QDENGA powder+solvent for injection medication leaflet

Qdenga powder and solvent for solution for injection

Qdenga powder and solvent for solution for injection in pre-filled syringe

Dengue tetravalent vaccine (live, attenuated)

After reconstitution, 1 dose (0.5 mL) contains:

Dengue virus serotype 1 (live, attenuated)*: ≥ 3.3 log10 PFU**/dose

Dengue virus serotype 2 (live, attenuated)#: ≥ 2.7 log10 PFU**/dose

Dengue virus serotype 3 (live, attenuated)*: ≥ 4.0 log10 PFU**/dose

Dengue virus serotype 4 (live, attenuated)*: ≥ 4.5 log10 PFU**/dose

*Produced in Vero cells by recombinant DNA technology. Genes of serotype-specific surface proteinsengineered into dengue type 2 backbone. This product contains genetically modified organisms(GMOs).

#Produced in Vero cells by recombinant DNA technology

**PFU = Plaque-forming units

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Prior to reconstitution, the vaccine is a white to off-white coloured freeze-dried powder (compactcake).

The solvent is a clear, colourless solution.

Qdenga is indicated for the prevention of dengue disease in individuals from 4 years of age.

The use of Qdenga should be in accordance with official recommendations.

Individuals from 4 years of age

Qdenga should be administered as a 0.5 mL dose at a two-dose (0 and 3 months) schedule.

The need for a booster dose has not been established.

Other paediatric population (children <4 years of age)

The safety and efficacy of Qdenga in children aged less than 4 years has not yet been established.

Currently available data are described in section 4.8 but no recommendation on a posology can bemade.

No dose adjustment is required in elderly individuals ≥60 years of age. See section 4.4.

After complete reconstitution of the lyophilised vaccine with the solvent, Qdenga should beadministered by subcutaneous injection preferably in the upper arm in the region of deltoid.

Qdenga must not be injected intravascularly, intradermally or intramuscularly.

The vaccine should not be mixed in the same syringe with any other vaccines or other parenteralmedicinal products.

For instructions on reconstitution of Qdenga before administration, see section 6.6.

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 orhypersensitivity to a previous dose of Qdenga.

* Individuals with congenital or acquired immune deficiency, including those receivingimmunosuppressive therapies such as high doses of systemic corticosteroids (e.g. 20 mg/dayor 2 mg/kg body weight/day of prednisone for 2 weeks or more) within 4 weeks prior tovaccination, or any other medicinal product with known immunosuppressive propertiesincluding chemotherapy. The time to avoid vaccination after immunosuppressive treatmentshould be considered on an individual basis.

* Individuals with symptomatic HIV infection or with asymptomatic HIV infection whenaccompanied by evidence of impaired immune function.

* Pregnant women (see section 4.6).

* Breast-feeding women (see section 4.6).

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

Anaphylaxis

Anaphylaxis has been reported in individuals who have received Qdenga. As with all injectablevaccines, appropriate medical treatment and supervision must always be readily available in the eventof a rare anaphylactic reaction following administration of the vaccine.

Review of medical history

Vaccination should be preceded by a review of the individual’s medical history (especially with regardto previous vaccination and possible hypersensitivity reactions which occurred after vaccination).

Vaccination with Qdenga should be postponed in subjects suffering from an acute severe febrileillness. The presence of a minor infection, such as a cold, should not result in a deferral of vaccination.

A protective immune response with Qdenga may not be elicited in all vaccinees against all serotypesof dengue virus and may decline over time (see section 5.1). It is currently unknown whether a lack ofprotection could result in an increased severity of dengue. It is recommended to continue personalprotection measures against mosquito bites after vaccination. Individuals should seek medical care ifthey develop dengue symptoms or dengue warning signs.

There are no data on the use of Qdenga in subjects above 60 years of age and limited data in patientswith chronic medical conditions.

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection.

It is important that precautions are in place to avoid injury from fainting.

As with other live attenuated vaccines, women of childbearing potential should avoid pregnancy for atleast one month following vaccination (see sections 4.6 and 4.3).

Qdenga must not be administered by intravascular, intradermal or intramuscular injection.

Qdenga contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Qdenga contains less than 1 mmol potassium (39 mg) per dose, that is to say essentially ‘potassium-free’.

For patients receiving treatment with immunoglobulins or blood products containingimmunoglobulins, such as blood or plasma, it is recommended to wait for at least 6 weeks, andpreferably for 3 months, following the end of treatment before administering Qdenga, in order to avoidneutralisation of the attenuated viruses contained in the vaccine.

