Efluelda TIV-HD, suspension for injection in pre-filled syringe

Efluelda TIV-HD is indicated for active immunisation in adults 60 years of age and older for the prevention of influenza disease.

The use of Efluelda TIV-HD should be based in accordance with official recommendations on vaccination against influenza.

Posology

In adults 60 years of age and older: one dose of 0.5 ml.

Paediatric population

The safety and effectiveness of Efluelda TIV-HD in children less than 18 years of age have not been established.

Method of administration

The preferred route of administration for this vaccine is intramuscular although it may also be given subcutaneously.

The recommended site for intramuscular injection is the deltoid region. The vaccine should not be injected into the gluteal region, or into areas where there may be a major nerve trunk.

For instructions on preparation of the medicinal product before administration, see Section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in Section 6.1 or to any component that may be present as traces such as eggs (ovalbumin, chicken proteins) and formaldehyde.

Traceability

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

Hypersensitivity

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following the administration of the vaccine.

Precaution for use

Efluelda TIV-HD should under no circumstances be administered intravascularly.

Intercurrent illness

Vaccination should be postponed in patients with acute febrile illness until the fever is resolved.

Guillain-Barré syndrome

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of any previous influenza vaccination, the decision to give Efluelda TIV-HD should be based on careful consideration of the potential benefits and risks.

Thrombocytopenia and coagulation disorders

As with other vaccines administered intramuscularly, the vaccine should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

Syncope

Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. Procedures should be in place to prevent injury from fainting and manage syncopal reactions.

Immunodeficiency

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

Protection

As with any vaccine, a protective response may not be elicited in all vaccine recipients.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium free”.

Co-administration of Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High Dose (QIV-HD) with an investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified/elasomeran) has been evaluated in a limited number of participants in a descriptive clinical study (see sections 4.8 and 5.1).

If Efluelda TIV-HD needs to be given at the same time as another injectable vaccine(s), immunisation should be carried out on separate limbs.

It should be noted that the adverse reactions may be intensified by any co-administration.

The immunological response may be reduced if the patient is undergoing immunosuppressant treatment.

Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been reported. An appropriate Western Blot test should be used to confirm or disprove the results of the ELISA test. The transient false positive reactions could be due to a non-specific IgM response induced by influenza vaccine.

Efluelda TIV-HD is only indicated for use in adults aged 60 years and older.

Efluelda TIV-HD has not been clinically evaluated in pregnant and breast-feeding women.

Pregnancy

Inactivated influenza standard dose vaccines (15 micrograms haemagglutinin of each virus strain per dose) can be used in all stages of pregnancy. Larger datasets on safety are available for the second and third trimester, compared with the first trimester. Data from worldwide use of inactivated influenza standard dose vaccines do not indicate any adverse foetal and maternal outcomes attributable to the vaccine. However, data on the use of influenza vaccines containing 60 micrograms haemagglutinin of each virus strain per dose in pregnant women are limited.

Breastfeeding

Efluelda TIV-HD may be used during breast-feeding. Based on experience with standard dose vaccines, no effects on the breast-fed infant are anticipated.

Fertility

Efluelda TIV-HD has not been evaluated for possible effects on human fertility.

Efluelda TIV-HD has no or negligible influence on the ability to drive and use machines.

a. Summary of the safety profile

Efluelda TIV-HD is identical to Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High Dose (QIV-HD) with the only difference of containing antigen from one less influenza B strain. The safety profile of QIV-HD is therefore relevant to the use of Efluelda TIV-HD.

The safety of QIV-HD was assessed in a pooled analysis of two clinical trials (QHD00013 and QHD00011) in which 2549 adults from 60 years of age and older (378 adults from 60 to 64 years of age and 2171 adults 65 years of age and older) received QIV-HD.

The most frequently reported adverse reaction after vaccination was injection site pain reported by 42.6% of study participants followed by myalgia (23.8%), headache (17.3%), and malaise (15.6%). Most of these reactions occurred and resolved within three days of vaccination. The intensity of most of these reactions was mild to moderate.

Overall, adverse reactions were generally less frequent in participants aged 65 years and older than in participants aged 60 to 64 years.

Reactogenicity of QIV-HD was slightly increased as compared to the standard dose vaccine (15 micrograms haemagglutinin of each virus strain per dose), but no major difference in intensity was observed.

The safety of QIV-HD was evaluated in a descriptive study (QHD00028) in which subjects received QIV-HD together with an investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified) (n=100), QIV-HD only (n=92) or an investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified) only (n=104). The frequency and severity of local and systemic adverse reactions was similar in subjects who were co-administered with QIV-HD and licensed COVID-19 mRNA vaccine and subjects administered with a booster dose of licensed COVID-19 mRNA vaccine.

b. Tabulated list of adverse reactions

The data below summarises the frequencies of adverse reactions that were recorded following vaccination with QIV-HD and adverse reactions reported during clinical development and post-marketing experience with the trivalent and the quadrivalent influenza high-dose vaccines.

