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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 proteins engineered 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 (compact cake).

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.

Posology

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 be made.

Elderly

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

Method of administration

After complete reconstitution of the lyophilised vaccine with the solvent, Qdenga should be administered 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 vaccines or other parenteral medicinal 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 or hypersensitivity to a previous dose of Qdenga.

• Individuals with congenital or acquired immune deficiency, including immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids (e.g. 20 mg/day or 2 mg/kg body weight/day of prednisone for 2 weeks or more) within 4 weeks prior to vaccination, as with other live attenuated vaccines.

• Individuals with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function.

• Pregnant women (see section 4.6).

• Breast-feeding women (see section 4.6).

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.

General recommendations

Anaphylaxis

As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in the event of 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 regard to previous vaccination and possible hypersensitivity reactions which occurred after vaccination).

Concurrent illness

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

Limitations of vaccine effectiveness

A protective immune response with Qdenga may not be elicited in all vaccinees against all serotypes of dengue virus and may decline over time (see section 5.1). It is currently unknown whether a lack of protection could result in an increased severity of dengue. It is recommended to continue personal protection measures against mosquito bites after vaccination. Individuals should seek medical care if they 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 patients with chronic medical conditions.

Anxiety-related reactions

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐related reactions 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.

Women of childbearing potential

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

Other

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

Excipients

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 containing immunoglobulins, such as blood or plasma, it is recommended to wait for at least 6 weeks, and preferably for 3 months, following the end of treatment before administering Qdenga, in order to avoid neutralisation of the attenuated viruses contained in the vaccine.

Qdenga should not be administered to subjects receiving immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids within 4 weeks prior to vaccination (see section 4.3).

Use with other vaccines

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

Qdenga may be administered concomitantly with an hepatitis A vaccine. Coadministration has been studied in adults.

Qdenga may be administered concomitantly with a yellow fever vaccine. In a clinical study involving approximately 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 decreased following concomitant administration of Qdenga and yellow fever 17D vaccine. The clinical significance of this finding is unknown.

Women of childbearing potential

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

Pregnancy

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 not sufficient to conclude on the absence of potential effects of Qdenga on pregnancy, embryo-foetal development, parturition and post-natal development.

Qdenga is a live attenuated vaccine, therefore Qdenga is contraindicated during pregnancy (see section 4.3).

Breast-feeding

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

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

Fertility

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.

Summary of the safety profile

In clinical studies, the most frequently reported reactions in subjects 4 to 60 years of age were injection 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 in severity, had a short duration (1 to 3 days) and were less frequent after the second injection of Qdenga than after the first injection.

Vaccine viremia

In clinical study DEN-205, transient vaccine viremia was observed after vaccination with Qdenga in 49% of study participants who had not been infected with dengue before and in 16% of study participants who had been infected with dengue before. Vaccine viremia usually started in the second week after the first injection and had a mean duration of 4 days. Vaccine viremia was associated with transient, mild to moderate symptoms, such as headache, arthralgia, myalgia and rash in some subjects. Vaccine viraemia was rarely detected after the second dose.

Tabulated list of adverse reactions

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

The safety profile presented below is based on a pooled analysis including 14,627 study participants 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

Table 1: Adverse reactions from Clinical Studies (Age 4 to 60 years)

^a Includes upper respiratory tract infection and viral upper respiratory tract infection

^b Includes pharyngotonsillitis and tonsillitis

^c Collected in children below 6 years of age in clinical studies

^d Includes rash, viral rash, rash maculopapular, rash pruritic

^e Reported in adults in clinical studies

Paediatric population

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 and 4629 aged 12 to 17 years). This includes reactogenicity data collected in 3042 children (1865 aged 4 to 11 years and 1177 aged 12 to 17 years).

Frequency, type and severity of adverse reactions in children were largely consistent with those in adults. Adverse reactions reported more commonly in children than in adults were fever (11% versus 3%), 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 reactions reported 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 one dose of Qdenga of which 13 subjects received the indicated 2-dose regimen. Reactions reported with very common frequency were irritability (25%), fever (17%), injection site pain (17%) and loss of appetite (15%). Somnolence (8%) and injection site erythema (3%) were reported with common frequency. Injection site swelling was not observed in subjects below 4 years of age.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

No cases of overdose have been reported.

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

Mechanism of action

Qdenga contains live attenuated dengue viruses. The primary mechanism of action of Qdenga is to replicate locally and elicit humoral and cellular immune responses against the four dengue virus serotypes.

Clinical efficacy

The clinical efficacy of Qdenga was assessed in study DEN-301, a pivotal Phase 3, double-blind, randomized, 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 randomized (2:1 ratio) to receive Qdenga or placebo, regardless of previous dengue infection.

