FLUENZ TETRA nasal spray, suspension medication leaflet

Fluenz Tetra nasal spray suspension

Influenza vaccine (live attenuated, nasal)

Reassortant influenza virus* (live attenuated) of the following four strains**:

A/Victoria/4897/2022 (H1N1)pdm09 - like strain(A/Norway/31694/2022, MEDI 369815) 107.0±0.5 FFU***

A/Darwin/9/2021 (H3N2) - like strain(A/Norway/16606/2021, MEDI 355293) 107.0±0.5 FFU***

B/Austria/1359417/2021 - like strain(B/Austria/1359417/2021, MEDI 355292) 107.0±0.5 FFU***

B/Phuket/3073/2013 - like strain(B/Phuket/3073/2013, MEDI 306444) 107.0±0.5 FFU***.................................................................................................................per 0.2 ml dose

* propagated in fertilised hens’ eggs from healthy chicken flocks.

** produced in VERO cells by reverse genetic technology. This product contains geneticallymodified organisms (GMOs).

*** fluorescent focus units.

This vaccine complies with the WHO recommendation (Northern Hemisphere) and EU decision forthe 2023/2024 season.

The vaccine may contain residues of the following substances: egg proteins (e.g. ovalbumin) andgentamicin. The maximum amount of ovalbumin is less than 0.024 micrograms per 0.2 ml dose (0.12micrograms per ml).

For the full list of excipients, see section 6.1.

Nasal spray, suspension

The suspension is colourless to pale yellow, clear to opalescent with a pH of approximately 7.2. Smallwhite particles may be present.

Prophylaxis of influenza in children and adolescents from 24 months to less than 18 years of age.

The use of Fluenz Tetra should be based on official recommendations.

Children and adolescents from 24 months:0.2 ml (administered as 0.1 ml per nostril).

For children who have not previously been vaccinated against seasonal influenza, a second doseshould be given after an interval of at least 4 weeks.

Fluenz Tetra should not be used in infants and toddlers below 24 months of age because of safetyconcerns regarding increased rates of hospitalisation and wheezing in this population (see section 4.8).

Immunisation must be carried out by nasal administration.

Do not inject Fluenz Tetra.

Fluenz Tetra is administered as a divided dose in both nostrils. After administering half of the dose inone nostril, administer the other half of the dose in the other nostril immediately or shortly thereafter.

The patient can breathe normally while the vaccine is being administered - there is no need to activelyinhale or sniff.

See section 6.6 for administration instructions.

- Hypersensitivity to the active substances, to any of the excipients listed insection 6.1 (e.g. gelatin), or to gentamicin (a possible trace residue).

- Severe allergic reaction (e.g. anaphylaxis) to eggs or to egg proteins (e.g. ovalbumin).

- Children and adolescents with clinical immunodeficiency due to conditions orimmunosuppressive therapy such as: acute and chronic leukaemias; lymphoma;symptomatic HIV infection; cellular immune deficiencies; and high-dose corticosteroids.

Fluenz Tetra is not contraindicated for use in individuals with asymptomatic HIVinfection; or individuals who are receiving topical/inhaled corticosteroids or low-dosesystemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. foradrenal insufficiency.

- Children and adolescents younger than 18 years of age receiving salicylate therapybecause of the association of Reye’s syndrome with salicylates and wild-type influenzainfection.

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

As with most vaccines, appropriate medical treatment and supervision should always be readilyavailable to manage an anaphylactic event or serious hypersensitivity event following theadministration of Fluenz Tetra.

Fluenz Tetra should not be administered to children and adolescents with severe asthma or activewheezing because these individuals have not been adequately studied in clinical studies.

Vaccine recipients should be informed that Fluenz Tetra is an attenuated live virus vaccine and has thepotential for transmission to immunocompromised contacts. Vaccine recipients should attempt toavoid, whenever possible, close association with severely immunocompromised individuals (e.g. bonemarrow transplant recipients requiring isolation) for 1-2 weeks following vaccination. Peak incidenceof vaccine virus recovery occurred 2-3 days post-vaccination in Fluenz clinical studies. Incircumstances where contact with severely immunocompromised individuals is unavoidable, thepotential risk of transmission of the influenza vaccine virus should be weighed against the risk ofacquiring and transmitting wild-type influenza virus.

