Dengvaxia

Evrópusambandið - enska - EMA (European Medicines Agency)

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Opinber matsskýrsla PAR
Virkt innihaldsefni:
chimeric yellow fever dengue virus serotype 1 (live, attenuated) / chimeric yellow fever dengue virus serotype 2 (live, attenuated) / chimeric yellow fever dengue virus serotype 3 (live, attenuated) / chimeric yellow fever dengue virus serotype 4 (live, attenuated)
Fáanlegur frá:
Sanofi Pasteur
ATC númer:
J07BX
INN (Alþjóðlegt nafn):
dengue tetravalent vaccine (live, attenuated)
Meðferðarhópur:
Vaccines,
Lækningarsvæði:
Dengue
Ábendingar:
Dengvaxia is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in individuals 9 to 45 years of age with prior dengue virus infection and living in endemic areas. The use of Dengvaxia should be in accordance with official recommendations.,
Vörulýsing:
Revision: 2
Leyfisstaða:
Authorised
Leyfisnúmer:
EMEA/H/C/004171
Leyfisdagur:
2018-12-12
EMEA númer:
EMEA/H/C/004171

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B. PACKAGE LEAFLET

Package Leaflet: Information for the User

Dengvaxia, powder and solvent for suspension for injection in pre-filled syringe

dengue tetravalent vaccine (live, attenuated)

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before you or your child is vaccinated because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This vaccine has been prescribed for you or your child only. Do not pass it on to others.

If you or your child get any side effects, talk to your doctor, pharmacist or nurse. This includes

any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Dengvaxia is and what it is used for

What you need to know before you or your child use Dengvaxia

How to use Dengvaxia

Possible side effects

How to store Dengvaxia

Contents of the pack and other information

1.

What Dengvaxia is and what it is used for

Dengvaxia is a vaccine. It is used to help protect you or your child against "dengue disease" caused by

dengue virus serotypes 1, 2, 3 and 4. It contains versions of these 4 varieties of the virus that have

been weakened so that they cannot cause the disease.

Dengvaxia is given to adults, young people and children (from 9 to 45 years of age) with prior dengue

virus infection and who live in endemic areas (also see sections 2 and 3).

Endemic areas are areas where the disease has been continuously present among the people who live

there and where outbreaks or epidemics have occurred.

Dengvaxia should be used according to official recommendations.

How the vaccine works

Dengvaxia stimulates the body’s natural defences (immune system), to produces antibodies that will

help protect against the viruses that cause dengue disease if the body is exposed to them in the future.

What is dengue and dengue disease?

Dengue is a viral infection which spreads through the bite of an infected

Aedes

mosquito. The virus

from an infected person can spread to other people through mosquito bites for about 4 to 5 days

(maximum 12 days) after the first symptoms appear. Dengue is not transmitted directly from person-

to-person.

Dengue disease results in symptoms including fever, headache, pain behind the eyes, muscle and joint

pain, feeling sick (nausea), being sick (vomiting), swollen glands or skin rash. Symptoms usually last

for 2 to 7 days. You can also have dengue but show no symptoms (called "asymptomatic").

Occasionally dengue can be severe enough for you to have to go to hospital and in rare cases it can

cause death. Severe dengue can give you a high fever and any of the following: severe abdominal

(belly) pain, persistent sickness (vomiting), rapid breathing, severe bleeding, bleeding in the stomach,

bleeding gums, feeling tired, feeling restless, coma, having fits (seizures) and organ failure.

2.

What you need to know before you or your child use Dengvaxia

To make sure that Dengvaxia is suitable for you or your child, it is important to tell your doctor,

pharmacist or nurse if any of the points below apply to you or your child. If there is anything you do

not understand, ask your doctor, pharmacist or nurse to explain.

