Dengvaxia - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, one dose (0.5 mL) contains:

Chimeric yellow fever dengue virus serotype 1 (live, attenuated)..­......... 4.5 – 6.0 log10 CCID50/dose

Chimeric yellow fever dengue virus serotype 2 (live, attenuated)..­......... 4.5 – 6.0 log10 CCID50/dose

Chimeric yellow fever dengue virus serotype 3 (live, attenuated)..­......... 4.5 – 6.0 log10 CCID50/dose

Chimeric yellow fever dengue virus serotype 4 (live, attenuated)..­......... 4.5 – 6.0 log10 CCID50/dose

*Produced in Vero cells by recombinant DNA technology. This product contains genetically modified organisms (GMOs).

• **CCID50: 50% Cell Culture Infectious Dose.

Excipients with known effect : (see Section 4.4)

Phenylalanine­.............­.....41 micro­grams

Sorbitol.....­.............­........9.38 mi­lligrams

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for suspension for injection

Prior to reconstitution, the vaccine is a white, homogenous, freeze-dried powder with possible retraction at the base (ring-shaped cake possible).

The solvent is a clear and colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Dengvaxia is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in individuals 6 to 45 years of age with test-confirmed previous dengue infection (see sections 4.2, 4.4 and 4.8).

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

4.2 Posology and method of administration

Posology

Children and adults 6 to 45 years of age

The vaccination schedule consists of 3 injections of one reconstituted dose (0.5 mL) to be administered at 6-month intervals.

Booster dose

The added value of and appropriate timing for booster dose(s) have not been established. Current available data are included in section 5.1.

Paediatric population aged less than 6 years

Dengvaxia should not be used in children less than 6 years of age (see sections 4.4 and 4.8).

Safety and efficacy have not been established in children aged less than 6 years (see sections 4.8 and 5.1).

Method of administration

Dengvaxia should only be administered to individuals with a previous dengue infection. Previous dengue infection must be confirmed by a test, either documented in the medical history or performed prior to vaccination (see section 4.4).

Immunisation should be carried out by subcutaneous (SC) injection preferably in the upper arm in the region of deltoid.

Do not administer by intravascular injection.

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

4.3 Contraindications

• • Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or after

prior administration of Dengvaxia or a vaccine containing the same components.

• • Individuals with congenital or acquired cell-mediated immune deficiency, including

immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids (e.g. 20mg or 2mg/kg of prednisone for 2 weeks or more) within 4 weeks prior to vaccination.

• • 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).

4.4 Special warnings and precautions for use

Traceability

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

Hypersensitivity

Appropriate medical treatment and supervision must always be readily available in the event of an anaphylactic reaction following administration of the vaccine.

The tip caps of the prefilled syringes contain a natural rubber latex derivative, which may cause allergic reactions in latex sensitive.

Intercurrent illness

Administration of Dengvaxia must be postponed in individuals suffering from moderate to severe febrile or acute disease.

Syncope

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

Prior dengue infection pre-vaccination screening

Individuals who have not been previously infected by dengue virus should not be vaccinated because of an increased risk of hospitalisation for dengue and clinically severe dengue a observed during the long-term follow up of the clinical trials in vaccinated individuals not previously infected (see section 4.8).

In the absence of documented prior dengue virus infection, previous infection must be confirmed by a test before vaccination (see section 4.2). To avoid vaccination of false positives, only test methods with adequate performance in terms of specificity and cross-reactivity based on the local disease epidemiology should be used in accordance with official recommendations.

In non-endemic areas or low transmission settings, the use of the vaccine should be restricted to individuals who have high probability of future exposure to dengue.

The lower the proportion of true seropositive individuals, the higher the risk of false seropositives with any test used to determine dengue serostatus. Thus, pre-vaccination testing and vaccination should be limited to individuals with high probability of past dengue infection (e.g. individuals who lived before or had recurrent stay in endemic areas). The objective is to minimize the risk of a false positive test.

Special populations

Women of childbearing potential

Women of childbearing potential have to use effective contraception during at least one month after each dose (see section 4.6).

Travellers

There are no clinical data to support vaccination of individuals living in non-endemic areas with low probability of past dengue infection and who only occasionally travel to endemic areas, therefore vaccination of these individuals is not recommended.

Protection

A protective immune response with Dengvaxia may not be elicited in all vaccinees. It is recommended to continue personal protection measures against mosquito bites after vaccination.