Fluenz Tetra should under no circumstances be injected.

No data exist regarding the safety of intranasal administration of Fluenz Tetra in children withunrepaired craniofacial malformations.

Do not administer Fluenz Tetra to children and adolescents receiving salicylate therapy(see section 4.3). Do not use salicylates in children and adolescents for 4 weeks after vaccinationunless medically indicated as Reye’s syndrome has been reported following the use of salicylatesduring wild-type influenza infection.

The co-administration of trivalent Fluenz with the live attenuated vaccines: measles, mumps, rubella,varicella and orally-administered poliovirus has been studied. No clinically meaningful changes inimmune responses to measles, mumps, varicella, orally-administered poliovirus or Fluenz have beenobserved. The immune response to rubella vaccine was significantly altered. However, this alterationmight not be of clinical relevance with the two dose immunisation schedule of the rubella vaccine.

This observation with trivalent Fluenz is relevant to the use of Fluenz Tetra because Fluenz Tetra(influenza vaccine-liveattenuated, nasal) is identical to Fluenz with the only difference being theaddition of a fourth strain (a second B strain) to Fluenz Tetra.

The co-administration of Fluenz Tetra with inactivated vaccines has not been studied.

The concurrent use of Fluenz Tetra with antiviral agents that are active against influenza A and/or Bviruses has not been evaluated. However, based upon the potential for influenza antiviral agents toreduce the effectiveness of Fluenz Tetra, it is recommended not to administer the vaccineuntil 48 hours after the cessation of influenza antiviral therapy. Administration of influenza antiviralagents within two weeks of vaccination may affect the response of the vaccine.

If influenza antiviral agents and Fluenz Tetra are administered concomitantly, revaccination should beconsidered based on clinical judgement.

There is a moderate amount of data from the use of Fluenz Tetra in pregnant women. There was noevidence of significant maternal adverse outcomes in 138 pregnant women who had a record ofreceiving trivalent Fluenz in a US-based health insurance claims database.

In more than 300 case reports in the AstraZeneca safety database of vaccine administration to pregnantwomen, no unusual patterns of pregnancy complications or foetal outcomes were observed.

While animal studies do not indicate direct or indirect harmful effects with respect to reproductivetoxicity, and post-marketing data offer some reassurance in the event of inadvertent administrationof the vaccine, Fluenz Tetra is not recommended during pregnancy.

It is not known whether Fluenz Tetra is excreted in human milk. Therefore, as some viruses areexcreted in human milk, Fluenz Tetra should not be used during breast-feeding.

Limited available evidence suggests that the trivalent Fluenz is not excreted in breastmilk.

No data exist regarding the possible effects of Fluenz Tetra on male and female fertility.

Fluenz Tetra has no or negligible influence on the ability to drive and use machines.

The safety experience with trivalent Fluenz is relevant to the use of Fluenz Tetra because Fluenz Tetra(influenza vaccine-live attenuated, nasal) is identical to Fluenz with the only difference being theaddition of a fourth strain (a second B strain) to Fluenz Tetra.

Safety data regarding use of Fluenz Tetra are based on data from Fluenz Tetra clinical studiesin 2,231 children and adolescents 2 to 17 years of age, Fluenz clinical studies in over 29,000 childrenand adolescents 2 to 17 years of age and Fluenz post-authorisation safety studies inover 84,000 children and adolescents 2 to 17 years of age. Additional experience has occurred withmarketed use of Fluenz.

In clinical studies, the safety profile of Fluenz Tetra was similar to the safety profile of Fluenz.

The most common adverse reaction observed in clinical studies was nasal congestion/rhinorrhoea.