Do not use Dengvaxia if you or your child

Know you are allergic to the active substances or any of the other ingredients of Dengvaxia

(listed in section 6).

had an allergic reaction after using Dengvaxia before. Signs of an allergic reaction may include

an itchy rash, shortness of breath and swelling of the face and tongue.

have a weak immune system (the body's natural defences). This may be due to a genetic defect

or HIV infection.

are taking a medicine that affects the immune system (such as high-dose corticosteroids or

chemotherapy). Your doctor will not use Dengvaxia until 4 weeks after you stop treatment.

are pregnant or breast-feeding.

Warnings and precautions

If you or your child have never been infected by dengue virus before vaccination, you may have an

increased risk of a more serious dengue illness that may lead to hospitalisation if you are later bitten

by a dengue-infected mosquito.

Before the administration of Dengvaxia, your doctor, pharmacist or nurse will check if you or your

child have ever been infected by dengue virus, and will tell you if a serotesting has to be performed.

Tell your doctor, pharmacist or nurse before using Dengvaxia if you or your child have:

a mild to high fever or acute disease. You will not get Dengvaxia until you or your child have

recovered.

ever had any health problems when given a vaccine. Your doctor will carefully consider the

risks and benefits of vaccination.

ever fainted from an injection. Fainting, and sometime falling, can occur (mostly in young

people) following, or even before, any injection with a needle.

had any allergic reaction to latex. The tip cap of the pre-filled syringe contains a natural rubber

latex which may cause an allergic reaction.

Travellers

Vaccination is not recommended if you live in area where dengue infections do not regularly occur

and if you plan to travel to an area where dengue infections regularly occur.

Outbreaks

Dengvaxia should not be used in the context of dengue outbreak (sudden occurrence of disease) in

non-endemic regions.

Important information about the protection provided

As with any vaccines, Dengvaxia may not protect everybody who has been vaccinated. You must

continue to protect yourself against mosquito bites even after vaccination.

After vaccination, you should consult a doctor if you or your child believe you might have a dengue

infection, and develop any of the following symptoms: high fever, severe abdominal pain, persistent

vomiting, rapid breathing, bleeding gums, tiredness, restlessness and blood in vomit.

Additional protection precautions

You should take precautions to prevent mosquito bites. This includes using insect repellents, wearing

protective clothing, and using mosquito nets.

Younger children

Children less than 9 years of age must not receive the vaccine.

Other medicines and Dengvaxia

Tell your doctor or pharmacist if you or your child are using, have recently used or might use any

other vaccines or medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following:

medicines that affect your body’s natural defences (immune system) such as high-dose

corticosteroids or chemotherapy. In this case, your doctor will not use Dengvaxia until 4 weeks

after you stop treatment. This is because Dengvaxia might not work as well.

medicines called “immunoglobulins” or blood products containing immuno globulins, such as

blood or plasma. In this case, your doctor will not use Dengvaxia until 6 weeks, and preferably

not for 3 months after you stop treatment. This is because Dengvaxia might not work as well.

Pregnancy and breast-feeding

Do not use Dengvaxia if you or your daughter are pregnant or breast-feeding. If you or your daughter:

are of child-bearing age, you must use an effective method of contraception to avoid pregnancy

for at least one month after each Dengvaxia dose.

think you or your daughter may be pregnant or are planning to have a baby, ask your doctor,

pharmacist or nurse for advice before using Dengvaxia.

Driving and using machines

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

Dengvaxia contains phenylalanine, sodium and sorbitol

Dengvaxia contains 41 micrograms of phenylalanine in each 0.5 ml dose. Phenylalanine may be

harmful if you have 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.

3.

How to use Dengvaxia

Dengvaxia is given by your doctor or nurse as an injection under the skin (subcutaneous injection) in

the upper arm. It must not be injected into a blood vessel.

You or your child will receive 3 injections of 0.5 mL – one every 6 months.

The first injection will be given at the chosen or scheduled date.

The second injection, 6 months after the first injection.

The third injection, 6 months after the second injection.

Dengvaxia should be used according to official recommendations.