Efficacy was assessed using active surveillance across the entire study duration. Any subject with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) was required to visit the study site for dengue fever evaluation by the investigator. Subjects/guardians were reminded of this requirement at least weekly to maximize the detection of all symptomatic virologically confirmed dengue (VCD) cases. Febrile episodes were confirmed by a validated, quantitative dengue RT-PCR to detect 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 30 days to 12 months after the second vaccination) are shown in Table 2. The mean age of the per protocol trial population was 9.6 years (standard deviation of 3.5 years) with 12.7% subjects in the 4-5 years, 55.2% in the 6-11 years and 32.1% in the 12-16 years age-groups. Of these, 46.5% were in Asia and 53.5% were in Latin America, 49.5% were females and 50.5% were males. The dengue serostatus at 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 seronegativity rate 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 12 months post second vaccination in study DEN-301 (Per Protocol Set)^a

CI: confidence interval; n: number of subjects with fever; VCD: virologically confirmed dengue

^a The primary analysis of efficacy data were based on the Per Protocol Set, which consisted of all randomized subjects who did not have any major protocol violations, including not receiving both doses of the correct assignment of Qdenga or placebo

^b 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 cases and VCD cases that met the 1997 WHO criteria for Dengue Haemorrhagic Fever (DHF). The criteria used 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 all cases of hospitalisation due to VCD utilizing predefined criteria which included an assessment of bleeding abnormality, plasma leakage, liver function, renal function, cardiac function, the central nervous system, and shock. In Trial DEN-301 VCD cases meeting the WHO 1997 criteria for DHF were identified using a programmed algorithm, i.e., without applying medical judgment. Broadly, the criteria 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 dengue serotype, VCD fever by baseline dengue serostatus, and severe forms of dengue from 30 days to 18 months post second vaccination in study DEN-301 (Per Protocol Set)

VE: vaccine efficacy; CI: confidence interval; n: number of subjects; VCD: virologically confirmed dengue; DENV: dengue virus serotype

^a Number of subjects evaluated

^b key secondary endpoint

^c 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 protection from 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 baseline dengue serostatus, and against individual serotypes by baseline serostatus from first dose to 54 months post second dose in study DEN-301 (Safety Set)

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, n: number of subjects, N: number of subjects evaluated, NP: not provided

^a Exploratory analyses; the study was neither powered nor designed to demonstrate a difference between the vaccine and the placebo group

^b Approximated using a one-sided 95% CI^c 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%) and in preventing clinically severe VCD cases caused by any serotype was 70.2% (95% CI: -24.7%, 92.9%).

In year-by-year analysis until four and a half years after the second dose, VE in preventing VCD was shown for all four serotypes in baseline dengue seropositive subjects. In baseline 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 5).

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

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, NP: not provided, N: total number of subjects 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 by bridging of immunogenicity data (see below).

Immunogenicity

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

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

The GMTs by baseline dengue serostatus in subjects 4 to 16 years of age in study DEN-301 are shown in Table 6.

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

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: not estimated

^a The immunogenicity subset was a randomly selected subset of subjects, and the Per Protocol Set for Immunogenicity was the 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 3 double-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)

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: not estimated

* 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 actual magnitude 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 (4-16 years) and DEN-304 (18-60 years) (Per Protocol Set for Immunogenicity)

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 titres remaining well above the pre-vaccination levels for all four serotypes, up to 51 months after the first dose.

No pharmacokinetic studies have been performed with Qdenga.

Non-clinical safety data revealed no special hazard for humans based on conventional studies of single dose, local tolerance, repeated dose toxicity, and toxicity to reproduction and development. In a distribution 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. A neurovirulence study shows that Qdenga is not neurotoxic.

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

Powder:

α,α-Trehalose dihydrate

Poloxamer 407

Human serum albumin

Potassium dihydrogen phosphate

Disodium hydrogen phosphate

Potassium chloride

Sodium chloride

Solvent:

Sodium chloride

Water for injections

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

18 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 to 32.5°C) from the time of reconstitution of the vaccine vial. After this time period, the vaccine must be discarded. 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 in pre-filled syringe:

• Powder (1 dose) in vial (Type-I glass), with a stopper (butyl rubber) and aluminium seal with green flip-off plastic cap + 0.5 mL solvent (1 dose) in pre-filled syringe (Type-I glass), with a plunger stopper (bromobutyl) and a tip cap (polypropylene), with 2 separate needlesPack size of 1 or 5.

• Powder (1 dose) in vial (Type-I glass), with a stopper (butyl rubber) and aluminium seal with green flip-off plastic cap + 0.5 mL solvent (1 dose) in pre-filled syringe (Type-I glass), with a plunger stopper (bromobutyl) and a tip cap (polypropylene), without needlesPack size of 1 or 5.

Not all pack sizes may be marketed.

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 solvent provided in the pre-filled syringe. The lyophilised vaccine must be reconstituted with solvent prior to administration.

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 syringe supplied with the vaccine 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 the vaccine.

Remove the vaccine vial and pre-filled syringe solvent from the refrigerator and place at room temperature for approximately 15 minutes.

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

Qdenga should be administered immediately after reconstitution. Chemical and physical in-use stability have been demonstrated for 2 hours at room temperature (up to 32.5°C) from the time of reconstitution of the vaccine vial. After this time period, the vaccine must be discarded. 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.

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

Takeda UK Limited

1 Kingdom Street

London

W2 6BD

United Kingdom

PLGB 16189/0126

26/01/2023

26/01/2023