Qdenga should not be administered to subjects receiving immunosuppressive therapies such as highdoses of systemic corticosteroids within 4 weeks prior to vaccination, or any other medicinal productwith known immunosuppressive properties including chemotherapy (see section 4.3). The time toavoid vaccination after immunosuppressive treatment should be considered on an individual basis.

If Qdenga is to be given at the same time as another injectable vaccine, the vaccines should always beadministered at different injection sites.

Qdenga may be administered concomitantly with a hepatitis A vaccine. Coadministration has beenstudied in adults.

Qdenga may be administered concomitantly with a yellow fever vaccine. In a clinical study involvingapproximately 300 adult subjects who received Qdenga concomitantly with yellow fever 17D vaccine,there was no effect on yellow fever seroprotection rate. Dengue antibody responses were decreasedfollowing concomitant administration of Qdenga and yellow fever 17D vaccine. The clinicalsignificance of this finding is unknown.

Qdenga may be administered concomitantly with a human papillomavirus (HPV) vaccine (see section5.1).

Women of childbearing potential should avoid pregnancy for at least one month followingvaccination. Women who intend to become pregnant should be advised to delay vaccination (seesections 4.4 and 4.3).

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

There is limited amount of data from the use of Qdenga in pregnant women. These data are notsufficient to conclude on the absence of potential effects of Qdenga on pregnancy, embryo-foetaldevelopment, parturition and post-natal development.

Qdenga is a live attenuated vaccine, therefore Qdenga is contraindicated during pregnancy (see section4.3).

It is unknown whether Qdenga is excreted in human milk. A risk to the newborns/infants cannot beexcluded.

Qdenga is contraindicated during breast-feeding (see section 4.3).

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

No specific studies have been performed on fertility in humans.

Qdenga has minor influence on the ability to drive and use machines.

In clinical studies, the most frequently reported reactions in subjects 4 to 60 years of age wereinjection site pain (50%), headache (35%), myalgia (31%), injection site erythema (27%), malaise(24%), asthenia (20%) and fever (11%).

These adverse reactions usually occurred within 2 days after the injection, were mild to moderate inseverity, had a short duration (1 to 3 days) and were less frequent after the second injection of Qdengathan after the first injection.

Vaccine viraemia

In clinical study DEN-205, transient vaccine viraemia was observed after vaccination with Qdenga in49% of study participants who had not been infected with dengue before and in 16% of studyparticipants who had been infected with dengue before. Vaccine viraemia usually started in the secondweek after the first injection and had a mean duration of 4 days. Vaccine viraemia was associated withtransient, mild to moderate symptoms, such as headache, arthralgia, myalgia and rash in some subjectsthat may also occur with dengue. Vaccine viraemia was rarely detected after the second dose.

Dengue diagnostic tests may be positive during vaccine viraemia and cannot be used to distinguishvaccine viraemia from wild type dengue infection.

Adverse reactions associated with Qdenga obtained from clinical studies and post-authorisationexperience are tabulated below (Table 1).

The safety profile presented below is based on data generated in placebo-controlled clinical studiesand post-authorisation experience. Pooled analysis of clinical studies included data from 14,627 studyparticipants aged 4 to 60 years (13,839 children and 788 adults) who have been vaccinated with

Qdenga. This included a reactogenicity subset of 3,830 participants (3,042 children and 788 adults).

Adverse reactions are listed according to the following frequency categories:

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 the available data

Table 1: Adverse reactions from clinical studies (age 4 to 60 years) and post-authorisationexperience (age 4 years and older)

MedDRA System Organ Frequency Adverse Reactions

Class

Infections and infestations Very common Upper respiratory tract infectiona

Common Nasopharyngitis

Pharyngotonsillitisb

Uncommon Bronchitis

Rhinitis

Blood and lymphatic system Very rare Thrombocytopeniacdisorders

MedDRA System Organ Frequency Adverse Reactions

Class

Immune system disorders Not known Anaphylactic reaction, includinganaphylactic shockc

Metabolism and nutrition Very common Decreased appetiteddisorders

Psychiatric disorders Very common Irritabilityd

Nervous system disorders Very common Headache

Somnolenced

Uncommon Dizziness

Eye disorders Not known Eye painc

Gastrointestinal disorders Uncommon Diarrhoea

Nausea

Abdominal pain

Skin and subcutaneous tissue Uncommon Rashedisorders Pruritusf

Urticaria

Rare Petechiaec

Very rare Angioedema

Musculoskeletal and connective Very common Myalgiatissue disorders Common Arthralgia