Previous dengue infection has to be assessed by laboratory confirmed history of dengue or through

serotesting according to official recommendations.

Instructions for preparing the vaccine intended for medical and healthcare professionals are

included at the end of the leaflet.

If you or your child miss an injection of Dengvaxia

If you or your child miss a scheduled injection, your doctor will decide when to give the missed

injection. It is important that you or your child follow the instructions of your doctor,

pharmacist or nurse regarding follow-up injection.

If you forget or are not able to go back at the schedule time, ask your doctor, pharmacist or

nurse for advice.

If you have any further questions on the use of this product, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, Dengvaxia can cause side effects, although not everybody gets them.

Serious allergic (anaphylactic) reactions

If any of these symptoms occur after leaving the place where you or your child received an injection,

contact a doctor immediately

difficulty breathing

blueness of the tongue or lips

a rash

swelling of the face or throat

low blood pressure causing dizziness or fainting

sudden and serious feeling of illness or unease with drop in blood pressure causing dizziness

and loss of consciousness, rapid heartbeat linked with breathing difficulty.

These signs or symptoms (anaphylactic reactions) usually develop soon after the injection is given and

while you or your child are still in the clinic or doctor’s surgery. They can also happen very rarely

after receiving any vaccine (may affect up to 1 in 10 000 people).

Other serious reactions

For some people who have not been infected by dengue before vaccination, there may be an increased

risk of getting a more serious dengue illness requiring hospitalisation if they become bitten by a

dengue-infected mosquito later. This increased risk may mainly begin during the third year following

the first injection.

Other side effects

The following side effects occurred during studies in children, young people and adults. Most of the

side effects occurred within 3 days of having the injection of Dengvaxia.

Very common:

(may affect more than 1 in 10 people)

headache

muscle pain (myalgia)

generally feeling unwell (malaise)

weakness (asthenia)

injection site pain

fever.

Common:

(may affect up to 1 in 10 people)

injection site reactions: redness (erythema), bruising (haematoma), swelling, and itching

(pruritus).

Uncommon:

(may affect up to 1 in 100 people)

infections of the nose or throat (upper respiratory tract)

feeling dizzy

sore throat (oropharyngeal pain)

cough

feeling sick (nausea)

rash (skin eruption)

neck pain

hardening of skin at the injection site (injection site induration).

Very rare:

(may affect up to 1 in 10 000 people)

allergic reactions.

Additional side effects in adults:

Uncommon:

(may affect up to 1 in 100 people)

pain or swelling of the nose or throat (nasopharyngitis)

swollen glands (lymphadenopathy)

dry mouth

skin eruption over the whole body (rash generalized)

joint pain (arthralgia)

injection site warmth

chills

fatigue.

Additional side effects in children and adolescents (from 9 to and including 17 years of age):

Uncommon:

(may affect up to 1 in 100 people)

itchy rash (urticaria).

Rare:

(may affect up to 1 in 1000 people)

runny nose (rhinorrhea).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national reporting

system listed in

Appendix V

. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Dengvaxia

Keep Dengvaxia out of the sight and reach of children.

Do not use Dengvaxia after the expiry date that is stated on the carton after EXP. The expiry date

refers to the last day of that month.

Store in a refrigerator (2

C to 8

Do not freeze.

Keep the vaccine in the outer carton in order to protect it from light.

After mixing (reconstitution) with the solvent provided, the product should be used immediately.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Dengvaxia contains

After reconstitution, one dose (0.5 mL) contains 4.5 - 6.0 log10 CCID

* of each serotype of the

chimeric yellow fever dengue virus** (1, 2, 3 and 4) (live, attenuated).

* CCID

: 50% Cell Culture Infectious Dose.

** Produced in Vero cells by recombinant DNA technology. This product contains genetically

modified organisms (GMOs).