Dengvaxia contains phenylalanine, sodium and sorbitol

Dengvaxia contains 41 micrograms of phenylalanine in each 0.5 ml dose. Phenylalanine may be harmful for people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Dengvaxia contains less than 1mmol of sodium (23 mg) per 0.5 ml dose, that is to say essentially “sodium-free”.

Dengvaxia contains 9.38 milligrams of sorbitol in each 0.5 ml dose.

4.5 Interaction with other medicinal products and other forms of interaction

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 Dengvaxia, in order to avoid neutralization of the attenuated viruses contained in the vaccine.

Dengvaxia 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

Dengvaxia has been evaluated in one clinical study on concomitant administration with Tdap (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed) (629 dengue seropositive subjects at baseline, 9 to 60 years of age). The non-inferiority of the humoral immune response to all Tdap antigens elicited by the Tdap booster dose concomitantly administered with the first dose of Dengvaxia compared to sequential administration was achieved, when measured 28 days after Tdap booster dose in dengue seropositive subjects. In dengue seropositive subjects, the first dose of Dengvaxia induced a similar immune response (in terms of geometric mean titres [GMTs] and seropositivity rates) against all 4 dengue serotypes in both concomitant and sequential administration groups.

Dengvaxia has been evaluated in two clinical studies with bivalent and quadrivalent HPV vaccines (Human Papillomavirus Vaccine, Recombinant) (305 dengue seropositive subjects at baseline, 9 to 14 years of age and 197 dengue seropositive subjects at baseline, 9 to 13 years of age). The noninferiority of the humoral immune response to bivalent and quadrivalent HPV vaccines / Dengvaxia at 28 days after the last injection could not be assessed because the number of evaluable subjects was limited. Immunogenicity analyses in the concomitant administration group and in the sequential administration group were only descriptive.

Bivalent HPV vaccine showed similar GMTs in both concomitant and sequential administration groups and GMT ratios between groups (concomitant/se­quential administration) were near to 1 for both HPV-16 and HPV-18. The GMT ratios between groups (concomitant/se­quential administration) were close to 1 for all 4 dengue serotypes.

For the quadrivalent HPV, GMT ratios between groups (concomitant/se­quential administration) were close to 1 for HPV-6, and around 0.80 for HPV-11, HPV-16, and HPV-18. The GMTs ratios between groups (concomitant/se­quential administration) were close to 1 for serotypes 1 and 4, and close to 0.80 for serotypes 2 and 3.

The clinical relevance of these observations is not known.

There was no evidence of an increased rate of reactogenicity or change in the safety profile of the vaccines when Tdap or HPV vaccines were administered concomitantly with Dengvaxia in any of these studies.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies did not indicate any direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

There is limited amount of data from the use of Dengvaxia in pregnant women. These data are not sufficient to conclude on the absence of potential effects of Dengvaxia on pregnancy, embryo-foetal development, parturition and post-natal development.

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

Women of childbearing potential have to use effective contraception during at least one month after each dose.

Breast-feeding

Animal studies did not indicate any direct or indirect harmful effects with respect to lactation.

There is very limited experience on dengue virus excretion via breast milk.

Also, considering that Dengvaxia is a live attenuated vaccine and that there is very limited experience from post marketing data with Dengvaxia in lactating women, the vaccine is contraindicated during lactation (see section 4.3).

Fertility

No specific studies have been performed on fertility.

Animal studies did not indicate any harmful effects with respect to female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

In subjects 6 to 45 years of age, the most frequently reported reactions whatever the dengue serostatus prior to vaccination, were headache (51%), injection site pain (49%), malaise (41%), myalgia (41%), asthenia (32%), and fever (14%).

Adverse reactions occurred within 3 days following vaccination except fever which appears within 14 days after the injection. The adverse reactions were usually mild to moderate in severity and of short duration (0 to 3 days).

Systemic adverse reactions tended to be less frequent after the second and third injections of Dengvaxia as compared to the first injection.

Allergic including anaphylactic reactions have been reported very rarely.

Overall, the same adverse reactions but at lower frequencies were observed in dengue seropositive subjects.

Tabulated list of adverse reactions

Adverse reactions are listed according to the following frequency categories:

Very common: > 1/10

Common: > 1/100 to < 1/10

Uncommon: > 1/1000 to < 1/100

Rare: > 1/10 000 to < 1/1000

Very rare: (<1/10 000)

Adverse reactions collected within 28 days after any injection during clinical studies from 6 to 45 years of age, on a reactogenicity subset of 1492 adults and 4434 children, and adverse reactions observed during commercial use are presented infor children 6 to 17 years old and in Table 2 for adults 18 to 45 years old.

