FLUZONE HIGH-DOSE QUADRIVALENT is indicated for active immunisation in adults 60 years of age and older for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine and the associated complication of pneumonia-related hospitalization.

The use of FLUZONE HIGH-DOSE QUADRIVALENT should be based in accordance with official recommendations on vaccination against influenza.

Posology

In adults 60 years of age and older: one dose of 0.7 ml.

Paediatric population

The safety and effectiveness of FLUZONE HIGH-DOSE QUADRIVALENT 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.

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.

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.

FLUZONE HIGH-DOSE QUADRIVALENT should under no circumstances be administered intravascularly.

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

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

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

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.

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

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

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

Co-administration of FLUZONE HIGH-DOSE QUADRIVALENT 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 FLUZONE HIGH-DOSE QUADRIVALENT needs to be given at the same time as another injectable vaccine(s), immunisation should be carried out on separate limbs.

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.

FLUZONE HIGH-DOSE QUADRIVALENT is only indicated for use in adults aged 60 years and older.

FLUZONE HIGH-DOSE QUADRIVALENT has not been clinically evaluated in pregnant and breast-feeding women.

Pregnancy

Animal reproductive studies have not been conducted with FLUZONE HIGH-DOSE QUADRIVALENT. It is also not known whether FLUZONE HIGH-DOSE QUADRIVALENT can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Data on the use of influenza high dose vaccine in pregnant women are limited. FLUZONE HIGH-DOSE QUADRIVALENT should be given to pregnant women only if clearly needed and following an assessment of the risks and benefits.

Breastfeeding

It is not known whether FLUZONE HIGH-DOSE QUADRIVALENT vaccine is excreted in human milk. Caution should be exercised when FLUZONE HIGH-DOSE QUADRIVALENT is administered to a nursing woman.

Fertility

FLUZONE HIGH-DOSE QUADRIVALENT has not been evaluated for possible effects on human fertility.

FLUZONE HIGH-DOSE QUADRIVALENT has no or negligible influence on the ability to drive and use machines. 

a. Summary of the safety profile

Adverse event information is based on data coming from two clinical trials with FLUZONE HIGH-DOSE QUADRIVALENT and on the clinical and post-marketing experience of Trivalent Influenza Vaccine (Split Virion, Inactivated) High-Dose (TIV-HD).

The safety of FLUZONE HIGH-DOSE QUADRIVALENT 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 FLUZONE HIGH-DOSE QUADRIVALENT.

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 FLUZONE HIGH-DOSE QUADRIVALENT was slightly increased as compared to the standard dose vaccine, but no major difference in intensity was observed.

The safety of FLUZONE HIGH-DOSE QUADRIVALENT (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 summarizes the frequencies of adverse reactions that were recorded following vaccination with FLUZONE HIGH-DOSE QUADRIVALENT and adverse reactions reported during clinical development and post-marketing experience with TIV-HD (marked with * in the table below).

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 TIV-HD in the QHD00013 trial.

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.

To reports any side effect(s):

Saudi Arabia:

·       The National Pharmacovigilance Centre (NPC):

-        SFDA Call Center: 19999

-        E-mail: npc.drug@sfda.gov.sa

-        Website: https://ade.sfda.gov.sa/

Other GCC States:

-        Please contact the relevant competent authority.

Sanofi Pharmacovigilance:

-        KSA_Pharmacovigilance@sanofi.com

For any other medical inquiry:

-        KSA.Medicalenquiry@sanofi.com

Cases of administration of more than the recommended dose have been reported with 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 TIV-HD.

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.

Pharmacodynamic effects

Immunogenicity - QHD00013

A randomized, active-controlled, modified double-blind Phase III clinical trial was conducted in the US in adults 65 years and older.

The objective was to demonstrate the noninferiority of FLUZONE HIGH-DOSE QUADRIVALENT over TIV-HD, as assessed by HAI (hemagglutinin inhibition) Geometric mean antibody titers (GMTs) at Day 28 and seroconversion rates.

A total of 2670 adults from 65 years of age were randomized to receive either one dose of FLUZONE HIGH-DOSE QUADRIVALENT or one dose of TIV-HD (one of two formulations of comparator vaccine [TIV-HD1 or TIV-HD2]); each TIV HD formulation contained a B strain that corresponds to one of the two B strains in FLUZONE HIGH-DOSE QUADRIVALENT (either a B strain of the Yamagata lineage or a B strain of the Victoria lineage).

The immunogenicity results are summarized below in Table 1 .

Table 1: Study 1^a: Analyses of Noninferiority of FLUZONE HIGH-DOSE QUADRIVALENT Relative to TIV-HD by Post-Vaccination HAI Antibody GMTs and Seroconversion Rates in Adults 65 Years of Age and Older, Per-Protocol Analysis Set 

^a NCT03282240

^b Seroconversion Rates: For subjects with a pre-vaccination titer <10 (1/dil), proportion of subjects with a post-vaccination titer ≥40 (1/dil) and for subjects with a pre-vaccination titer ≥10 (1/dil), proportion of subjects with a ≥four-fold increase from pre- to post-vaccination titer.