List of adverse reactions

Adverse reaction frequencies are reported as:

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)

Uncommon: Hypersensitivity reactions (including facial oedema, urticaria and very rareanaphylactic reactions)

Very common: Decreased appetite

Common: Headache

Very common: Nasal congestion/rhinorrhoea

Uncommon: Epistaxis

Uncommon: Rash

Common: Myalgia

Very common: Malaise

Common: Pyrexia

In an active-controlled clinical study (MI-CP111), an increased rate of hospitalisations (for any cause)through 180 days after final vaccination dose was observed in infants and toddlers 6-11 months of age(6.1% Fluenz versus 2.6% injectable influenza vaccine). Most hospitalisations were due togastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. Therate of hospitalisations was not increased in Fluenz recipients 12 months and older. In the same study,an increased rate of wheezing through 42 days was observed in infants and toddlers 6-23 months ofage (5.9% Fluenz versus 3.8% injectable influenza vaccine). The rate of wheezing was not increasedin Fluenz recipients 24 months and older. Fluenz Tetra is not indicated for use in infants and toddlersyounger than 24 months (see section 4.2).

Very rare reports of Guillain-Barré syndrome and exacerbation of symptoms of Leigh syndrome(mitochondrial encephalomyopathy) have also been observed in the post-marketing settingwith Fluenz.

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. Healthcareprofessionals are asked to report any suspected adverse reactions via national reporting systemlisted in Appendix V.

Overdose with Fluenz Tetra is unlikely due to its presentation as a pre-filled sprayer. Administrationof a higher than recommended dose of Fluenz Tetra was reported rarely and the adverse reactionprofile was comparable to that observed with the recommended dose of Fluenz Tetra.

Pharmacotherapeutic group: Influenza vaccines, influenza live attenuated; ATC Code: J07BB03

Since 1985, two distinct lineages of influenza B viruses (Victoria and Yamagata) have circulatedworldwide. Fluenz Tetra is a tetravalent vaccine that contains antigens for four influenza virus strains,an A/(H1N1) strain, an A/(H3N2) strain, and two B strains (one from each lineage). Fluenz Tetra ismanufactured according to the same process as Fluenz. The influenza virus strains in Fluenz Tetra are(a) cold-adapted (ca); (b) temperature-sensitive (ts); and (c) attenuated (att). As a result, they replicatein the nasopharynx and induce protective immunity.

Clinical studies

Clinical experience with Fluenz is relevant to Fluenz Tetra because both vaccines are manufacturedusing the same process and have overlapping compositions.

Paediatric studies

Fluenz efficacy

Fluenz’s efficacy data in the paediatric population consist of 9 controlled studies comprisingover 20,000 infants and toddlers, children and adolescents, conducted during 7 influenza seasons. Fourplacebo-controlled studies included second season revaccination. Fluenz has demonstrated superiorityin 3 active-controlled studies with injectable influenza vaccine. See Table 1 and 2 for a summary ofefficacy results in the paediatric population.

Table 1 Fluenz Efficacy in Placebo Controlled Paediatric Studies

Number of (95% CI)c

Study Age Influenza (95% CI)c

Region a Study All strains

Number Range Season Matched

Participantsb regardlessstrainsof match85.4% 85.9%2000-2001(74.3, 92.2) (76.3, 92.0)

D153-P502 Europe 6 to 35 M 1,61688.7% 85.8%2001-2002(82.0, 93.2) (78.6, 90.9)73.5% 72.0%

Africa, 2001(63.6, 81.0)d (61.9, 79.8)d

D153-P504 Latin 6 to 35 M 1,88673.6% 46.6%

America 2002(33.3, 91.2) (14.9, 67.2)

Asia/ 62.2% 48.6%

D153-P513 6 to 35 M 1,041 2002

Oceania (43.6, 75.2) (28.8, 63.3)

Europe,

Asia/78.4% 63.8%

D153-P522 Oceania, 11 to 24 M 1,150 2002-2003(50.9, 91.3) (36.2, 79.8)

Latin

America72.9% 70.1%2000-2001

Asia/ (62.8, 80.5) (60.9, 77.3)

D153-P501 12 to 35 M 2,764

Oceania 84.3% 64.2%2001-2002(70.1, 92.4)e (44.2, 77.3)e93.4% 93.4%1996-1997(87.5, 96.5) (87.5, 96.5)

AV006 USA 15 to 71 M 1,259100% 87.1%1997-1998(63.1, 100) (77.7, 92.6)fa M=months.b Number of study participants for year 1 efficacy analysis.c Reduction in culture-confirmed influenza illness relative to placebo.d Data presented for clinical trial D153-P504 are for study participants who received two doses of study vaccine.

