Qdenga

Prior to reconstitution, the vaccine is a white to off-white colored freeze-dried powder (compact cake).
The diluent (solvent) is a clear, colorless solution.
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.
#Produced in Vero cells by recombinant DNA technology.
**PFU = Plaque-forming units.
Excipients/Inactive Ingredients: Powder: α,α-Trehalose dihydrate, Poloxamer 407, Human serum albumin, Potassium dihydrogen phosphate, Disodium hydrogen phosphate, Potassium chloride, Sodium chloride.
Diluent (Solvent): Sodium chloride, Water for injections.

Pharmacotherapeutic group: Vaccines, Viral vaccines. ATC code: J07BX04.
Pharmacology: Pharmacodynamics: Clinical Studies: Mechanism of action: Qdenga contains live attenuated dengue viruses.
The primary mechanism of action of Qdenga is to replicate locally and elicit neutralizing antibodies to confer protection against dengue disease caused by any of the four dengue virus serotypes. Qdenga activates multiple arms of the immune system, including binding antibodies, complement fixing antibodies, functional antibodies to dengue nonstructural protein 1 (NS1), and cell mediated immune responses (CD4+, CD8+, and natural killer cells).
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.
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 Micro Neutralization 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%.
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 1. (See Table 1.)

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VE results according to the secondary endpoints, preventing hospitalization due to VCD fever, preventing VCD fever by serostatus, by serotype and preventing severe VCD fever are shown in Table 2. 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. (See Table 2.)

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Rapid 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.
Clinical efficacy for subjects 17 to 60 years of age: No clinical efficacy study has been conducted in subjects from 17 years of age. The clinical efficacy of Qdenga in subjects from 17 years of age is based on bridging of immunogenicity data from clinical efficacy in subjects from 4-16 years of age (see Immunogenicity data for subjects 18 to 60 years of age in non-endemic areas as follows).
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 3). (See Table 3.)

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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%).
Up to 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.
Immunogenicity: During clinical development, immunogenicity data were collected in 9 studies with 3877 subjects who received 2 doses of Qdenga 3 months apart; 2796 of these subjects lived in dengue endemic areas and 1081 subjects lived in non-endemic areas.
Neutralizing antibody titers for each serotype were measured with the microneutralization test (MNT₅₀) and presented as Geometric Mean Titers (GMTs).
In the tables as follows, the dengue serostatus at baseline (before the first injection) was identified as: Dengue seropositive if the MNT₅₀ titer was ≥10 (the lower limit of detection, LLOD), against at least one serotype; Dengue seronegative if the MNT₅₀ titer was < the LLOD against all 4 serotypes.
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 4. (See Table 4.)

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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 5. (See Table 5.)

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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 6). Protection against dengue disease is expected in adults although the actual magnitude of efficacy relative to that observed in children and adolescents is unknown. (See Table 6.)

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Long-term persistence of antibodies: The long-term persistence of neutralizing antibodies was shown in study DEN-301, with titers remaining well above the pre-vaccination levels for all four serotypes, up to 51 months after the first dose.
Pharmacokinetics: No pharmacokinetic studies have been performed with Qdenga.
Toxicology: Nonclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal Toxicology and/or Pharmacology: 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 feces 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.

Qdenga is indicated for the prevention of dengue disease caused by any dengue virus serotype in individuals from 4 years of age.
The use of Qdenga should be in accordance with official recommendations.

Dosage: Individuals from 4 years of age at time of first injection: 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.
Special Patient Populations: Elderly Patients: No dose adjustment is required in elderly individuals ≥60 years of age. See Precautions.
Pediatric Patients: The safety and efficacy of Qdenga in children aged less than 4 years has not yet been established. Currently available data are described in Adverse Reactions but no recommendation on a posology can be made.
Impaired Renal Function: The safety and efficacy of Qdenga in this population have not been established.
Impaired Hepatic Function: The safety and efficacy of Qdenga in this population have not been established.
Method of administration: After complete reconstitution of the lyophilized vaccine with the diluent (solvent), Qdenga should be administered by subcutaneous (SC) injection preferably in the upper arm in the region of deltoid.
Qdenga must not be injected intravascularly, intradermally or intramuscularly. The vaccine should not be mixed in the same syringe with any other vaccines or other parenteral medicinal products.
For instructions on reconstitution of Qdenga before administration, see Instructions for Use/Handling under Cautions for Usage.

No cases of overdose have been reported.

Hypersensitivity to the active substances or to any of the excipients listed in Description 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/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 Use in Pregnancy & Lactation).
Breast-feeding women (see Use in Pregnancy & Lactation).

Anaphylaxis: Events of anaphylaxis have been reported post authorization.
Appropriate medical treatment and supervision should 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 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 Pharmacology: Pharmacodynamics under Actions). 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.
Other: Qdenga must not be administered by intravascular, intradermal or intramuscular injection.
Drug Abuse and Dependence: Qdenga has no known potential for abuse or dependence.
Effects on ability to drive and use machines: No studies on the effects of Qdenga on the ability to drive and use machines have been performed. Some of the effects mentioned under Adverse Reactions may temporarily have a minor influence on the ability to drive and use machines.
Use in Pregnancy: 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 Use in Pregnancy & Lactation).

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.
Pregnancy: Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
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-fetal development, parturition and post-natal development.
Qdenga is a live attenuated vaccine, therefore Qdenga is contraindicated during pregnancy (see Contraindications).
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 Contraindications).
Fertility: Animal studies did not indicate any harmful effects with respect to female fertility (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions). No specific studies have been performed on fertility in humans.