^c N is the number of vaccinated participants with available data for the immunologic endpoint listed

^d TIV-HD1 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008 (B1, Victoria lineage).

^e TIV-HD2 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Phuket/3073/2013 (B2, Yamagata lineage).

^f Predefined noninferiority criterion for seroconversion rates: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (FLUZONE HIGH-DOSE QUADRIVALENT minus TIV-HD) is >-10%. Predefined noninferiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (FLUZONE HIGH-DOSE QUADRIVALENT divided by TIV-HD) is >0.667.

^g For the A strain comparison, TIV-HD1 and TIV-HD2 were pooled into a TIV-HD group for comparison with FLUZONE HIGH-DOSE QUADRIVALENT.

FLUZONE HIGH-DOSE QUADRIVALENT was as immunogenic as TIV-HD for GMTs and seroconversion rates for the common influenza strains. Moreover, FLUZONE HIGH-DOSE QUADRIVALENT induced a superior immune response with respect to the additional B strain than the immune response induced by TIV-HD that does not contain the corresponding B.

The efficacy and effectiveness results of TIV-HD are thus inferred to FLUZONE HIGH-DOSE QUADRIVALENT given the demonstration of statistically comparable immunogenicity between TIV-HD and FLUZONE HIGH-DOSE QUADRIVALENT.

QHD00011

A randomized, active-controlled, modified double-blind, Phase III clinical trial conducted in Europe in adults 60 years and older to demonstrate the superiority of FLUZONE HIGH-DOSE QUADRIVALENT over QIV-SD for all strains, as assessed by HAI (hemagglutinin inhibition) geometric mean antibody titers (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 randomized to receive either one dose of FLUZONE HIGH-DOSE QUADRIVALENT or one dose of QIV-SD.

Table 2: Study 2^a: Analyses of Superiority of FLUZONE HIGH-DOSE QUADRIVALENT Relative to QIV-SD by Post-Vaccination HAI Antibody GMTs in Adults 60-64 Years of Age and 65 Years of Age and Older, Full Analysis Set 

^a NCT04024228

^b N is the number of participants with available data for the considered endpoint

^c Superiority was concluded if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (QIV-HD/QIV-SD) was > 1 for each strain and in each age group

The efficacy and effectiveness results of TIV-HD are thus inferred to FLUZONE HIGH-DOSE QUADRIVALENT, given the demonstration of statistically comparable immunogenicity between TIV-HD and FLUZONE HIGH-DOSE QUADRIVALENT in adults 65 years of age and older (QHD00013) and similar immune responses observed in adults 60 to 64 years of age and in adults 65 years of age and older (QHD00011).

In addition, FLUZONE HIGH-DOSE QUADRIVALENT induced an immune response that was superior to the responses induced by QIV-SD for all 4 virus strains 28 days post-vaccination in adults 60 to 64 years of age and in adults 65 years of age and older.

Pivotal Clinical Efficacy (FIM12)

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 the 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 the 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

Effectiveness Studies

Randomized Clinical Trials

A cluster-randomized, controlled clinical trial in United States nursing homes assessed the relative effect of TIV-HD versus a standard dose of influenza vaccine in hospitalizations among 53008 individuals during the 2013-2014 influenza season.

During the 2013-2014 season, the incidence of respiratory-related hospital admissions (primary objective) was significantly reduced in facilities where residents received TIV-HD compared with those that received standard-dose influenza vaccines by 12.7% (adjusted risk ratio [ARR] 0.873, 95% CI 0.776 to 0.982, p=0.023). Moreover, with respect to secondary endpoints, TIV-HD reduced hospital admissions for pneumonia by 20.9% (ARR 0.791, 95% CI: 0.267 to 0.953, p=0.013) and all-cause hospital admissions by 8% (ARR 0.915, 95% CI: 0.863 to 0.970, p=0.0028).

Observational Studies

Several retrospective studies, over 8 influenza seasons and in more than 24 million individuals 65 years of age and older, confirmed the superior protection offered by TIV-HD compared to standard-dose influenza vaccines against complications of influenza such as pneumonia and influenza hospitalization (13.4% (95%CI: 7.3% to 19.2%, p<0.001)), cardio-respiratory hospitalizations 17.9% (95%CI :14.9% to 20.9%, p<0.001) and all –cause hospitalization 8.1% (95%CI: 5.9% to 10.3%, p<0.001) ; although the impact may vary per season.

Concomitant Administration 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 FLUZONE HIGH-DOSE QUADRIVALENT alone (N=92), Group 2 (N=100) received FLUZONE HIGH-DOSE QUADRIVALENT 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 hemagglutination 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.

FLUZONE HIGH-DOSE QUADRIVALENT 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.

Store in a refrigerator (2 °C – 8 °C). Do not freeze.

0.7 ml of suspension in pre-filled syringe (Type I glass) with separate needle, equipped with a plunger stopper (bromobutyl rubber) and a tip-cap – pack size of 1.

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.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.