The other ingredients are: essential amino acids including Phenylalanine, non-essential amino

acids, Arginine hydrochloride, Sucrose, Trehalose dihydrate, Sorbitol (E420), trometamol, urea,

sodium chloride, water for injections and hydrochloric acid and sodium hydroxide for pH

adjustment.

What Dengvaxia looks like and contents of the pack

Dengvaxia is a powder and solvent for suspension for injection. Dengvaxia is provided as a powder in

a single-dose vial and a solvent in single-dose pre-filled syringe (0.5 mL) with 2 separate needles or

with no needle. The powder and the solvent must be mixed together before use.

Dengvaxia is available in packs of 1 or 10. Not all pack sizes may be marketed.

The powder is a white, homogenous, freeze-dried powder with possible retraction at the base (ring-

shaped cake possible).

The solvent (0.4% sodium chloride solution) is a clear and colourless solution.

After reconstitution with the solvent provided, Dengvaxia is a clear, colourless liquid with the possible

presence of white to translucent particles.

Marketing Authorisation Holder:

Sanofi Pasteur

14 Espace Henry Vallée

69007 Lyon

France

Manufacturer:

SANOFI PASTEUR

Parc Industriel d'Incarville

27100 Val de Reuil

France

SANOFI PASTEUR NVL

31-33 Quai Armand Barbès

69250 Neuville-sur-Saône

France

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/

Belgique /Belgien

Sanofi Belgium

tel.: +32 2 710.54.00

Lietuva

Sanofi – Aventis Lietuva, UAB

Tel.: +370 5 2755224

България

Sanofi Bulgaria EOOD

Teл.: +359 2 970 53 00

Luxembourg/Luxemburg

Sanofi Belgium

tel.: +32 2 710.54.00

Česká republika

Sanofi Pasteur

divize. vakcín sanofi-aventis, s.r.o.

Tel: +420 233 086 111

Magyarország

sanofi-aventis zrt

Tel.: +36 1 505 0055

Danmark

Sanofi A/S

Tel: +45 4516 7000

Malta

Sanofi S.p.A.

Tel: +39 02 39394983

Deutschland

Sanofi-Aventis Deutschland GmbH

Tel.: 0800 54 54 010

Tel. aus dem Ausland: +49 69 305 21 130

Nederland

sanofi-aventis Netherlands B.V.

Tel: +31 20 245 4000

Eesti

Sanofi-Aventis Estonia OÜ

Tel.: +372 627 3488

Norge

Sanofi-aventis Norge AS

Tel: + 47 67 10 71 00

Ελλάδα

Sanofi-aventis AEBE

Τηλ.+30 210 900 16 00

Österreich

Sanofi-Aventis GmbH

Tel: +43 (1) 80185-0.

España

sanofi-aventis, S.A.

Tel: +34 93 485 94 00

Polska

Sanofi Pasteur Sp. z o.o.

Tel.: +48 22 280 05 00

France

Sanofi Pasteur Europe

Tél: 0800 42 43 46

Appel depuis l’étranger : +33 1 57 63 67 97

Portugal

Sanofi – Produtos Farmacêuticos, Lda.

Tel: + 351 21 35 89 400

Hrvatska

sanofi-aventis Croatia d.o.o

Tel.: +385 1 6003 400

România

Sanofi Romania SRL

Tel.: +40(21) 317 31 36

Ireland

sanofi-aventis Ireland T/A SANOFI

Tel: + 353 (0) 1 4035 600

Slovenija

sanofi-aventis d.o.o.

Tel.: +386 1 560 48 00

Ísland

Vistor

Tel : +354 535 7000

Slovenská

republika

sanofi-aventis Pharma Slovakia s.r.o.

divízia vakcín Sanofi Pasteur

Tel.: +421 2 33 100 100

Italia

Sanofi S.p.A.

Tel: 800536389

Tel dall'estero: +39 02 39394983

Suomi/Finland

Sanofi Oy

Tel: +358 (0) 201 200 300

Κύπρος

sanofi-aventis Cyprus Ltd.

