Dengvaxia

Dengvaxia

Manufacturer:

Sanofi Pasteur
Full Prescribing Info
Contents
Dengue tetravalent vaccine (live, attenuated).
Description
After reconstitution, one dose (0.5 mL) contains: CYD dengue virus serotype 1* 4.8-6.0 log10 CCID50/dose**; CYD dengue virus serotype 2* 4.8-6.0 log10 CCID50/dose**; CYD dengue virus serotype 3* 4.8-6.0 log10 CCID50/dose**; CYD dengue virus serotype 4* 4.8-6.0 log10 CCID50/dose**.
*Produced in serum-free Vero cells by recombinant DNA technology.
**CCID50: 50% Cell Culture Infectious Dose.
Prior to reconstitution, the vaccine is a white, homogenous, freeze-dried powder with possible retraction at the base, and may form a ring-shaped cake.
The solvent is a clear, colorless liquid.
Excipients/Inactive Ingredients: Powder: Essential amino acids including L-Phenylalanine, Non-essential amino acids, L-Arginine hydrochloride, Sucrose, D-Trehalose dehydrate, D-Sorbitol, Trometamol, Urea.
Solvent for reconstitution: Sodium chloride, Water for injections.
No adjuvants and no preservatives are added.
Action
Pharmacotherapeutic group: Viral vaccines. ATC code: J07BX.
Pharmacology:
Pharmacodynamics: Mechanism of action: The vaccine 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.
Immunogenicity: Immunogenicity data were collected in a total of approximately 3104 subjects 9 through 45 years of age from endemic areas who received at least one injection of the final formulation of the vaccine according to the claimed vaccination schedule in 10 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies. Most of the subjects were 9 through 17 years of age (n= 2810).
The immunogenicity data presented correspond to the neutralizing antibody titers for each serotype as measured with the plaque reduction neutralization test (PRNT). The results are presented as geometric mean titers (GMTs), expressed in reciprocal dilutions (l/dil) measured at baseline and 28 days after the third injection of the vaccine.
GMT data on subjects 18 through 45 years of age included in Phase II safety and immunogenicity studies conducted in endemic areas (CYD22, CYD28 and CYD47) and on subjects 9 through 17 years of age included in the 3 efficacy studies (Phase IIb efficacy study, CYD23, and the two large-scale Phase III efficacy studies, CYD14 and CYD 15) are presented by study and region in the Dengue Group and in the Placebo Group in Table 1 (serotypes 1 and 2) and Table 2 (serotypes 3 and 4).(See Table 1 and Table 2.)


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In all age groups in all studies, an increase in GMTs was observed for each of the 4 serotypes 28 days after the third injection as compared to baseline, regardless of the region, i.e., Asia Pacific or Latin America.
Differences in GMTs 28 days after the third injection were observed depending on dengue immune statusa before the first injection, the age and the region. Overall: The higher the GMTs before the first injection, the higher the GMTs 28 days after the third injection; GMTs 28 days after the third injection were higher in subjects who were dengue immune before the first injection compared to subjects who were not dengue immune before the first injection; Dengue immune status before the first injection is a confounding factor of age: the older the subject, the higher the GMTs before the first injection and the higher the GMTs 28 days after the third injection, i.e., the immune response in terms of GMTs 28 days after the third injection increases with age.
Data on long-term persistence of antibodies: In subjects 9 years of age and older in endemic areas a decrease in the GMTs against all 4 serotypes was observed one year after the third injection and then a trend toward stabilization was observed in the subsequent years. The decrease in GMTs was variable depending on age and the dengue immune status of subjects before the first injection. Long-term GMTs for each serotype remained higher than GMTs before the first injection.
Efficacy: The efficacy of the vaccine was assessed in 3 randomized, observer-blinded, placebo-controlled efficacy studies: one supportive Phase IIb efficacy study (CYD23), and 2 pivotal large-scale Phase III efficacy studies conducted in 5 countries each, CYD14 in Asia and CYD15 in Latin America.
In the 2 pivotal Phase III studies, efficacy was assessed in a total of 17,230 subjects 9 through 16 years of age who received at least one injection of the vaccine: 3316 subjects 9 through 14 years of age in CYD14 and the entire study population in CYD15, i.e., 13,914 subjects 9 through 16 years of age. A time window of +/- 20 days was applied for the second and third injections. More than 70% of subjects were dengue immune at baseline.
In subjects 9 through 16 years of age, the efficacy of the vaccine against symptomatic virologically confirmed dengue (VCD) cases due to any and each of the 4 serotypes was demonstrated in both studies, CYD14 and CYD15, and in the meta-analysis. The assessment period extended from the first injection to the end of the active phase, i.e. over the 25-month period after the first injection.
The efficacy of the vaccine against severe VCD cases and against hospitalized VCD cases (i.e., hospital admission due to dengue, whatever the severity) were also evaluated. For severe VCD cases, two types of endpoints were considered: clinically severe VCD case and VCD cases that met WHO criteria for dengue hemorrhagic fever (DHF). Vaccine efficacy was demonstrated for these three endpoints in both studies and in the meta-analysis.
The efficacy results were also analyzed according to covariates, i.e., age at the time of the first injection and dengue immune status before the first injection. In subjects 9 through 16 years of age no significant effect of age on vaccine efficacy was observed, while a trend toward higher efficacy was observed in dengue immune subjects at baseline compared to dengue non-immune subjects at baseline (see Table 3).
The efficacy results in subjects 9 through 16 years of age are presented in Table 3 for each of the two phase III efficacy studies and in the meta-analysis. The results are presented for the entire active phase of 25 months.