General disorders and Very common Injection site painadministration site conditions Injection site erythema

Malaise

Asthenia

Fever

Common Injection site swelling

Injection site bruisingf

Injection site pruritusf

Influenza like illness

Uncommon Injection site haemorrhagef

Fatiguef

Injection site discolourationfa Includes upper respiratory tract infection and viral upper respiratory tract infectionb Includes pharyngotonsillitis and tonsillitisc Adverse reaction observed post-authorisationd Collected in children below 6 years of age in clinical studiese Includes rash, viral rash, rash maculopapular, rash pruriticf Reported in adults in clinical studies

Paediatric data in subjects 4 to 17 years of age

Pooled safety data from clinical trials are available for 13839 children (9210 aged 4 to 11 years and4629 aged 12 to 17 years). This includes reactogenicity data collected in 3042 children (1865 aged 4 to11 years and 1177 aged 12 to 17 years).

Frequency, type and severity of adverse reactions in children were largely consistent with those inadults. Adverse reactions reported more commonly in children than in adults were fever (11% versus3%), upper respiratory tract infection (11% versus 3%), nasopharyngitis (6% versus 0.6%),pharyngotonsillitis (2% versus 0.3%), and influenza like illness (1% versus 0.1%). Adverse reactionsreported less commonly in children than adults were injection site erythema (2% versus 27%), nausea(0.03% versus 0.8%) and arthralgia (0.03% versus 1%).

The following reactions were collected in 357 children below 6 years of age vaccinated with Qdenga:

decreased appetite (17%), somnolence (13%) and irritability (12%).

Paediatric data in subjects below 4 years of age, i.e. outside the age indication

Reactogenicity in subjects below 4 years of age was assessed in 78 subjects who received at least onedose of Qdenga of which 13 subjects received the indicated 2-dose regimen. Reactions reported withvery common frequency were irritability (25%), fever (17%), injection site pain (17%) and loss ofappetite (15%). Somnolence (8%) and injection site erythema (3%) were reported with commonfrequency. Injection site swelling was not observed in subjects below 4 years of age.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose have been reported.

Pharmacotherapeutic group: Vaccines, Viral vaccines, ATC code: J07BX04

Qdenga contains live attenuated dengue viruses. The primary mechanism of action of Qdenga is toreplicate locally and elicit humoral and cellular immune responses against the four dengue virusserotypes.

The clinical efficacy of Qdenga was assessed in study DEN-301, a pivotal Phase 3, double-blind,randomised, placebo-controlled study conducted across 5 countries in Latin America (Brazil,

Colombia, Dominican Republic, Nicaragua, Panama) and 3 countries in Asia (Sri Lanka, Thailand, the

Philippines). A total of 20,099 children aged between 4 and 16 years were randomised (2:1 ratio) toreceive Qdenga or placebo, regardless of previous dengue infection.

Efficacy was assessed using active surveillance across the entire study duration. Any subject withfebrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) was required to visit the studysite for dengue fever evaluation by the investigator. Subjects/guardians were reminded of thisrequirement at least weekly to maximise the detection of all symptomatic virologically confirmeddengue (VCD) cases. Febrile episodes were confirmed by a validated, quantitative dengue RT-PCR todetect specific dengue serotypes.

Clinical efficacy data for subjects 4 to 16 years of age

The Vaccine Efficacy (VE) results, according to the primary endpoint (VCD fever occurring from 30days to 12 months after the second vaccination) are shown in Table 2. The mean age of the perprotocol trial population was 9.6 years (standard deviation of 3.5 years) with 12.7% subjects in the 4-5years, 55.2% in the 6-11 years and 32.1% in the 12-16 years age-groups. Of these, 46.5% were in Asiaand 53.5% were in Latin America, 49.5% were females and 50.5% were males. The dengue serostatusat baseline (before the first injection) was assessed in all subjects by microneutralisation test (MNT50)to allow Vaccine Efficacy (VE) assessment by baseline serostatus. The baseline dengue seronegativityrate for the overall per protocol population was 27.7%.