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).

^a Dyspepsia, lethargy, and muscular weakness were observed with Efluelda TIV-HD in the QHD00013 trial.

* Reported during post-marketing experience with Efluelda TIV-HD or QIV-HD

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 Medicines and Healthcare products Regulatory Agency (MHRA), Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Cases of administration of more than the recommended dose have been reported with Efluelda TIV-HD associated with inadvertent use in the population below 60 years of age due to medication error. When adverse reactions were reported, the information was consistent with the known safety profile of Efluelda TIV-HD (see section 4.8).

Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02.

Annual influenza vaccination is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year.

Clinical Efficacy

FIM12 was a multi-centre, double-blind efficacy trial conducted in the US and Canada in which adults 65 years of age and older were randomised (1:1) to receive Efluelda TIV-HD or a standard dose vaccine. The study was conducted over two influenza seasons (2011-2012 and 2012-2013) to assess the occurrence of laboratory-confirmed influenza caused by any influenza viral type/subtype, in association with influenza-like illness (ILI) as the primary endpoint.

Participants were monitored for the occurrence of a respiratory illness by both active and passive surveillance, starting 2 weeks post-vaccination for approximately 7 months. After an episode of respiratory illness, nasopharyngeal swab samples were collected for analysis; attack rates and vaccine efficacy were calculated. The pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95% CI of the vaccine efficacy for Efluelda TIV-HD relative to standard dose vaccine >9.1%) was met.

Table 3: Relative vaccine efficacy to prevent influenza-like illness^a in adults ≥ 65 years

^a Occurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature >37.2 °C, chills, tiredness, headaches or myalgia

^b N is the number of vaccinated participants in the per-protocol analysis set for efficacy assessments

^c n is the number of participants with protocol-defined influenza-like illness with laboratory confirmation

^d Laboratory-confirmed: culture- or polymerase-chain-reaction-confirmed

^e Primary endpoint

Immunogenicity

Immunogenicity study comparing Efluelda TIV-HD with a standard dose vaccine in adults 65 years and older: FIM05

A phase 3 randomised, double-blind, active-controlled, multi-centre trial was conducted in US in adults aged 65 years and older to demonstrate the superiority of Efluelda TIV-HD versus a standard dose vaccine, as assessed by seroconversion rates and GMT ratios. A total of 3,876 adults were randomised to receive either one dose of Efluelda TIV-HD or standard dose vaccine.

Efluelda TIV-HD induced superior immune response against A/H1N1 and A/H3N2 strains and a non-inferior immune response against B strain, both in terms of GMT ratios and seroconversion rates 28 days after vaccination, compared to standard dose vaccine.

Immunogenicity study comparing Efluelda TIV-HD with QIV-HD in adults 65 years and older: QHD00013

A randomised, active-controlled, modified double-blind Phase III clinical trial was conducted in the U.S. in adults 65 years and older to demonstrate the noninferiority of QIV-HD over Efluelda TIV-HD as assessed by HAI (haemagglutinin inhibition) Geometric mean antibody titres (GMTs) at Day 28 and seroconversion rates.

A total of 2670 adults were randomised to receive either one dose of QIV-HD or one dose of Efluelda TIV-HD (one of two formulations of comparator vaccine, containing either a B strain of the Yamagata lineage or a B strain of the Victoria lineage).

QIV-HD was as immunogenic as Efluelda TIV-HD for HAI GMTs and seroconversion rates for the common influenza strains. These data allow extrapolating the immunogenicity, efficacy and effectiveness results of QIV-HD to Efluelda TIV-HD.

Immunogenicity study comparing High dose Influenza vaccine with Standard dose influenza vaccine in adults 60 years and older: QHD00011

A randomised, active-controlled, modified double-blind, Phase III clinical trial was conducted in Europe in adults 60 years and older to demonstrate the superiority of QIV-HD over Standard dose influenza vaccine for all strains, as assessed by HAI (haemagglutinin inhibition) geometric mean antibody titres (GMTs) at Day 28 in adults 60 to 64 years of age and in adults 65 years of age and older.

A total of 1539 adults (760 adults 60 to 64 years of age and 779 adults 65 years of age and older) were randomised to receive either one dose of QIV-HD or one dose of Standard dose influenza vaccine.

QIV-HD induced a superior immune response to Standard dose influenza vaccine for all 4 virus strains 28 days post-vaccination in adults 60 to 64 years of age, and this response was at least similar to the immune response in adults 65 years and above. The efficacy and effectiveness data from 65 years of age and above can thus be inferred to adults from 60 years of age and above.

Effectiveness Studies

The effectiveness of High-dose influenza vaccine compared to standard-dose influenza vaccine has been evaluated for the prevention of influenza-related complications in adults 65 years and older across multiple study designs, settings and populations.