Table 1: Adverse reactions from Clinical Studies and reported during commercial use in children (6 to 17 years old)

System Organ Class	Frequency	Adverse Events
Infections and infestations	Uncommon	Upper respiratory tract infection
	Rare	Nasopharyngitis
Immune system disorders	Very rare	Allergic including anaphylactic reactions*
Nervous system disorders	Very common	Headache
	Rare	Dizziness
Respiratory, thoracic and mediastinal disorders	Rare	Rhinorrhoea Cough Oropharyngeal pain
Gastrointestinal disorders	Uncommon	Vomiting
	Rare	Nausea
Skin and subcutaneous tissue disorders
	Rare	Rash Urticaria
Musculoskeletal and connective tissue disorders	Very common	Myalgia
	Rare	Neck pain
General disorders and administration site conditions	Very common	Malaise Asthenia Fever Injection site reactions (pain, erythema)
	Common	Injection site swelling
	Uncommon	Injection site reactions (pruritus, induration, haemorrhage, hematoma)
	Rare	Chills

* Adverse reactions from spontaneous reporting.

Table 2: Adverse reactions from Clinical Studies and reported during commercial use in adults (18 to 45 years old)

System Organ Class	Frequency	Adverse Events
Infections and infestations	Uncommon	Upper respiratory tract infection Nasopharyngitis
Blood and lymphatic tissue disorders	Uncommon	Lymphadenopathy
Immune system disorders	Very rare	Allergic including anaphylactic reactions*
Nervous system disorders	Very common	Headache
	Uncommon	Dizziness
Respiratory, thoracic and mediastinal disorders	Uncommon	Oropharyngeal pain Cough
Gastrointestinal disorders	Uncommon	Nausea Vomiting Dry mouth
Skin and subcutaneous tissue disorders	Uncommon	Rash
Musculoskeletal and connective tissue disorders	Very common	Myalgia
	Uncommon	Neck pain Arthralgia
General disorders and administration site conditions	Very common	Injection site pain Malaise Asthenia
	Common	Fever Injection site reactions (erythema, hematoma, swelling, pruritus)
	Uncommon	Injection site reactions (induration, warmth) Fatigue Chills
	Rare	Injection site haemorrhage

* Adverse reactions from spontaneous reporting.

Hospitalised and/or clinically severe dengue fever in long-term safety follow-up data

In an exploratory analysis of the long-term follow up from the first injection in three efficacy studies, an increased risk of hospitalisation for dengue including clinically severe dengue (predominantly Dengue Haemorrhagic Fever grade 1 or 2 [WHO 1997]) has been observed in vaccinees with no previous dengue infection. Data obtained in the pivotal clinical trials show that over a period of 6 years, in subjects with no previous dengue infection, the risk of severe dengue is increased in subjects 6 to 16 years of age vaccinated with Dengvaxia as compared to non-vaccinated subjects in the same age group. Estimates from the long-term analysis suggest the onset of increased risk was mainly during the 3rd year following the first injection.

This increased risk was not observed in individuals who have been previously infected by dengue virus (refer to Section 5.1).

Paediatric population

Paediatric data in subjects 6 to 17 years of age

In paediatric population, fever and injection site erythema have been observed with a higher frequency

(very common) than in adults (common).

Urticaria (rare) was only reported in subjects 6 to 17 years of age (none in adults).

Paediatric data in subjects below 6 years of age, i.e., outside the age indication

The reactogenicity subset in subjects below 6 years of age includes 2192 subjects as follows: 1287 subjects below 2 years of age and 905 subjects between 2 and 5 years of age.

In subjects 2 to 5 years of age, as compared to subjects above 6 years of age, injection site swelling was more frequently reported (frequency: very common), and additional adverse events were reported (frequency: uncommon): rash maculo-papular and decreased appetite.

In subjects 2 to 5 years of age, with no previous dengue infection, long-term safety follow-up data showed an increased risk of dengue disease requiring hospitalisation including clinically severe dengue in vaccinated subjects as compared to non-vaccinated subjects (see section 4.4).

In subjects below 2 years of age, the most frequently reported adverse reactions following any injection of Dengvaxia were fever, irritability, appetite lost, abnormal crying and injection site tenderness.