Table 2: Vaccine efficacy in preventing VCD fever caused by any serotype from 30 days to 12months post second vaccination in study DEN-301 (Per Protocol Set)a

Qdenga Placebo

N = 12,700b N = 6316b

VCD fever, n (%) 61 (0.5) 149 (2.4)

Vaccine efficacy (95% CI) (%) 80.2 (73.3, 85.3)p-value <0.001

CI: confidence interval; n: number of subjects with fever; VCD: virologically confirmed denguea The primary analysis of efficacy data were based on the Per Protocol Set, which consisted of all randomised subjects whodid not have any major protocol violations, including not receiving both doses of the correct assignment of Qdenga orplacebob Number of subjects evaluated

VE results according to the secondary endpoints, preventing hospitalisation due to VCD fever,preventing VCD fever by serostatus, by serotype and preventing severe VCD fever are shown in

Table 3. For severe VCD fever, two types of endpoints were considered: clinically severe VCD casesand VCD cases that met the 1997 WHO criteria for Dengue Haemorrhagic Fever (DHF). The criteriaused in Trial DEN-301 for the assessment of VCD severity by an independent “Dengue Case severity

Adjudication Committee” (DCAC) were based on the WHO 2009 guidelines. The DCAC assessed allcases of hospitalisation due to VCD utilizing predefined criteria which included an assessment ofbleeding abnormality, plasma leakage, liver function, renal function, cardiac function, the centralnervous system, and shock. In Trial DEN-301 VCD cases meeting the WHO 1997 criteria for DHFwere identified using a programmed algorithm, i.e., without applying medical judgment. Broadly, thecriteria included presence of fever lasting 2 to 7 days, haemorrhagic tendencies, thrombocytopenia,and evidence of plasma leakage.

Table 3: Vaccine efficacy in preventing hospitalisation due to VCD fever, VCD fever by dengueserotype, VCD fever by baseline dengue serostatus, and severe forms of dengue from 30 days to18 months post second vaccination in study DEN-301 (Per Protocol Set)

Qdenga Placeboa a VE (95% CI)

N=12,700 N=6316

VE in preventing hospitalisations due to VCD feverb, n (%)

Hospitalisations due to VCD feverc 13 (0.1) 66 (1.0) 90.4 (82.6, 94.7)d

VE in preventing VCD fever by dengue serotype, n (%)

VCD fever caused by DENV-1 38 (0.3) 62 (1.0) 69.8 (54.8, 79.9)

VCD fever caused by DENV-2 8 (<0.1) 80 (1.3) 95.1 (89.9, 97.6)

VCD fever caused by DENV-3 63 (0.5) 60 (0.9) 48.9 (27.2, 64.1)

VCD fever caused by DENV-4 5 (<0.1) 5 (<0.1) 51.0 (-69.4, 85.8)

VE in preventing VCD fever by baseline dengue serostatus, n (%)

VCD fever in all subjects 114 (0.9) 206 (3.3) 73.3 (66.5, 78.8)

VCD fever in baseline seropositive subjects 75 (0.8) 150 (3.3) 76.1 (68.5, 81.9)

VCD fever in baseline seronegative subjects 39 (1.1) 56 (3.2) 66.2 (49.1, 77.5)

VE in preventing DHF induced by any dengue serotype, n (%)

Overall 2 (<0.1) 7 (0.1) 85.9 (31.9, 97.1)

VE in preventing severe dengue induced by any dengue serotype, n (%)

Overall 2 (<0.1) 1 (<0.1) 2.3 (-977.5, 91.1)

VE: vaccine efficacy; CI: confidence interval; n: number of subjects; VCD: virologically confirmed dengue; DENV: denguevirus serotypea Number of subjects evaluatedb key secondary endpointc Most of the cases observed were due to DENV-2 (0 cases in Qdenga arm and 46 cases in Placebo arm)d p-value <0.001

Early onset of protection was seen with an exploratory VE of 81.1% (95% CI: 64.1%, 90.0%) against

VCD fever caused by all serotypes combined from first vaccination until second vaccination.

Long term protection

In study DEN-301, a number of exploratory analyses were conducted to estimate long term protectionfrom first dose up to 4.5 years after the second dose (Table 4).