Clinical Studies: In clinical studies, the most frequently reported reactions in subjects aged 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 viremia was detected rarely after the second dose.
Dengue diagnostic tests may be positive during vaccine viremia and cannot be used to distinguish vaccine viremia from wild type dengue infection.
Tabulated list of adverse reactions: Adverse reactions associated with Qdenga obtained from clinical studies and post-authorization experience are tabulated as follows.
The safety profile presented as follows is based on data generated in placebo-controlled clinical studies and post-authorization experience. Pooled analysis of clinical studies included data from 14627 study participants aged 4 to 60 years (13839 children and 788 adults) who have been vaccinated with Qdenga. This included a reactogenicity subset of 3830 participants (3042 children and 788 adults).
Adverse reactions are listed according to the following frequency categories: Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1,000 to <1/100; Rare: ≥1/10,000 to <1/1,000; Very rare: <1/10,000; Not known: cannot be estimated from the available data. (See Table 7.)

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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.

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 to avoid neutralization 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 Contraindications).
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 a 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 the yellow fever seroprotection rates. Dengue antibody responses were decreased following concomitant administration of Qdenga and yellow fever 17D vaccine. The clinical significance of this finding is unknown.
Qdenga may be administered concomitantly with a human papillomavirus vaccine.
Coadministration has been studied in subjects aged 9 to 14 years.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other vaccine or medicinal products except for the diluent (solvent) provided.
Instructions for Use/Handling: Instructions for reconstitution of the vaccine with the diluent (solvent) presented in vial: Qdenga is a 2-component vaccine that consists of a vial containing lyophilised vaccine and a vial containing diluent (solvent). The lyophilised vaccine must be reconstituted with diluent prior to administration.
Use only sterile syringes for reconstitution and injection of Qdenga. Qdenga should not be mixed with other vaccines in the same syringe.
To reconstitute Qdenga, use only the diluent (0.22% sodium chloride solution) 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 and diluent (solvent) vials from the refrigerator and place at room temperature for approximately 15 minutes.
Remove the caps from both vials and clean the surface of stoppers on top of the vials using an alcohol wipe.
Attach a sterile needle to a sterile 1 mL syringe and insert the needle into the diluent (solvent) vial. The recommended needle is 23G.
Slowly press the plunger completely down.
Turn the vial upside down, withdraw the entire contents of the vial and continue to pull plunger out to 0.75 mL. A bubble should be seen inside of the syringe.
Remove the needle syringe assembly from the diluent vial.
Invert the syringe to bring the bubble back to the plunger.
Insert the needle of the syringe assembly into the lyophilised vaccine vial.
Direct the flow of the diluent (solvent) toward the side of the vial while slowly depressing the plunger to reduce the chance of forming bubbles.
Release the finger from the plunger and, holding the assembly on a flat surface, gently swirl the vial in both directions with the needle syringe assembly attached.
DO NOT SHAKE. Foam and bubbles may form in the reconstituted product.
Let the vial and syringe assembly sit for a while until the solution becomes clear. This takes about 30-60 seconds.
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.
Withdraw the entire volume of the reconstituted Qdenga solution with the same syringe until an air bubble appears in the syringe.
Remove the needle syringe assembly from the vial.
Hold the syringe with the needle pointing upwards, tap the side of the syringe to bring the air bubble to the top, discard the attached needle and replace with a new sterile needle, expel the air bubble until a small drop of the liquid forms at the top of the needle. The recommended needle is 25G 16 mm.
Qdenga is ready to be administered by subcutaneous injection.
Qdenga should be administered immediately after reconstitution. Chemical and physical in-use stability have been demonstrated for 2 hours 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.
Instructions for reconstitution of the vaccine with diluent (solvent) presented in pre-filled syringe: Qdenga is a 2-component vaccine that consists of a vial containing lyophilised vaccine and diluent (solvent) provided in the pre-filled syringe. The lyophilised vaccine must be reconstituted with diluent prior to administration.
Qdenga should not be mixed with other vaccines in the same syringe.
To reconstitute Qdenga, use only the diluent (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 diluent (solvent) from the refrigerator and place at room temperature for approximately 15 minutes.
Remove the cap from the vaccine vial and clean the surface of stopper on top of the vial using an alcohol wipe.
Attach a sterile needle to the pre-filled syringe and insert the needle into the vaccine vial. The recommended needle is 23G.
Direct the flow of the diluent (solvent) toward the side of the vial while slowly depressing the plunger to reduce the chance of forming bubbles.
Release the finger from the plunger and, holding the assembly on a flat surface, gently swirl the vial in both directions with the needle syringe assembly attached.
DO NOT SHAKE. Foam and bubbles may form in the reconstituted product.
Let the vial and syringe assembly sit for a while until the solution becomes clear. This takes about 30-60 seconds.
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.
Withdraw the entire volume of the reconstituted Qdenga solution with the same syringe until an air bubble appears in the syringe.
Remove the needle syringe assembly from the vial. Hold the syringe with the needle pointing upwards, tap the side of the syringe to bring the air bubble to the top, discard the attached needle and replace with a new sterile needle, expel the air bubble until a small drop of the liquid forms at the top of the needle. The recommended needle is 25G 16 mm.
Qdenga is ready to be administered by subcutaneous injection.
Qdenga should be administered immediately after reconstitution. Chemical and physical in-use stability have been demonstrated for 2 hours 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at a temperature between +2°C and +8°C. Do not freeze.
Store in the original package.
Shelf Life: After reconstitution with the diluent (solvent) provided: Qdenga should be used immediately.
If not used immediately, Qdenga must be used within 2 hours from reconstitution.

Vaccines, Antisera & Immunologicals

J07BX04 - dengue virus vaccines ; Belongs to the class of other viral vaccines. Used for active immunization against Dengue virus.

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