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 listed in

4.9 Overdose

No cases of overdose have been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vaccines, Viral vaccines, ATC code: J07BX/ Not Yet assigned

Mechanism of action

Dengvaxia contains live attenuated viruses. Following administration, the viruses replicate locally and elicit neutralizing antibodies and cell-mediated immune responses against the four dengue virus serotypes (see detailed data below, subsection Immunogenicity).

Clinical efficacy

The clinical efficacy of Dengvaxia was assessed in 3 studies: one supportive Phase IIb efficacy study (CYD23) in Thailand, and 2 pivotal large-scale Phase III efficacy studies, CYD14 in Asia (Indonesia, Malaysia, the Philippines, Thailand, Vietnam) and CYD15 in Latin America (Brazil, Colombia, Honduras, Mexico, Puerto Rico).

In the Phase IIb study, a total of 4002 subjects aged 4 to 11 years were randomised to receive Dengvaxia or a control, regardless of previous dengue infection. Of these subjects 3285 subjects were 6 to 11 years of age (2184 in vaccine group and 1101 in Control Group).

In the two pivotal Phase III studies (CYD14 and CYD15), a total of approximately 31000 subjects aged 2 to 16 years were randomised to receive either Dengvaxia or placebo, regardless of previous dengue infection. Of these subjects, 19 107 subjects who received Dengvaxia (5193 subjects in CYD14 and 13914 in CYD15) and 9538 subjects who received placebo (2598 in CYD14 and 6940 in CYD15) were 6 to 16 years of age.

At the start of the CYD14 and CYD15 trials, dengue seroprevalence for the overall population at the trial sites ranged from 52.8%-81.1% in CYD14 (Asia-Pacific) and 55.7%-92.7% in CYD15 (Latin America).

The efficacy was assessed during an Active Phase of 25 months, in which surveillance was designed to maximize the detection of all symptomatic virologically-confirmed dengue (VCD) cases regardless of the severity. The active detection of symptomatic dengue cases started on the day of the first injection and lasted until 13 months after the third injection.

For the primary endpoint, the incidence of symptomatic VCD cases occurring during the 12-month period from 28 days after the third injection was compared between the vaccine and the Control Group.

Exploratory vaccine efficacy analyses according to dengue serostatus measured by plaque reduction neutralization test (PRNT50) at baseline (before the first injection) were performed in the immunogenicity subset of 2000 subjects each in CYD14 and CYD15 and 300 subjects in CYD23. Of the 2580 subjects 6 to 16 years old in this subset (approximately 80%) who were dengue seropositive at baseline, 1729 subjects received the vaccine (656 subjects in CYD14 and 1073 in CYD15) and 851 subjects received placebo (339 in CYD14 and 512 in CYD15) (see also subsection Immunogenicity).

Clinical efficacy data for subjects 6 to 16 years of age in endemic areas, any serostatus at baseline

The Vaccine Efficacy (VE) results according to the primary endpoint (symptomatic VCD cases occurring during the 25-month period after the first dose) in subjects 6 to 16 years of age (any serostatus at baseline) are shown infor studies CYD14, CYD15 and CYD23.

Table 3: VE against symptomatic VCD cases during the 25-month period after the first dose due to any of the 4 serotypes in subjects 6 to 16 years (any serostatus at baseline).

	CYD14		CYD15		CYD23		Pooled CYD14+CYD15		Pooled* CYD14+CYD15+ CYD23
	Vaccine group	Control group	Vaccine group	Control group	Vaccin e group	Control group	Vaccine group	Control group	Vaccine group	Control group
Cases / personyears	166/103 52	220/503 9	227/268 83	385/132 04	62/433 6	46/218 4	393/372 35	605/182 43	455/415 71	651/204 27
VE % (95%C I)	63.3 (54.9 ; 70.2)		64.7 (58.7; 69.8)		32.1 (-1.7; 54.4)		64.2 (59.6; 68.4)		62.0 (57.3; 66.2)

N: number of subjects per study

Cases: number of subjects with at least one symptomatic virologically-confirmed dengue episode in the considered period. Person-years: sum of time-at-risk (in years) for the subjects during the study period.

CI: confidence interval.

*Pooled results of CYD14, 15 and 23 need to be interpreted cautiously because of differences in the Dengue confirmatory test and acute febrile illness definition between CYD14/15 and CYD23.