Table 4: Vaccine efficacy in preventing VCD fever and hospitalisation overall, by baselinedengue serostatus, and against individual serotypes by baseline serostatus from first dose to 54months post second dose in study DEN-301 (Safety Set)

VE (95% CI) in VE (95% CI) in

Qdenga Placebo preventing VCD Qdenga Placebo preventingn/N n/N Fevera n/N n/N Hospitalisation due to

VCD Fevera

Overall 442/13380 547/6687 61.2 (56.0, 65.8) 46/13380 142/6687 84.1 (77.8, 88.6)

Baseline Seronegative, N=5,546

Any 147/3714 153/1832 53.5 (41.6, 62.9) 17/3714 41/1832 79.3 (63.5, 88.2)serotype

DENV-1 89/3714 79/1832 45.4 (26.1, 59.7) 6/3714 14/1832 78.4 (43.9, 91.7)

DENV-2 14/3714 58/1832 88.1 (78.6, 93.3) 0/3714 23/1832 100 (88.5, 100)b

DENV-3 -15.536/3714 16/1832 11/3714 3/1832 -87.9 (-573.4, 47.6)(-108.2, 35.9)

DENV-4 -105.612/3714 3/1832 0/3714 1/1832 NPc(-628.7, 42.0)

Baseline Seropositive, N=14,517

Any 295/9663 394/4854 64.2 (58.4,69.2) 29/9663 101/4854 85.9 (78.7, 90.7)serotype

DENV-1 133/9663 151/4854 56.1 (44.6, 65.2) 16/9663 24/4854 66.8 (37.4, 82.3)

DENV-2 54/9663 135/4854 80.4 (73.1, 85.7) 5/9663 59/4854 95.8 (89.6, 98.3)

DENV-3 96/9663 97/4854 52.3 (36.7, 64.0) 8/9663 15/4854 74.0 (38.6, 89.0)

DENV-4 12/9663 20/4854 70.6 (39.9, 85.6) 0/9663 3/4854 NPc

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, n: number of subjects, N: number ofsubjects evaluated, NP: not provideda Exploratory analyses; the study was neither powered nor designed to demonstrate a difference between the vaccine and theplacebo groupb Approximated using a one-sided 95% CIc VE estimate not provided since fewer than 6 cases, for both TDV and placebo, were observed

Additionally, VE in preventing DHF caused by any serotype was 70.0% (95% CI: 31.5%, 86.9%) andin preventing clinically severe VCD cases caused by any serotype was 70.2% (95% CI: -24.7%,92.9%).

VE in preventing VCD was shown for all four serotypes in baseline dengue seropositive subjects. Inbaseline seronegative subjects, VE was shown for DENV-1 and DENV-2, but not suggested for

DENV-3 and could not be shown for DENV-4 due to lower incidence of cases (Table 4).

A year-by-year analysis until four and a half years after the second dose was conducted (Table 5).

Table 5: Vaccine efficacy in preventing VCD fever and hospitalisation overall and by baselinedengue serostatus in yearly intervals 30 days post second dose in study DEN-301 (Per Protocol

Set)

VE (95% CI) inpreventing

VE (95% CI) in Hospitalisation duepreventing VCD Fever to VCD Fevera

N = 19,021 Na = 19,021

Year 1b Overall 80.2 (73.3, 85.3) 95.4 (88.4, 98.2)

By baseline dengue serostatus

Seropositive 82.2 (74.5, 87.6) 94.4 (84.4, 98.0)

Seronegative 74.9 (57.0, 85.4) 97.2 (79.1, 99.6)

Year 2c Overall 56.2 (42.3, 66.8) 76.2 (50.8, 88.4)

By baseline dengue serostatus

Seropositive 60.3 (44.7, 71.5) 85.2 (59.6, 94.6)

Seronegative 45.3 (9.9, 66.8) 51.4 (-50.7, 84.3)

Year 3d Overall 45.0 (32.9, 55.0) 70.8 (49.6, 83.0)

By baseline dengue serostatus

Seropositive 48.7 (34.8, 59.6) 78.4 (57.1, 89.1)

Seronegative 35.5 (7.4, 55.1) 45.0 (-42.6, 78.8)

Year 4e Overall 62.8 (41.4, 76.4) 96.4 (72.2, 99.5)

By baseline dengue serostatus

Seropositive 64.1 (37.4, 79.4) 94.0 (52.2, 99.3)

Seronegative 60.2 (11.1, 82.1) NPf

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, NP: not provided, N: total number ofsubjects in the per analysis set, a number of subjects evaluated in each year is different.b Year 1 refers to 11 months starting 30 days after second dose.c Year 2 refers to 13 to 24 months after second dose.d Year 3 refers to 25 to 36 months after second dose.e Year 4 refers to 37 to 48 months after second dose.f VE estimate not provided since fewer than 6 cases, for both TDV and placebo, were observed.

Clinical efficacy for subjects from 17 years of age

No clinical efficacy study has been conducted in subjects from 17 years of age. The efficacy of

Qdenga in subjects from 17 years of age is inferred from the clinical efficacy in 4 to 16 years of age bybridging of immunogenicity data (see below).

