DENGVAXIA- dengue tetravalent vaccine, live
Sanofi Pasteur Inc.
DENGVAXIA® (Dengue Tetravalent Vaccine, Live) is a vaccine indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3, and 4. DENGVAXIA is approved for use in individuals 9 through 16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas.
Limitations of use
- DENGVAXIA is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. Those not previously infected are at increased risk for severe dengue disease when vaccinated and subsequently infected with dengue virus. [See Warnings and Precautions (5.1).] Previous dengue infection can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing prior to vaccination.
- The safety and effectiveness of DENGVAXIA have not been established in individuals living in dengue nonendemic areas who travel to dengue endemic areas.
For subcutaneous use only.
Three doses (0.5 mL each) 6 months apart (at month 0, 6, and 12).
The package contains a vial of lyophilized vaccine antigen and a vial of saline diluent (0.4% NaCl).
After removing the “flip-off” caps, cleanse the lyophilized vaccine antigen and diluent vial stoppers with a suitable germicide. Do not remove the vial stoppers or metal seals holding them in place.
To reconstitute DENGVAXIA, use a sterile needle and syringe to withdraw 0.6 mL from the diluent vial and inject it into the vial of the lyophilized vaccine antigen. Swirl the vial gently.
Changing needles between withdrawing the vaccine from the vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated.
|Figure 1||Figure 2||Figure 3||Figure 4|
|Insert the syringe needle through the stopper of the vial of diluent and withdraw 0.6 mL liquid content.||Insert the syringe needle through the stopper of the vial of lyophilized vaccine antigen and inject the liquid into the vial.||Swirl vial gently. The syringe needle is not removed while swirling the vial.||After reconstitution, withdraw 0.5 mL.DENGVAXIA should be used immediately after reconstitution.|
After reconstitution, the suspension is colorless and may develop trace amounts of white to translucent endogenous proteinaceous particles. [See Description (11).]
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy or contains particles other than trace amounts of white to translucent particles.
Discard reconstituted vaccine if not used within 30 minutes. [See How Supplied/Storage and Handling (16.2).]
DENGVAXIA should not be mixed in the same syringe with other parenteral products.
After reconstitution, withdraw 0.5 mL of DENGVAXIA and administer subcutaneously immediately or store refrigerated at 2°C to 8°C (36°F to 46°F) and use within 30 minutes. Do not administer DENGVAXIA by intramuscular injection.
DENGVAXIA is a suspension for injection (supplied as a lyophilized powder to be reconstituted with the supplied diluent, 0.4% NaCl). A single dose, after reconstitution, is 0.5 mL.
Do not administer DENGVAXIA to individuals with a history of severe allergic reaction to a previous dose of DENGVAXIA or to any component of DENGVAXIA. [See Description (11).]
Do not administer DENGVAXIA to individuals with severe immunodeficiency or immunosuppression due to disease or therapy.
5.1 Increased Risk of Severe Dengue Disease Following DENGVAXIA in Persons not Previously Infected with Dengue Virus
In unvaccinated individuals, first dengue infections rarely cause severe dengue, while second dengue infections with a different serotype are associated with an increased risk of severe dengue. DENGVAXIA administration to individuals not previously infected by dengue virus is associated with an increased risk of severe dengue disease when the vaccinated individual is subsequently infected with any dengue virus serotype. Therefore, healthcare professionals must evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus.
Previous infection by dengue virus can be evaluated through a medical record of previous laboratory-confirmed dengue infection or through serotesting prior to vaccination.
There is no FDA cleared test available to determine a previous dengue infection. Available non-FDA cleared tests may yield false positive results (e.g., due to cross-reactivity with other flaviviruses).
DENGVAXIA may cause hypersensitivity reactions, including anaphylaxis. Appropriate medical treatment and supervision must be available following administration of DENGVAXIA.
Vaccination with DENGVAXIA may not protect all individuals. It is recommended to continue personal protection measures against mosquito bites after vaccination.
Syncope (fainting) can occur following, or even before, vaccination with DENGVAXIA as a psychogenic response to injection with a needle. Procedures should be in place to prevent injury from falling and to manage syncopal reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
The safety of DENGVAXIA in subjects 9 through 16 years of age was evaluated in 9 randomized, placebo-controlled, multicenter clinical trials. In these studies, a total of 19,102 subjects 9 through 16 years of age received at least one dose of DENGVAXIA and 9,484 received placebo (0.9% sodium chloride). Overall, 50.9% of trial participants who received DENGVAXIA or placebo were female. Racial groups were reported as 18.9% Asian, 13% American Indian or Alaska native, 6.4% Caucasian, 2.6% black, and 59.1% as other. In the largest study (Study 1, NCT01374516; N = 20,869) conducted in four Latin American countries and Puerto Rico, most subjects (99.9%) reported Hispanic ethnicity. All studies enrolled subjects irrespective of evidence of previous dengue infection.
Solicited Adverse Reactions
In a multi-center, observer-blind, randomized (2:1), placebo-controlled trial conducted in four Latin American countries and Puerto Rico (Study 1, NCT01374516), 2,000 subjects (out of a total of 20,869 subjects) were recruited during the first 2 months of enrollment for inclusion in the reactogenicity subset. Solicited adverse reactions were recorded daily for 14 days following each vaccination.