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aDengue immune status at baseline (i.e. before the first injection) measured by PRNT is defined as: Immune: subjects with quantified ( ≥10 [l/dil], the lower limit of quantitation) neutralizing antibodies against at least one dengue serotype in the baseline sample; Non-immune: subjects without quantified (<the lower limit of quantitation) neutralizing antibodies against any of the 4 dengue serotypes in the baseline sample.
The terms "immune and non-immune" are used to describe the presence or not of antibodies at baseline. Immune is not used to imply that subjects are protected from dengue infection.
Pharmacokinetics: No pharmacokinetic studies have been performed on the vaccine.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special risks for humans based on a repeated-dose toxicity and local tolerance study, a distribution and shedding study, a neurovirulence study and a developmental and reproductive toxicology program.
Indications/Uses
Dengvaxia is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in individuals 9 through 16 years of age living in endemic areas.
Dosage/Direction for Use
Posology: Primary vaccination: The primary vaccination schedule consists of 3 injections of one reconstituted dose (0.5 mL) to be administered at 6-month intervals.
If flexibility in the vaccination schedule is necessary, a time window of +/- 20 days is acceptable (see Pharmacology: Pharmacodynamics under Actions).
Dengvaxia should not be administered in individuals less than 9 years of age as available clinical data are not sufficient to conclude on the benefit/risk of vaccination with Dengvaxia in this population.
Booster dose: The need for a booster dose after primary vaccination with Dengvaxia has not yet been established.
Method of Administration: Once the freeze-dried vaccine has been completely reconstituted using the solvent provided, it is administered by subcutaneous (SC) injection. The recommended injection site is the deltoid region.
Precautions to be taken before handling or administering the medicinal product: Do not administer by intravascular injection.
Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
Overdosage
No cases of overdose have been reported.
Contraindications
Dengvaxia must not be administered to individual with a history of severe allergic reaction to any component of Dengvaxia or after prior administration of Dengvaxia or a vaccine containing the same components.
Administration of Dengvaxia must be postponed in individuals suffering from moderate to severe febrile or acute disease.
Dengvaxia must not be administered to individuals with congenital or acquired immune deficiency that impairs cell-mediated immunity, including immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids generally given for 2 weeks or more.
Dengvaxia must not be administered to individuals with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function.
Dengvaxia must not be administered to pregnant women.
Dengvaxia must not be administered to breastfeeding women.
Special Precautions
As with any vaccine, vaccination with Dengvaxia may not protect 100% of vaccinated individuals. It is recommended to continue personal protection measures against mosquito bites after vaccination.
In individuals who have a history of serious or severe reactions within 48 hours after a prior administration of Dengvaxia or of a vaccine containing similar component, the risk and benefits of administering Dengvaxia must be carefully considered.
Before administering any biological, the person responsible for administration must take all precautions to prevent allergic or other reaction. As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in the event of an anaphylactic reaction following administration of the vaccine. Epinephrine (1:1000) and other appropriate agents used to control immediate allergic reactions must be available to treat unexpected events such as anaphylaxis.
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.
For patients receiving treatment with high doses of systemic corticosteroids given for 2 weeks or more (daily receipt of prednisone or equivalent 20 mg or 2 mg/kg body weight is considered as a substantially immunosuppressive dose), it is advisable to wait until immune function has recovered, i.e., for at least 4 weeks after stopping treatment, before administering Dengvaxia.
Dengvaxia must not be administered by intravascular injection under any circumstances.
No studies have been performed on the interference of the vaccine with laboratory and/or tests.
Effects on ability to drive and use machines: No studies have been performed on the effects of the vaccine on the ability to drive or to use machines.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy constitutes a contraindication (see Contraindications).
Women of childbearing age should avoid becoming pregnant for 4 weeks after receiving any injection of Dengvaxia.
Animal studies did not indicate any direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Breastfeeding: Dengvaxia is contraindicated during breastfeeding (see Contraindications).
It is not known whether this vaccine is excreted into human milk. The effect on breastfed infants of administration of Dengvaxia to their mothers has not been studied.
Animal studies did not indicate any direct or indirect harmful effects with respect to lactation (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Fertility: No specific studies have been performed on fertility.
Animal studies did not indicate any harmful effects with respect to female fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Adverse Reactions
Summary of the safely profile: A total of approximately 20,667 subjects 9 through 60 years of age received at least one injection of the final formulation of the vaccine according to the claimed vaccination schedule in 13 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies.
The safety profile was assessed in a total of 1547 subjects 18 through 60 years of age and 19,120 subjects 9 through 17 years of age. To support the indication, the safety profile presented as follows is focused on the pooled analysis of safety data in children and adolescents from 9 years of age i.e. subjects 9 through 17 years of age. Reactogenicity was assessed in a subset of 3068 out of those 19,120 subjects.
Safety was monitored during the first 28 days following each injection in the reactogenicity subset, and serious adverse event (SAEs), including dengue cases, were collected throughout the studies in all subjects, up to at least 6 months after the last injection of the vaccine.
In subjects 9 through 17 years of age, the most frequently reported ARs following any injection of the vaccine were headache, injection site pain, malaise and myalgia.
The ARs were usually mild to moderate in severity and of short duration (0 to 3 days). Onset was typically observed 0 to 3 days after the injection, except for fever which appeared within 14 days after the injection.
Systemic ARs tended to be less frequent after the second and third injections as compared to the first injection.
Tabulated list of adverse reactions: Adverse reactions are listed according to the following frequency categories: Very common: ≥1/10 (≥10%); Common: ≥1/100 to <1/10 (≥1% and <10%); Uncommon: ≥1/1000 to <1/100 (≥0.1% and <1%); Rare: ≥1/10,000 to <1/1000 (≥0.01% and <0.1%).
Related ARs within 28 days after any injection in subjects 9 through 17 years of age are presented in Table 4, based on safety data collected during clinical studies. (See Table 4.)