In the absence of correlates of protection for Dengue, the clinical relevance of immunogenicity dataremains to be fully understood.

Immunogenicity data for subjects 4 to 16 years of age in endemic areas

The Geometric Mean Titres (GMTs) by baseline dengue serostatus in subjects 4 to 16 years of age instudy DEN-301 are shown in Table 6.

Table 6: Immunogenicity by baseline dengue serostatus in study DEN-301 (Per Protocol Set for

Immunogenicity)a

Baseline Seropositive Baseline Seronegative1 month 1 month

Pre-Vaccination Post-Dose 2 Pre-Vaccination Post-Dose 2

N=1816* N=1621 N=702 N=641

DENV-1

GMT 411.3 2115.2 5.0 184.295% CI (366.0, 462.2) (1957.0, 2286.3) NE** (168.6, 201.3)

DENV-2

GMT 753.1 4897.4 5.0 1729.995% CI (681.0, 832.8) (4645.8, 5162.5) NE** (1613.7, 1854.6)

DENV-3

GMT 357.7 1761.0 5.0 228.095% CI (321.3, 398.3) (1645.9, 1884.1) NE** (211.6, 245.7)

DENV-4

GMT 218.4 1129.4 5.0 143.995% CI (198.1, 240.8) (1066.3, 1196.2) NE** (133.6, 155.1)

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: notestimateda The immunogenicity subset was a randomly selected subset of subjects, and the Per Protocol Set for Immunogenicity wasthe collection of subjects from that subset who also belong to the Per Protocol Set

* For DENV-2 and DENV-3: N= 1815

** All subjects had GMT values below LLOD (10), hence were reported as 5 with no CI values

Immunogenicity data for subjects 18 to 60 years of age in non-endemic areas

The immunogenicity of Qdenga in adults 18 to 60 years of age was assessed in DEN-304, a Phase 3double-blind, randomized, placebo-controlled study in a non-endemic country (US). The post-dose 2

GMTs are shown in Table 7.

Table 7: GMTs of dengue neutralising antibodies in study DEN-304 (Per Protocol Set)

Baseline Seropositive* Baseline Seronegative*1 month 1 month

Pre-Vaccination Post-Dose 2 Pre-Vaccination Post-Dose 2

N=68 N=67 N=379 N=367

DENV-1

GMT 13.9 365.1 5.0 268.195% CI (9.5, 20.4) (233.0, 572.1) NE** (226.3, 317.8)

DENV-2

GMT 31.8 3098.0 5.0 2956.995% CI (22.5, 44.8) (2233.4, 4297.2) NE** (2635.9, 3316.9)

DENV-3

GMT 7.4 185.7 5.0 128.995% CI (5.7, 9.6) (129.0, 267.1) NE** (112.4, 147.8)

DENV-4

GMT 7.4 229.6 5.0 137.495% CI (5.5, 9.9) (150.0, 351.3) NE** (121.9, 155.0)

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: notestimated

* Pooled data from Dengue tetravalent vaccine Lots 1, 2 and 3

** All subjects had GMT values below LLOD (10), hence were reported as 5 with no CI values

The bridging of efficacy is based on immunogenicity data and results from a non-inferiority analysis,comparing post-vaccination GMTs in the baseline dengue seronegative populations of DEN-301 and

DEN-304 (Table 8). Protection against dengue disease is expected in adults although the actualmagnitude of efficacy relative to that observed in children and adolescents is unknown.

Table 8: GMT ratios between baseline dengue seronegative subjects in studies DEN-301 (4-16years) and DEN-304 (18-60 years) (Per Protocol Set for Immunogenicity)

GMT Ratio* DENV-1 DENV-2 DENV-3 DENV-4(95% CI)1m post-2nd dose 0.69 (0.58, 0.82) 0.59 (0.52, 0.66) 1.77 (1.53, 2.04) 1.05 (0.92, 1.20)6m post-2nd dose 0.62 (0.51, 0.76) 0.66 (0.57, 0.76) 0.98 (0.84, 1.14) 1.01 (0.86, 1.18)

DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; m: month(s)

*Non-inferiority: upper bound of the 95% CI less than 2.0.

Long-term persistence of antibodies

The long-term persistence of neutralising antibodies was shown in study DEN-301, with titresremaining well above the pre-vaccination levels for all four serotypes, up to 51 months after the firstdose.