Τηλ.: +357 – 22 871600

Sverige

Sanofi AB

Tel: +46 8-634 50 00

Latvija

Sanofi Aventis Latvia SIA Vakcīnu nodaļa

Tel.: +371 67332451

United Kingdom

Sanofi

Tel: +44 845 372 7101

This leaflet was last revised in [{MM/YYYY}].

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

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

Path to more information on dengue and vaccination by scanning the QR code included on the outer

carton with a smartphone. The same information is also available on the following URL:

http://qr.sanofi.com/dengvaxia

-----------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

As with all injectable vaccines, appropriate medical treatment and supervision must always be

readily available in the event of an anaphylactic reaction following the administration of

Dengvaxia.

Dengvaxia must not be mixed with other medicinal products in the same syringe.

Dengvaxia must not be administered by intravascular injection under any circumstances.

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

in the region of the deltoid.

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.

Reconstitution and handling of single-dose presentation

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-labeled 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.

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.

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

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.

Package Leaflet: Information for the User

Dengvaxia, powder and solvent for suspension for injection in multidose containers

dengue tetravalent vaccine (live, attenuated)

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before you or your child is vaccinated because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This vaccine has been prescribed for you or your child only. Do not pass it on to others.

If you or your child get any side effects, talk to your doctor, pharmacist or nurse. This includes

any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Dengvaxia is and what it is used for

What you need to know before you or your child use Dengvaxia

How to use Dengvaxia

Possible side effects

How to store Dengvaxia

Contents of the pack and other information

1.

What Dengvaxia is and what it is used for

Dengvaxia is a vaccine. It is used to help protect you or your child against "dengue disease" caused by

dengue virus serotypes 1, 2, 3 and 4. It contains versions of these 4 varieties of the virus that have

been weakened so that they cannot cause the disease.

Dengvaxia is given to adults, young people and children (from 9 to 45 years of age) with prior dengue

virus infection and who live in endemic areas (also see sections 2 and 3).

Endemic areas are areas where the disease has been continuously present among the people who live

there and where outbreaks or epidemics have occurred.

Dengvaxia should be used according to official recommendations.

How the vaccine works

Dengvaxia stimulates the body’s natural defences (immune system), to produces antibodies that will

help protect against the viruses that cause dengue disease if the body is exposed to them in the future.

What is dengue and dengue disease?

Dengue is a viral infection which spreads through the bite of an infected

Aedes

mosquito. The virus

from an infected person can spread to other people through mosquito bites for about 4 to 5 days

(maximum 12 days) after the first symptoms appear. Dengue is not transmitted directly from person-

to-person.

Dengue disease results in symptoms including fever, headache, pain behind the eyes, muscle and joint

pain, feeling sick (nausea), being sick (vomiting), swollen glands or skin rash. Symptoms usually last

for 2 to 7 days. You can also have dengue but show no symptoms (called "asymptomatic").

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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.

1.

NAME OF THE MEDICINAL PRODUCT

Dengvaxia, powder and solvent for suspension for injection in pre-filled syringe

dengue tetravalent vaccine (live, attenuated)

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 log

CCID

/dose**

Chimeric yellow fever dengue virus serotype 2 (live, attenuated)* ........... 4.5 - 6.0 log

CCID

/dose**

Chimeric yellow fever dengue virus serotype 3 (live, attenuated)* ........... 4.5 - 6.0 log

CCID

/dose**

Chimeric yellow fever dengue virus serotype 4 (live, attenuated)* ........... 4.5 - 6.0 log

CCID

/dose**

*Produced in Vero cells by recombinant DNA technology. This product contains genetically modified

organisms (GMOs).

**CCID

: 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 PARTICULARS

4.1

Therapeutic indications

Dengvaxia is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3

and 4 in individuals 9 to 45 years of age with prior dengue virus infection and living in endemic areas

(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 9 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.