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Long-term safety follow-up data: SAEs have been collected and followed-up from at least one year after the third injection in pivotal efficacy studies described in Pharmacodynamics.
In subjects 9 years of age and older, no difference in the safety profile was observed from the long­ term follow-up data.
Drug Interactions
Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
Separate syringes and needles, separate injection sites and preferably separate limbs must be used if any other vaccine(s) or medicinal product(s) is/are concomitantly administered.
For patient receiving treatment with immunoglobulins or blood products containing immunoglobulins, such as blood or plasma, it is advisable 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.
For immunosuppressive therapy or corticosteroid therapy, see Contraindications and Precautions.
No specific studies have been performed on concomitant administration of the vaccine with any other medicinal product(s) in individuals 9 through 16 years of age living in endemic areas.
Caution For Usage
Special precautions for disposal and other handling: Contact with disinfectants is to be avoided since they may inactivate the vaccine viruses.
Separate syringes and needles, separate injection sites and preferably separate limbs must be used if any other vaccine(s) or medicinal product(s) is/are concomitantly administered.
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. The pre-filled syringe is fitted with a sterile needle for this transfer. The vial is then gently swirled. 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.
The suspension should be visually inspected prior to administration. After reconstitution, Dengvaxia is a clear, colorless liquid with the possible presence of white to translucent particles (of endogenous nature).
After reconstitution with the solvent provided, Dengvaxia must be used immediately.
Any unused product or waste material should be disposed of, preferably by heat inactivation or incineration, in accordance with local regulations.
Incompatibilities: In the absence of compatibility studies, Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
Storage
Store in a refrigerator (2°C-8°C). Do not freeze. Store in outer carton in order to protect from light.
For storage conditions after reconstitution of Dengvaxia, see Shelf-Life as follows.
Shelf-Life: 3 years (36 months).
After reconstitution with solvent provided, Dengvaxia should be used immediately. However, in-use stability studies have shown that the reconstituted vaccine can be kept for up to 6 hours between 2°C and 8°C (i.e., in a refrigerator) and protected from light.
ATC Classification
J07BX - Other viral vaccines ; Used for active immunizations.
Presentation/Packing
Powd for inj 1 dose (vial) + 0.5 mL (pre-filled syringe) solvent x 1's.
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