Co-administration with HPV vaccine

In study DEN-308 involving approximately 300 subjects aged 9 to 14 years who received Qdengaconcomitantly with a 9-valent HPV vaccine, there was no effect on the immune response to the HPVvaccine. The study only tested co-administration of the first doses of Qdenga and the 9-valent HPVvaccine. Non-inferiority of the Qdenga immune response, when Qdenga and the 9-valent HPV vaccinewere co-administered, has not been directly assessed in the study. In the dengue seronegative studypopulation, dengue antibody responses after co-administration were in the same range as thoseobserved in the Phase 3 study (DEN-301) where efficacy against VCD and hospitalised VCD wasshown.

No pharmacokinetic studies have been performed with Qdenga.

Non-clinical safety data revealed no special hazard for humans based on conventional studies of singledose, local tolerance, repeated dose toxicity, and toxicity to reproduction and development. In adistribution and shedding study, there was no shedding of Qdenga RNA in faeces and urine,confirming a low risk for vaccine shedding to the environment or transmission from vaccinees. Aneurovirulence study shows that Qdenga is not neurotoxic.

Although no relevant hazard was identified, the relevance of the reproductive toxicity studies islimited, since rabbits are not permissive for dengue virus infection.

α,α-Trehalose dihydrate

Poloxamer 407

Human serum albumin

Potassium dihydrogen phosphate

Disodium hydrogen phosphate

Potassium chloride

Sodium chloride

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other vaccineor medicinal products except for the solvent provided.

24 months.

After reconstitution with the solvent provided, Qdenga should be used immediately.

If not used immediately, Qdenga must be used within 2 hours.

Chemical and physical in-use stability have been demonstrated for 2 hours at room temperature (up to32.5°C) from the time of reconstitution of the vaccine vial. After this time period, the vaccine must bediscarded. Do not return it to the refrigerator.

From a microbiological point of view Qdenga should be used immediately. If not used immediately,in-use storage times and conditions are the responsibility of the user.

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

Store in the original package.

For storage conditions after reconstitution of Qdenga, see section 6.3.

Qdenga powder and solvent for solution for injection:

* Powder (1 dose) in glass vial (Type-I glass), with a stopper (butyl rubber) and aluminium sealwith green flip-off plastic cap + 0.5 mL solvent (1 dose) in glass vial (Type-I glass), with astopper (bromobutyl rubber) and aluminium seal with purple flip-off plastic cap

Pack size of 1 or 10.

Qdenga powder and solvent for solution for injection in pre-filled syringe:

* Powder (1 dose) in vial (Type-I glass), with a stopper (butyl rubber) and aluminium seal withgreen flip-off plastic cap + 0.5 mL solvent (1 dose) in pre-filled syringe (Type-I glass), with aplunger stopper (bromobutyl) and a tip cap (polypropylene), with 2 separate needles

Pack size of 1 or 5.

* Powder (1 dose) in vial (Type-I glass), with a stopper (butyl rubber) and aluminium seal withgreen flip-off plastic cap + 0.5 mL solvent (1 dose) in pre-filled syringe (Type-I glass), with aplunger stopper (bromobutyl) and a tip cap (polypropylene), without needles

Pack size of 1 or 5.

Not all pack sizes may be marketed.

Instructions for reconstitution of the vaccine with the solvent presented in vial

Qdenga is a 2-component vaccine that consists of a vial containing lyophilised vaccine and a vialcontaining solvent. The lyophilised vaccine must be reconstituted with solvent prior to administration.

Use only sterile syringes for reconstitution and injection of Qdenga. Qdenga should not be mixed withother vaccines in the same syringe.

To reconstitute Qdenga, use only the solvent (0.22% sodium chloride solution) supplied with thevaccine since it is free of preservatives or other anti-viral substances. Contact with preservatives,antiseptics, detergents, and other anti-viral substances is to be avoided since they may inactivate thevaccine.

Remove the vaccine and solvent vials from the refrigerator.

* Remove the caps from both vials and clean the surfaceof stoppers on top of the vials using an alcohol wipe.

* Attach a sterile needle to a sterile 1 mL syringe andinsert the needle into the solvent vial. The recommendedneedle is 23G.

* Slowly press the plunger completely down.

* Turn the vial upside down, withdraw the entire contentsof the vial and continue to pull plunger out to 0.75 mL.

Solvent vial A bubble should be seen inside of the syringe.

* Invert the syringe to bring the bubble back to theplunger.