Other paediatric population

Dengvaxia should not be used in children less than 9 years of age (see sections 4.8).

In vaccinees 2 to 8 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. Available data are not sufficient to confirm the safety and efficacy in individuals previously

infected by any dengue virus and younger than 9 years.

Method of administration

Previous dengue infection has to be assessed before vaccination by laboratory confirmed history of

dengue or through an appropriately validated serological test (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

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.

Special patient groups

Individuals who have not been previously infected by dengue virus or for whom this information is

unknown

Individuals who have not been previously infected by dengue virus or for whom this information is

unknown should not be vaccinated because an increased risk of hospitalisation for dengue and

clinically severe dengue (predominantly grade 1 or 2 Dengue Hemorrhagic Fever) has been observed

in these individuals during the long-term follow up of clinical trials (see Section 4.8).

In the absence of documented prior dengue virus infection, previous infection has to be confirmed by

serotesting before vaccination. 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.

Travellers

There are no safety, immunogenicity or efficacy data to support vaccination of individuals living in

non-endemic areas and travelling to endemic areas, therefore vaccination of these individuals is not

recommended.

Outbreaks

Dengvaxia should not be used in the context of dengue outbreak in non-endemic regions.

Others

Administration of Dengvaxia must be postponed in individuals suffering from moderate to severe

febrile or acute disease.

Vaccination should be preceded by a review of the individual's medical history (in particular, previous

vaccinations and possible adverse reactions which occurred after vaccination).

Appropriate medical treatment and supervision must always be readily available in the event of an

anaphylactic reaction following administration of the vaccine.

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.

The tip caps of the prefilled syringes contain a natural rubber latex derivative, which may cause

allergic reactions in latex sensitive individuals.

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

each dose (see section 4.6).

Dengvaxia must not be administered by intravascular injection under any circumstances.

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.

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.

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).

As there are no data on co-administration of Dengvaxia vaccine with other vaccines for the population

from 9 years and above, the concomitant use of Dengvaxia with other vaccines is not recommended.

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 9 to 45 years of age, the most frequently reported reactions whatever the dengue serostatus

prior to vaccination, were headache (54%), injection site pain (49%), malaise (44%), myalgia (43%),

asthenia (34%), and fever (16%).

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 9 to 45

years of age, on a reactogenicity subset of 1306 adults and 3067 children, and adverse reactions

observed during commercial use are presented in

Table 1

for children 9 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 (9 to 17 years old)

System Organ Class

Frequency

Adverse Events

Infections and infestations

Rare

Upper respiratory tract infection

Immune system disorders

Very rare

Allergic including anaphylactic reactions*

Nervous system disorders

Very common

Headache

Rare

Dizziness

Respiratory, thoracic and

mediastinal disorders

Rare

Oropharyngeal pain

Cough

Rhinorrhoea

Gastrointestinal disorders

Rare

Nausea

Skin and subcutaneous

tissue disorders

Uncommon

Urticaria

Rare

Rash

Musculoskeletal and

connective tissue disorders

Very common

Myalgia

Rare

Neck pain

General disorders and

administration site

conditions

Very common

Injection site pain

Malaise

Asthenia

Fever

Common

Injection site reactions (erythema, swelling)

Uncommon

Injection site reactions (hematoma, pruritus)

Injection site induration

* 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

Dry mouth

Skin and subcutaneous

tissue disorders

Uncommon

Rash

Rash generalised

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 induration

Injection site warmth

Chills

Fatigue

* 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. Over a period of 6 years, in subjects with no previous dengue infection, the

risk of severe dengue is increased by 2.41 fold (95% CI: 0.50; 11.75) in subjects 9 to 16 years of age

vaccinated with Dengvaxia as compared to non-vaccinated subjects in the same age group. In subjects

9 years of age or older, it was estimated that during a 6 year follow-up about 5 additional hospitalized

dengue cases or 3 additional severe dengue cases per 1000 vaccinees with no previous dengue

infection could occur following vaccination. 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, where it was estimated that 16 hospitalized dengue cases or 4 severe dengue cases could be

prevented per 1000 vaccinees with previous dengue infection during 6 years of follow up from the first

injection.

