams) per dose, that is to say essentially ‘potassium-free’.

ZOSTAVAX can be administered concomitantly with inactivated influenza vaccine as separate injections and at different body sites (see section 5.1).

The concomitant use of ZOSTAVAX and a 23-valent pneumococcal polysaccharide vaccine resulted in reduced immunogenicity of ZOSTAVAX in a small clinical trial. However, data collected in a large observational study did not indicate increased risk for developing herpes zoster after concomitant administration of the two vaccines.

No data are currently available regarding concomitant use with other vaccines.

Concurrent administration of ZOSTAVAX and anti-viral medications known to be effective against VZV has not been evaluated.

Pregnancy

There are no data on the use of ZOSTAVAX in pregnant women. Traditional non-clinical studies are insufficient with respect to reproductive toxicity (see section 5.3). However naturally-occurring varicella-zoster virus infection is known to sometimes cause foetal harm. ZOSTAVAX is not recommended to be administered to pregnant women. In any case, pregnancy should be avoided for one month following vaccination (see section 4.3).

Breast-feeding

It is unknown whether VZV is secreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to not administer ZOSTAVAX taking into account the benefit of breast-feeding for the child and the benefit of vaccination for the woman.

Fertility

ZOSTAVAX has not been evaluated in fertility studies.

No studies on the effects on the ability to drive or use machines have been performed. However, ZOSTAVAX is expected to have no or negligible influence on ability to drive and use machines.

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:

¹ Clinical trials experience.
² Solicited adverse reaction within 5 days post-vaccination.

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).

ZOSTAVAX was administered either subcutaneously (SC) or intramuscularly (IM) in subjects 50 years of age or older (see section 5.1). The general safety profiles of the SC and IM routes were otherwise comparable, but injection-site adverse reactions were significantly less frequent in the IM group (34%) compared with the SC group (64%).

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 postvaccination 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.