In subjects 6 to 16 years of age, the efficacy of Dengvaxia against symptomatic virologically-confirmed dengue (VCD) cases due to any of the 4 serotypes was demonstrated in all three studies, CYD14, CYD15 and CYD23 (see.

Clinical efficacy data  for subjects 6 to 16 years of age in endemic areas, dengue seropositive at baseline

VE against symptomatic VCD cases in subjects 6 to 16 years ofage

The Vaccine Efficacy (VE) results according to exploratory analysis of symptomatic VCD cases occurring during the 25-month period after the first dose in subjects 6 to 16 years of age, seropositives at baseline are shown in for the immunogenicity subset of studies CYD14, CYD15 and CYD23.

Table 4: VE against symptomatic VCD cases during the 25-month period after the first dose due

to any of the 4 serotypes in subjects 6 to 16 years (dengue seropositive at baseline).

	CYD14		CYD15		CYD23		Pooled CYD14+CYD15		Pooled * CYD14+CYD15+ CYD23
	Vaccine group	Control group	Vaccine group	Control group	Vaccine group	Control group	Vaccine group	Control group	Vaccine group	Control group
Cases / personyears	12/1320	25/671	8/2116	23/994	2/248	5/114	20/3436	48/1665	22/3684	53/1779
VE % (95%CI)	75.6 (49.6; 88.8)		83.7 (62.2; 93.7)		81.6 (-12.6; 98.2)		79.7 (65.7; 87.9)		79.9 (66.9; 87.7)

N: number of subjects per study

Cases: number of subjects with at least one symptomatic virologically-confirmed dengue episode in the considered period. Person-years: sum of time-at-risk (in years) for the subjects during the study period.

CI: confidence interval.

NC: Not computed (the absence of cases in vaccine and control group does not permit to calculate VE nor CI) *Pooled results of CYD14, 15 and 23 need to be interpreted cautiously because of differences in the Dengue confirmatory test and acute febrile illness definition between CYD14/15 and CYD23.

The four serotypes contributed to the overall Vaccine Efficacy (VE). Data are limited because baseline immunostatus was initially collected in a limited subset of subjects. VE against symptomatic VCD due to serotype 1 [76.8 (46.1; 90.0)] and to serotype 2 [55.5 (-15.5; 82.8)] tends to be lower compared to serotypes 3 [89.6 (63.7; 97.0)] and serotype 4 [96.5 (73.4; 99.5)] during the 25-month period after the first dose, for subjects 6 to 16 years who are seropositive at baseline (immunogenicity subset of studies CYD14, CYD15 and CYD23).

Efficacy tends to be slightly lower in the 6–8 years of age compared to children 9–16 years of age.

VE against hospitalized and severe VCD cases in subjects 6 to 16 years of age

In subjects 6 to 16 years of age, dengue seropositive at baseline (immunogenicity subset), two clinically severe VCD cases in CYD14 and one in CYD15 were reported during the 25-month period after the first injection in the control group versus none in the vaccine group. Eight hospitalized VCD cases in CYD14 were reported in the control group versus one in the vaccine group and two hospitalized VCD cases in CYD15 were reported in the control group versus none in the vaccine group. These data are inconclusive due to the low number of cases in the immunogenicity subset.

Efficacy was assessed in moderate-high endemic areas. The magnitude of protection may not be extrapolated to other epidemiological situations.

Clinical efficacy data for subjects 17 to 45 years of age in endemic areas

No clinical efficacy study has been done in subjects from 17 to 45 years from endemic areas. The clinical efficacy of the vaccine is based on bridging of immunogenicity data (see below section Immunogenicity data  for subjects 18 to 45 years of age in endemic areas ).

Long-term protection

Limited data suggest a trend for efficacy to decrease over time. During the last 2 years of follow-up (Year 5 and 6) after the initial dose, vaccine efficacy against symptomatic VCD (Immunogenicity Subset, pooled CYD14+CYD15) was 14.6% (95% CI: –74.7; 58.3) in subjects 6 to 16 years with previous dengue infection. Efficacy persistence may vary according to the epidemiological situations.

Immunogenicity

No immune correlate of protection has been established. During clinical development, immunogenicity data were collected in a total of 7262 subjects 9 months to 60 years of age that received at least one injection of the vaccine.

Among these subjects, a total of 3498 subjects 6 to 45 years of age from endemic areas and dengue immune received at least one injection of Dengvaxia. Most of the subjects were 6 to 17 years of age (n=2836).