Meta-analysis of observational studies among adults 65 years and older:

Several retrospective studies, over 11 influenza seasons and in more than 45 million individuals 65 years of age and older, confirmed the superior protection offered by High-Dose influenza vaccine compared to standard-dose influenza vaccines against complications of influenza such as pneumonia and influenza hospitalisation (13.4% (95%CI: 7.3% to 19.2%, p<0.001)), cardio-respiratory hospitalisation 17.9% (95%CI :14.7% to 21.0%, p<0.001) and all–cause hospitalisation 7.8% (95%CI: 5.3% to 10.3%, p<0.001); although the impact may vary per season.

Individually randomised adults 65 years and older (FLUNITY-HD study):

The benefit of High-Dose influenza vaccine compared to standard-dose influenza vaccine was confirmed in the FLUNITY-HD study, a prespecified pooled analysis of two methodologically harmonised, individually randomised, pragmatic registry-based trials conducted in Denmark and Spain during the 2022/2023 to 2024/2025 influenza seasons enrolling 466 320 participants (mean age 73.3±5.4 years) of whom 49% had at least one chronic condition (e.g. history of cardiovascular disease, chronic lung disease, diabetes). For the primary objective, high-dose influenza vaccine reduced influenza or pneumonia hospitalisation by 8.8% (95% CI: 1.7- 15.5%, p=0.0082), although there was heterogeneity between the trials for the primary outcome: the reduction was 5.9% (95% CI: -2.1 to 13.3%) in Denmark versus 23.7% (95% CI: 6.6 to 37.7%) in Spain. Relative vaccine effectiveness (rVE) was also demonstrated against cardio-respiratory hospitalisation (rVE= 6.3%, 95% CI:2.5-10.0%, p=0.0006), all-cause hospitalisation (rVE=2.2%, 95% CI: 0.3-4.1%, p=0.012). and laboratory-confirmed influenza hospitalisation (rVE=31.9%, 95% CI: 19.7-42.2%, p<0.0001).

Cluster-randomised trial in adults 65 years and older in nursing homes:

A US cluster- randomised trial in 53 008 nursing home residents during the 2013-2014 season, demonstrated that Efluelda significantly reduced respiratory-related hospital admissions by 12.7% (adjusted risk ratio [ARR] 0.873, 95% CI 0.776 to 0.982, p=0.023), pneumonia admissions by 20.9% (ARR 0.791, 95% CI: 0.267 to 0.953, p=0.013), and all-cause admissions by 8.0% (ARR 0.915, 95% CI: 0.863 to 0.970, p=0.0028) compared to standard-dose influenza vaccine in nursing home populations.

Concomitant Administration of QIV-HD with COVID-19 mRNA Vaccine (nucleoside modified)

In a descriptive open-label clinical study (NCT04969276), healthy adults aged 65 years and older were divided in three groups: Group 1 received QIV-HD alone (N=92), Group 2 (N=100) received QIV-HD concomitantly with an investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified) at least 5 months after the second dose of the primary series, Group 3 (N=104) received only the investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified).

Co-administration resulted in no change to influenza vaccine immune responses as measured by haemagglutination inhibition (HAI) assay. Co-administration resulted in similar responses to COVID-19 mRNA vaccine, as assessed by an anti-spike IgG assay (see section 4.5 and 4.8).

Not applicable.

Nonclinical data reveal no special hazards for humans based on conventional studies of local tolerance and repeated dose toxicity studies.

Efluelda TIV-HD has not been evaluated for carcinogenic or mutagenic potential nor for developmental and reproductive toxicity study.

• Sodium phosphate-buffered isotonic sodium chloride solution
  o Sodium chloride,
  o Monobasic sodium phosphate
  o Dibasic sodium phosphate
  o Water for injections
• Octoxinol-9

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

12 months

Store in a refrigerator (2 °C – 8 °C). Do not freeze. Keep the syringe in the outer carton in order to protect from light.

0.5 ml of suspension in pre-filled syringe (Type I glass) equipped with a plunger stopper (bromobutyl rubber) and a tip-cap.

Pack of 1, 5 or 10 pre-filled syringe(s) without needle(s).

Pack of 1, 5 or 10 pre-filled syringe(s) with separate needle(s) (stainless steel).

Pack of 1 or 10 pre-filled syringe(s) with separate needle(s) (stainless steel) with safety shield (polycarbonate).

Not all pack sizes may be marketed.

The vaccine should be allowed to reach room temperature before use.

Shake before use.

The vaccines should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.

Preparation for Administration

The pre-filled syringe can be supplied with a Luer Lock with either Rigid Tip Cap (Picture A) or Soft Tip Cap (Picture D). The syringe with suspension for injection should be visually inspected prior to administration. In the event of any foreign particulate matter, leakage, premature activation of the plunger or faulty tip seal, discard the pre-filled syringe.

Picture A: Luer Lock Syringe with Rigid Tip Cap

Instructions for use of Safety Needle with Luer Lock pre-filled syringe:

Follow Step 1 and 2 above to prepare the Luer Lock syringe and needle for attachment.

Picture D: Luer Lock Syringe with Soft Tip Cap

The syringe is intended for single use only and must not be reused. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.