Table 1 presents the frequency and severity of solicited injection site reactions reported within 7 days and systemic adverse reactions reported within 14 days following receipt of DENGVAXIA or placebo.
|Dose 1||Dose 2||Dose 3|
|DENGVAXIA%N = 1,264–1,326||Placebo%N = 635–657||DENGVAXIA%N = 1,228–1,298||Placebo%N = 594–639||DENGVAXIA%N = 1,215–1,279||Placebo%N = 597 –631|
|N: range number of subjects with available data for the specified endpointsStudy 1, NCT01374516Placebo: 0.9% sodium chloride|
|Injection Site Reactions|
|Pain *||AnyGrade 3||32.40.8||26.30.9||25.60.5||16.40.0||22.50.9||16.50.3|
|Erythema †||AnyGrade 3||4.10.0||4.70.2||1.9<0.1||1.70.0||1.50.0||1.60.0|
|Swelling †||AnyGrade 3||3.50.0||2.70.2||1.90.0||0.90.0||1.60.0||1.30.0|
|Systemic Adverse Reactions|
|Asthenia ‡||AnyGrade 3||24.62.7||22.52.6||17.81.8||16.41.1||16.31.3||17.41.3|
|Fever §||AnyGrade 3||6.81.7||6.61.1||5.90.8||7.11.2||7.31.1||8.70.8|
|Headache ‡||AnyGrade 3||39.95.1||41.64.1||29.82.1||28.52.3||29.62.6||25.01.9|
|Malaise ‡||AnyGrade 3||24.52.4||25.92.3||20.81.3||16.61.3||19.31.4||15.21.1|
|Myalgia ‡||AnyGrade 3||29.22.2||27.41.5||21.01.6||15.80.8||20.01.5||18.40.8|
Unsolicited Non-serious Adverse Reactions
In Study 1, 1.2% of subjects in the DENGVAXIA group (16/1,333) and 0.8% of subjects in the placebo group (5/664) reported at least 1 unsolicited non-serious adverse reaction within 28 days following any dose.
In this study, 0.7% of the subjects in the DENGVAXIA group and 0.5% in the placebo group reported at least one unsolicited non-serious injection site adverse reaction. The unsolicited non-serious adverse reactions were injection site pain, hematoma, pruritus and anesthesia in the vaccine group and pain and induration in the control group.
In this study, 0.5% of the subjects in the DENGVAXIA group and 0.3% in the placebo group reported at least one unsolicited non-serious systemic adverse reaction. The unsolicited non-serious systemic adverse reactions were malaise, abdominal pain, vomiting, dyspnea, generalized erythema, vertigo, asthma crisis and urticaria in the vaccine group and pruritus and lymphadenitis in the control group.
Most unsolicited non-serious adverse reactions started within 3 days of any injection and resolved within 3 days or less.
A total of 2 subjects (one subject with asthma crisis and urticaria occurring the day of the first dose, and one subject with malaise occurring 20 days after the first dose) in the DENGVAXIA group (0.2%) and none in the placebo group reported unsolicited non-serious Grade 3 (significant; prevents daily activity) adverse reactions.
Severe Dengue Following Vaccination with DENGVAXIA and Subsequent Dengue Infection
Subjects were monitored for severe dengue from Day 0 (day of first study vaccination) to Month 60–72 (after first study vaccination) in three multi-center, observer-blind, randomized (2:1), placebo-controlled trials conducted in Latin America and Puerto Rico (Study 1, NCT01374516) and the Asia-Pacific region (Study 2, NCT01373281; Study 3, NCT00842530). A subset of 3,203 subjects (80.1%) enrolled in Study 3 were re-consented to participate in an extension study to evaluate safety of DENGVAXIA for 72 months (Study 4, NCT01983553). A total of 18,265 children and adolescents 9 through 16 years of age enrolled in these trials received at least one dose of DENGVAXIA. Table 2 presents the incidences and hazard ratios of severe dengue from Month 13 to Month 60–72 post vaccination with DENGVAXIA or placebo in children and adolescents 9 through 16 years of age, by dengue baseline serostatus. An increased rate of severe dengue was observed following vaccination with DENGVAXIA and subsequent infection with any dengue virus serotype in persons not previously infected by dengue virus. [See Warnings and Precautions (5.1).]
|Dengue Infection Status at Month 13‡||DENGVAXIAn(Incidence §, %)||Placebon(Incidence §, %)||Hazard Ratio of Severe Dengue(95% CI)|
|n: number of subject with severe dengue casesCI: confidence intervalStudy 1, NCT01374516; Study 2, NCT01373281; Study 3, NCT00842530; Study 4, NCT01983553|
|Previous Dengue Infection(Dengue seropositive at Month 13)||10(0.068)||27(0.401)||0.18 (0.09; 0.37)|
|No Previous Dengue Infection(Dengue seronegative at Month 13)||12(0.380)||1(0.069)||6.25 (0.81; 48.32)|
Non-fatal Serious Adverse Events
In the 9 studies conducted among subjects 9 through 16 years of age (NCT 01374516, NCT01373281, NCT00842530, NCT00993447, NCT00875524, NCT00788151, NCT00880893, NCT01187433, NCT01254422), subjects were monitored for serious adverse events (SAEs) for at least 6 months after the last dose of DENGVAXIA.
The proportions of subjects who reported at least 1 non-fatal SAE within 28 days following any dose were 0.6% (123/19,102) in the DENGVAXIA group and 0.8% (73/9,484) in the placebo group. The following events were considered related to DENGVAXIA: asthma attack (day of Dose 1), urticaria (day of Dose 2) and convulsion (day of Dose 1).
The proportions of subjects who reported at least 1 non-fatal SAE after 28 days and up to 6 months after any dose were similar in the 2 groups: 2.8% in the DENGVAXIA group (534/19,102) and 3.2% in the placebo group (307/9,484). None of these SAEs were considered related to the vaccination.
From the first administered dose up to Month 72, 51 deaths (0.3%) for subjects who received DENGVAXIA and 26 deaths (0.3 %) for subjects who received placebo were reported in the 9 studies conducted among subjects 9 though 16 years of age. None of the deaths were considered related to vaccination. Causes of death among subjects were consistent with those generally reported in children and adolescent populations.
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