During clinical development, neutralizing antibody titres for each serotype were measured with the plaque reduction neutralization test (PRNT) and presented as geometric mean titres (GMTs).

In the following Tables the dengue serostatus at baseline (before the first injection), was defined as:

• • Dengue seropositivity if the PRNT50 titre > 10 [1/dil] (the lower limit of quantification,

LLOQ), against at least one serotype.

• • Dengue seronegativity if the PRNT50 titre < the lower limit of quantification against any of the

4 serotypes.

Immunogenicity data for subjects 6 to 8 years of age in endemic areas

GMTs at baseline and 28 days post-dose 3 in subjects 6 to 8 years of age in CYD14 are shown in the Table 5

Table 5: Immunogenicity for dengue seropositive subjects 6 to 8 years of age in CYD14 from endemic areas

		Serotype 1		Serotype 2		Serotype 3		Serotype 4
Study	N	Predose 1 GMT (95%CI)	Postdose 3 GMT (95%CI)	Predose 1 GMT (95%CI)	Postdose 3 GMT (95%CI)	Predose 1 GMT (95%CI)	Postdose 3 GMT (95%CI)	Predose 1 GMT (95%CI)	Postdose 3 GMT (95%CI)
CYD14	168	80.8 (57.3; 114)	203 (154; 268)	118 (86.0; 161)	369 (298; 457)	105 (75.5; 145)	316 (244; 411)	48.4 (37.2; 63.0)	175 (145; 211)

N: number of subjects with available antibody titre for the relevant endpoint

Dengue seropositive subjects are subjects with titres above or equal to LLOQ against at least one dengue serotype at baseline CI: Confidence Interval

CYD14: Indonesia, Malaysia, the Philippines, Thailand, Vietnam.

Immunogenicity data for subjects 9 to 17 years of age in endemic areas

GMTs at baseline and 28 days post-dose 3 in subjects 9 to 16 years of age in CYD14 and CYD15 are shown in the Table 6.

Table 6: Immunogenicity for dengue seropositive subjects 9 to 16 years of age in CYD14 and

CYD15 from endemic areas

		Serotype 1		Serotype 2		Serotype 3		Serotype 4
Study	N	Pre-injectionl GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)
CYD14	485	167 (138; 202)	437(373; 511)	319 (274; 373)	793(704; 892)	160 (135; 190)	443(387; 507)	83.8 (72.0; 97.6)	272(245; 302)
CYD15	1048	278 (247; 313)	703(634; 781)	306 (277; 338)	860(796; 930)	261 (235; 289)	762(699; 830)	73.3 (66.6; 80.7)	306(286; 328)

N: number of subjects with available antibody titre for the relevant endpoint

Dengue seropositive subjects are subjects with titres above or equal to LLOQ against at least one dengue serotype at baseline

CI: Confidence Interval

CYD14: Indonesia, Malaysia, the Philippines, Thailand, Vietnam.

CYD15: Brazil, Colombia, Honduras, Mexico, Puerto Rico.

Immunogenicity data  for subjects 18 to 45 years of age in endemic areas

The immunogenicity of the final formulation of the CYD dengue vaccine in adults aged 18 to 45 years in endemic areas was assessed in 3 studies conducted all in Asia-Pacific (CYD22 in Vietnam, CYD28 in Singapore and CYD47 in India).

GMTs at baseline and 28 days post-dose 3 in subjects 18 to 45 years of age are shown in the Table 7

Table 7: Immunogenicity for dengue seropositive subjects 18 to 45 years of age from endemic areas

		Serotype 1		Serotype 2		Serotype 3		Serotype 4
Study	N	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)	Preinjection 1 GMT (95%CI)	Postinjection 3 GMT (95%CI)
CYD22	19	408 (205; 810)	785 (379; 1626)	437 (240; 797)	937 (586; 1499)	192 (117; 313)	482 (357; 651)	86.5 (41.2; 182)	387 (253; 591)
CYD28	66	59.8 (36.8;97.4)	235 (135; 409)	67.1 (40.9; 110)	236 (144; 387)	48.4 (32.9;71.0)	239 (166; 342)	22.1 (14.7;33.4)	211 (155; 287)
CYD47	109	324 (236; 445)	688 (524; 901)	363 (269; 490)	644 (509; 814)	394 (299; 519)	961 (763; 1211)	80.7 (613; 106)	413(331; 516)

N: number of subjects with available antibody titre for the relevant endpoint

Dengue seropositive subjects are subjects with titres above or equal to LLOQ against at least one dengue serotype at baseline CI: Confidence Interval

CYD28: Low endemic country

CYD22: Vietnam; CYD28: Singapore; CYD47: India;

The bridging of efficacy is based on above available data and overall results. Immunogenicity data available from studies in adults aged 18 to 45 years in endemic regions show that post-injection 3 GMTs against each serotype are generally higher in adults than in children and adolescents in CYD14 and CYD15. Therefore, protection is expected in adults in endemics areas although the actual magnitude of efficacy relative to that observed in children and adolescents is unknown.