In previously unvaccinated study participants who received one dose in year 1, efficacy was 57.7%(95% CI: 44.7, 67.9) and 56.3% (95% CI: 43.1, 66.7), respectively, thus supporting the need for two dosesof vaccine in previously unvaccinated children.e In study participants who received 2 doses in year 1 and placebo in year 2, efficacy in year 2 was 56.2%(95% CI: 30.5, 72.7) and 44.8% (95% CI: 18.2, 62.9), respectively, in D153-P501, thus supporting the need forsecond-season revaccination.f The primary circulating strain was antigenically dissimilar from the H3N2 strain represented in the vaccine;efficacy against the mismatched A/H3N2 strain was 85.9% (95% CI: 75.3, 91.9).

Table 2 Fluenz Relative Efficacy in Active-controlled Paediatric Studies with Injectable

Influenza Vaccine

Improved

Number of Improved Efficacy

Study Age Influenza (95% CI)b

Region Study (95% CI)b

Number Rangea Season All strains

Participants Matched strainsregardlessof match44.5% 54.9%

USA,(22.4, 60.6) (45.4, 62.9)c

MI-CP111 Europe, 6 to 59 M 7,852 2004-2005fewer cases than fewer cases than

Asia/Oceaniainjectable injectable52.7% 52.4%(21.6, 72.2) (24.6, 70.5)d

D153-P514 Europe 6 to 71 M 2,085 2002-2003fewer cases than fewer cases thaninjectable injectable34.7% 31.9%(3.9, 56.0) (1.1, 53.5)

D153-P515 Europe 6 to 17 Y 2,211 2002-2003fewer cases than fewer cases thaninjectable injectablea M=months. Y=years. Age range as described in the protocol for the study.b Reduction in culture-confirmed influenza illness relative to injectable influenza vaccine.c Fluenz demonstrated 55.7% (39.9, 67.6) fewer cases than injectable influenza vaccine in 3,686 infants andtoddlers 6-23 months of age and 54.4% (41.8, 64.5) fewer cases in 4,166 children 24-59 months of age.d Fluenz demonstrated 64.4% (1.4, 88.8) fewer cases than injectable influenza vaccine in 476 infants andtoddlers 6-23 months of age and 48.2% (12.7, 70.0) fewer cases in 1,609 children 24-71 months of age.

Fluenz safety

Chronic conditions

Although safety in children and adolescents with mild to moderate asthma has been established,data in children with other pulmonary diseases or with chronic cardiovascular, metabolic or renaldiseases are limited.

In a study (D153-P515) of children 6 to 17 years of age with asthma (trivalent Fluenz: n=1,114,trivalent injectable influenza vaccine: n=1,115), there were no significant differences betweentreatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate, asthmasymptom scores, or night-time awakening scores. The incidence of wheezing within 15 days aftervaccination was lower in Fluenz recipients relative to inactivated vaccine recipients(19.5% vs. 23.8%, P=0.02).

In a study of children and adolescents 9 to 17 years of age with moderate to severe asthma(trivalent Fluenz: n=24, placebo: n=24), the primary safety criterion, change in percent predictedforced expiratory volume in 1 second (FEV1) measured before and after vaccination, did not differbetween treatment arms.

In studies of adults in which a high percentage of individuals had underlying chronic medicalconditions, the safety profile of trivalent Fluenz was comparable to the safety profile observedin individuals without these conditions.

Immunocompromised

In 24 HIV-infected children and 25 HIV-negative children 1 through 7 years of age, andin 243 HIV-infected children and adolescents 5 through 17 years of age receiving stable anti-retroviraltherapy, the frequency and duration of vaccine virus shedding were comparable to that seen in healthyindividuals. No adverse effects on HIV viral load or CD4 counts were identified following trivalent

Fluenz administration. Twenty mild to moderately immunocompromised children andadolescents 5 through 17 years of age (receiving chemotherapy and/or radiation therapy or who hadrecently received chemotherapy) were randomised 1:1 to trivalent Fluenz or placebo. Frequency andduration of vaccine virus shedding in these immunocompromised children and adolescents werecomparable to that seen in healthy children and adolescents. The effectiveness of Fluenz and Fluenz

Tetra in preventing influenza illness in immunocompromised individuals has not been evaluated.