The estimations described above for a 6 year period are derived from data obtained in the pivotal

clinical trials in countries with a particular dengue seroprevalence and epidemiological context. These

figures may not be extrapolated to other regions with different seroprevalence and epidemiological

situations.

Paediatric population

Paediatric data in subjects 9 to 17 years of age

In paediatric population, fever has been observed with a higher frequency (very common) than in

adults (common).

Urticaria (uncommon) was only reported in subjects 9 to 17 years of age (none in adults).

Paediatric data in subjects below 9 years of age, i.e., outside the age indication

The reactogenicity subset in subjects below 9 years of age includes 2960 subjects as follows: 1287

subjects below 2 years of age, 905 subjects between 2 and 5 years of age and 768 subjects between 6

and 8 years of age.

In subjects 2 to 8 years of age, as compared to subjects above 9 years of age, injection site erythema

and swelling were more frequently reported (frequency: very common), and additional adverse events

were reported (frequency: uncommon): injection site haemorrhage, decreased appetite and vomiting.

In subjects 2 to 8 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.

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

Appendix V

4.9

Overdose

No cases of overdose have been reported.

5.

PHARMACOLOGICAL PROPERTIES

5.1

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 3).

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).

The Control Group in dengue studies was defined as subjects who received at least one injection of

placebo or comparator vaccine.

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. Efficacy in subjects 9 to 11 years of

age was assessed in 1554 subjects (1032 in vaccine group and 522 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. Efficacy in subjects 9 years of age and older was assessed in 17 230 subjects who

received Dengvaxia (3316 subjects in CYD14 and 13914 in CYD15) and 8596 subjects who received

placebo (1656 in CYD14 and 6940 in CYD15).

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 each subject had been followed for at least 13 months after the third

injection. This phase includes therefore the primary endpoint observation period from 28 days after the

third injection up to the end of the Active Phase.

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 to 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 2930 subjects 9 to 16 years old in this subset (approximately 80%) who were dengue seropositive

at baseline, 1974 subjects received the vaccine (901 subjects in CYD14 and 1073 in CYD15) and 956

subjects received placebo (444 in CYD14 and 512 in CYD15) (see also subsection 3).

2.1

Clinical efficacy data

for subjects 9 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 12-month period starting from 28 days after the third injection) in subjects 9 to 16

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EMA/739699/2018

EMEA/H/C/004171

Dengvaxia (dengue tetravalent vaccine [live, attenuated])

An overview of Dengvaxia and why it is authorised in the EU

What is Dengvaxia and what is it used for?

Dengvaxia is a vaccine used to help protect against dengue disease.

Dengue disease is a mosquito-borne tropical disease caused by the dengue virus leading to mild, flu-

like symptoms in most people. However, a small number of patients develop severe disease, with

potentially fatal bleeding and organ damage. The risk of severe disease is higher in people who have

been infected a second time.

There are several varieties (called serotypes) of dengue virus and Dengvaxia protects against

serotypes 1, 2, 3 and 4.

Dengvaxia is only for use in people from 9 to 45 years of age who have been infected with dengue

virus before and who live in areas where this infection is endemic. Endemic areas are areas where the

disease occurs regularly throughout the year.

Dengvaxia contains attenuated (weakened) yellow fever viruses that have been manipulated so that

they contain proteins from dengue virus.

How is Dengvaxia used?

Dengvaxia must only be given to people who have had a positive test result showing a previous

infection with dengue virus. The vaccine is given as 3 doses, 6 months apart. The injection is given

under the skin, preferably in the upper arm.

Dengvaxia can only be obtained with a prescription and should be used according to official

recommendations. For more information about using Dengvaxia, see the package leaflet or contact

your doctor or pharmacist.