* Insert the needle of the syringe assembly into thelyophilised vaccine vial.

* Direct the flow of the solvent toward the side of the vialwhile slowly depressing the plunger to reduce the chanceof forming bubbles.

Lyophilised vaccine vial

* Release your finger from the plunger and, holding theassembly on a flat surface, gently swirl the vial in bothdirections with the needle syringe assembly attached.

* DO NOT SHAKE. Foam and bubbles may form in thereconstituted product.

* Let the vial and syringe assembly sit for a while until thesolution becomes clear. This takes about 30-60 seconds.

Reconstituted vaccine

Following reconstitution, the resulting solution should be clear, colourless to pale yellow, andessentially free of foreign particulates. Discard the vaccine if particulates are present and/or if itappears discoloured.

* Withdraw the entire volume of the reconstituted Qdengasolution with the same syringe until an air bubbleappears in the syringe.

* Remove the needle syringe assembly from the vial.

* Hold the syringe with the needle pointing upwards, tapthe side of the syringe to bring the air bubble to the top,discard the attached needle and replace with a newsterile needle, expel the air bubble until a small drop of

Reconstituted vaccine the liquid forms at the top of the needle. Therecommended needle is 25G 16 mm.

* Qdenga is ready to be administered by subcutaneousinjection.

Qdenga should be administered immediately after reconstitution. Chemical and physical in-usestability have been demonstrated for 2 hours at room temperature (up to 32.5°C) from the time ofreconstitution of the vaccine vial. After this time period, the vaccine must be discarded. Do not returnit to the refrigerator. From a microbiological point of view Qdenga should be used immediately. If notused immediately, in-use storage times and conditions are the responsibility of the user.

Instructions for reconstitution of the vaccine with solvent presented in pre-filled syringe

Qdenga is a 2-component vaccine that consists of a vial containing lyophilised vaccine and solventprovided in the pre-filled syringe. The lyophilised vaccine must be reconstituted with solvent prior toadministration.

Qdenga should not be mixed with other vaccines in the same syringe.

To reconstitute Qdenga, use only the solvent (0.22% sodium chloride solution) in the pre-filled syringesupplied with the vaccine since it is free of preservatives or other anti-viral substances. Contact withpreservatives, antiseptics, detergents, and other anti-viral substances is to be avoided since they mayinactivate the vaccine.

Remove the vaccine vial and pre-filled syringe solvent from the refrigerator.

* Remove the cap from the vaccine vial and clean thesurface of stopper on top of the vial using an alcoholwipe.

* Attach a sterile needle to the pre-filled syringe and insertthe needle into the vaccine vial. The recommendedneedle is 23G.

* Direct the flow of the solvent toward the side of the vialwhile slowly depressing the plunger to reduce thechance of forming bubbles.

Lyophilised vaccine vial

* Release your finger from the plunger and, holding theassembly on a flat surface, gently swirl the vial in bothdirections with the needle syringe assembly attached.

* DO NOT SHAKE. Foam and bubbles may form in thereconstituted product.

* Let the vial and syringe assembly sit for a while until thesolution becomes clear. This takes about 30-60 seconds.

Reconstituted vaccine

Following reconstitution, the resulting solution should be clear, colourless to pale yellow, andessentially free of foreign particulates. Discard the vaccine if particulates are present and/or if itappears discoloured.

* Withdraw the entire volume of the reconstituted Qdengasolution with the same syringe until an air bubbleappears in the syringe.

* Remove the needle syringe assembly from the vial. Holdthe syringe with the needle pointing upwards, tap theside of the syringe to bring the air bubble to the top,discard the attached needle and replace with a newsterile needle, expel the air bubble until a small drop ofthe liquid forms at the top of the needle. The

Reconstituted vaccine recommended needle is 25G 16 mm.

* Qdenga is ready to be administered by subcutaneousinjection.

Qdenga should be administered immediately after reconstitution. Chemical and physical in-usestability have been demonstrated for 2 hours at room temperature (up to 32.5°C) from the time ofreconstitution of the vaccine vial. After this time period, the vaccine must be discarded. Do not returnit to the refrigerator. From a microbiological point of view Qdenga should be used immediately. If notused immediately, in-use storage times and conditions are the responsibility of the user.

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

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

Ireland

EU/1/22/1699/001

EU/1/22/1699/002

EU/1/22/1699/003

EU/1/22/1699/004

EU/1/22/1699/005

EU/1/22/1699/006

Date of first authorisation: 05 December 2022

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

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