Fluenz Tetra immunogenicity

A multicentre, randomised, double-blind, active-controlled, non-inferiority study was conducted toassess the immunogenicity of Fluenz Tetra compared to Fluenz (active control) in children andadolescents 2-17 years of age. A total of 2,312 children and adolescents were randomised by site ata 3:1:1 ratio to receive either Fluenz Tetra or one of two formulations of comparator vaccine Fluenz,each containing a B strain that corresponded to one of the two B strains in Fluenz Tetra (a B strain ofthe Yamagata lineage and a B strain of the Victoria lineage).

Immunogenicity was evaluated by comparing geometric mean titres (GMTs) of strain-specific serumhaemagglutination inhibition (HAI) antibodies post dosing. Fluenz Tetra demonstrated immunologicnon-inferiority to the two formulations of Fluenz as the upper bound for each of the four 95% CIs forthe post-dose strain-specific GMT HAI antibody ratios was ≤ 1.5.

Adult studies

Several studies against placebo have shown that Fluenz may have some efficacy in adults. However,a conclusion on clinical benefit of this vaccine in adults could not be made given that results observedin some studies versus injectable influenza vaccines were suggestive of a lower efficacy of Fluenz.

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional non-clinical studies ofrepeated dose toxicity, reproduction and developmental toxicity, local tolerance and neurovirulence.

Sucrose

Dipotassium phosphate

Potassium dihydrogen phosphate

Gelatin (porcine, Type A)

Arginine hydrochloride

Monosodium glutamate monohydrate

Water for injections

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

18 weeks.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the nasal applicator in the outer carton in order to protect from light.

Before use, the vaccine may be taken out of the refrigerator once for a maximum period of 12 hours ata temperature not above 25°C. Stability data indicate that the vaccine components are stable for 12hours when stored at temperatures from 8°C to 25°C. At the end of this period, Fluenz Tetra should beused immediately or discarded.

Fluenz Tetra is supplied as a 0.2 ml suspension in a single-use nasal applicator (Type 1 glass), withnozzle (polypropylene with polyethylene transfer valve), nozzle tip-protector cap (synthetic rubber),plunger rod, plunger-stopper (butyl rubber) and a dose-divider clip.

Pack size of 1 or 10.

Not all pack sizes may be marketed.

Fluenz Tetra IS FOR NASAL USE ONLY.

- DO NOT USE WITH A NEEDLE. Do not inject.

- Do not use Fluenz Tetra if the expiry date has passed or the sprayer appears damaged, forexample, if the plunger is loose or displaced from the sprayer or if there are any signs ofleakage.

- Check the appearance of the vaccine before administration. The suspension should be colourlessto pale yellow, clear to opalescent. Small white particles may be present.

- Fluenz Tetra is administered as a divided dose in both nostrils.

- After administering half of the dose in one nostril, administer the other half of the dose in theother nostril immediately or shortly thereafter.

- The patient can breathe normally while the vaccine is being administered - there is no needto actively inhale or sniff.

- Refer to the Fluenz Tetra administration diagram (Figure 1) for step-by-step administrationinstructions.

Figure 1 Fluenz Tetra Administration

Check expiry date Prepare the applicator Position the applicator

Product must not be Remove rubber tip With the patient in anused after date on protector. Do not remove upright position, placeapplicator label. dose-divider clip at the the tip just inside theother end of the nostril to ensure Fluenzapplicator. Tetra is delivered intothe nose.

Depress the plunger Remove dose-divider Spray in other nostril

With a single motion, clip Place the tip just insidedepress plunger as For administration in the the other nostril andrapidly as possible other nostril, pinch and with a single motion,until the dose-divider remove the dose-divider depress plunger asclip prevents you from clip from plunger. rapidly as possible togoing further. deliver remainingvaccine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements for medical waste.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/13/887/003 Top load carton assembly. 1 sprayer.

EU/1/13/887/004 Top load carton assembly. 10 sprayers.

Date of first authorisation: 04 December 2013

Date of latest renewal: 20 November 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.