How does Dengvaxia work?

Vaccines work by ‘teaching’ the immune system (the body’s natural defences) how to defend the body

against a disease. Dengvaxia contains weakened viruses that do not cause disease. When a person is

given the vaccine, the immune system recognises the dengue proteins in the weakened viruses as

Dengvaxia (dengue tetravalent vaccine [live, attenuated])

EMA/739699/2018

Page 2/3

‘foreign’ and makes antibodies against them. In the future, when the person comes into contact with

dengue virus, these antibodies together with other components of the immune system will be able to

kill the virus and help protect against the disease.

What benefits of Dengvaxia have been shown in studies?

Three studies were carried out in Asia and Latin America involving over 35,000 children aged 2 to 16

years. The studies included both children who had and had not been infected with dengue virus in the

past. Children were given either 3 injections of Dengvaxia or 3 injections of placebo (a dummy

vaccine) with 6 months between each injection. Cases of dengue disease were recorded for one year

after the last injection.

Overall, among children aged between 9 and 16 years and who had previous dengue infection, there

were around 79% fewer cases of dengue disease in children vaccinated with 3 doses of Dengvaxia

compared with placebo. Available data are not sufficient to confirm how well the vaccine works in

individuals previously infected by dengue virus and younger than 9 years.

However, among children aged between 9 and 16 years who had not had previous dengue infection,

the risk of severe dengue disease if they later became infected with the virus was higher in people

vaccinated compared with those given placebo (estimated at 2 additional cases per 1000 people

vaccinated over 5 years).

Additional studies showed that the vaccine is also effective in people aged 16 to 45 years.

What are the risks associated with Dengvaxia?

The most common side effects with Dengvaxia (which may affect more than 1 in 10 people) are

headache, injection site pain, malaise (feeling unwell), muscle pain, weakness and fever. Allergic

reactions, which may be severe, are a very rare side effect of Dengvaxia.

Dengvaxia must not be given to people with weakened immune systems, including people whose

immune system has been weakened by HIV infection or medicines such as cancer medicines or high

doses of corticosteroids. Dengvaxia must also not be given to women who are pregnant or

breastfeeding.

For the full list of side effects and restrictions with Dengvaxia, see the package leaflet.

Why is Dengvaxia authorised in the EU?

Dengvaxia is effective at reducing the number of cases of dengue disease in people aged between 9

and 45 years who have had the infection in the past. However, people who have not had dengue

infection in the past may have a higher risk of severe dengue disease if they become infected with the

virus after vaccination with Dengvaxia. Therefore, the vaccine should only be given to people who have

had a previous dengue infection, as confirmed by laboratory testing.

There is no other vaccine for dengue disease and neither is there a specific treatment. Dengvaxia’s

side effects are usually mild or moderate and do not last longer than three days.

The European Medicines Agency therefore decided that Dengvaxia’s benefits are greater than its risks

and it can be authorised for use in the EU in areas where dengue disease is endemic.

Dengvaxia (dengue tetravalent vaccine [live, attenuated])

EMA/739699/2018

Page 3/3

What measures are being taken to ensure the safe and effective use of

Dengvaxia?

The company that markets Dengvaxia will provide educational material for healthcare professionals

with information on the use of Dengvaxia including the need to test for previous dengue infection and

how to detect early dengue disease.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Dengvaxia have also been included in the summary of product characteristics and

the package leaflet.

As for all medicines, data on the use of Dengvaxia are continuously monitored. Side effects reported

with Dengvaxia are carefully evaluated and any necessary action taken to protect patients.

Other information about Dengvaxia

Dengvaxia received a marketing authorisation valid throughout the EU on 12 December 2018.

Further information on Dengvaxia can be found on the Agency’s website:

ema.europa.eu/medicines/human/EPAR/Dengvaxia

This overview was last updated in 12-2018.

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