Long-term persistence of antibodies

The GMTs persisted post dose 3 up to 5 years in subjects 6 years of age and older in studies CYD14 and CYD15. At year 5 after the third injection, GMTs were still higher to pre-vaccination GMTs despite decrease in the GMTs against all 4 serotypes compared to post-dose 3 GMTs. The GMTs levels depend on age and dengue serostatus at baseline.

The effect of a booster dose was assessed in subjects 9–50 years living in endemic areas after a 3-dose schedule (studies CYD63, CYD64, CYD65). No or modest transient increase of neutralizing Ab titers was observed after the boost. The booster effect was variable across serotypes and studies. Why there is a lack/limited booster effect with Dengvaxia remains not understood in terms of mechanisms and clinical implications.

5.2 Pharmacokinetic properties

No pharmacokinetic studies have been performed on Dengvaxia.

5.3 Preclinical safety data

Non-clinical safety data revealed no special risks for humans based on a repeated-dose toxicity including assessment of local tolerance, and a developmental and reproductive toxicology program. There was no shedding of Dengvaxia RNA in a distribution and shedding study, hence no risk of dissemination to the environment or transmission from vaccinees. A neurovirulence study shows that CYD dengue vaccine is not neurotoxic.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder:

Essential amino acids including Phenylalanine

Non-essential amino acids

Arginine hydrochloride

Sucrose

Trehalose dihydrate

Sorbitol (E420)

Trometamol

Urea

Hydrochloric acid and sodium hydroxide for pH adjustment

Solvent:

Sodium chloride

Water for injections

6.2 Incompatibilities

Dengvaxia must not be mixed with any other vaccine or medicinal product.

6.3 Shelf life

3 years

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

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

• • Powder (1 dose) in vial (Type-I glass), with a stopper (halobutyl) and a flip-off cap (aluminium,

polypropylene) + 0.5 mL of solvent in a pre-filled syringe (Type-I glass), with a plunger stopper (halobutyl) and a tip cap (elastomer) with 2 separate needles.

Pack size of 1 or 10.

• • Powder (1 dose) in vial (Type-I glass), with a stopper (halobutyl) and a flip-off cap (aluminium,

polypropylene) + 0.5 mL of solvent in pre-filled syringe (Type-I glass), with a plunger stopper (halobutyl) and a tip cap (elastomer).

Pack size of 1 or 10.

The tip caps of the pre-filled syringes contain a natural rubber latex derivative.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Contact with disinfectants is to be avoided since they may inactivate the vaccine viruses.

Dengvaxia must be reconstituted prior to administration.

Dengvaxia is reconstituted by transferring all of the solvent (0.4% sodium chloride solution) provided in the blue-labelled pre-filled syringe into the vial of freeze-dried powder with a yellowish green flip-off cap.

• 1. Attach a sterile needle to the pre-filled syringe for the transfer of the solvent. The needle must be fitted firmly to the syringe, rotating it by a one-quarter turn.

• 2. Transfer the entire content of the pre-filled syringe into the vial containing the powder.

• 3. Swirl gently until the powder is completely dissolved.

The suspension should be visually inspected prior to administration. After reconstitution, Dengvaxia is a clear, colourless liquid with the possible presence of white to translucent particles (of endogenous nature).

After complete dissolution, a 0.5 mL dose of the reconstituted suspension is withdrawn into the same syringe. For injection, the syringe should be fitted with a new sterile needle.

After reconstitution with the solvent provided, Dengvaxia must be used immediately.

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

7. MARKETING AUTHORISATION HOLDER

Sanofi Pasteur

14 Espace Henry Vallée

69007 Lyon

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1338/001

EU/1/18/1338/002

EU/1/18/1338/003

EU/1/18/1338/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 December 2018

10. DATE OF REVISION OF THE TEXT

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

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.