Vaccine Information: DENGVAXIA (Page 2 of 3)

6.2 Data from Postmarketing Experience

In addition to events reported in clinical trials for DENGVAXIA, the following adverse events have been spontaneously reported during postapproval use. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to DENGVAXIA.

Immune system disorders

Allergic including anaphylactic reactions.

Infections and infestations

Severe dengue infection, including hospitalization and death, in individuals for whom dengue infection status prior to vaccination was unknown and who were subsequently infected with dengue following vaccination.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

Data are not available to establish the safety and immunogenicity of concomitant administration of DENGVAXIA with recommended adolescent vaccines.

7.2 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to DENGVAXIA.

7.3 Drug/Laboratory Test Interactions

DENGVAXIA may cause temporary depression of tuberculin purified protein derivative (PPD) test sensitivity, leading to false negative results. Tuberculin testing should be performed before DENGVAXIA is administered or at least 1 month following vaccination with DENGVAXIA.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DENGVAXIA during pregnancy. Women who receive DENGVAXIA during pregnancy are encouraged to contact directly, or have their healthcare professional contact, Sanofi Pasteur Inc. at 1-800-822-2463 (1-800-VACCINE) to enroll in or obtain information about the registry.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

No specific studies of DENGVAXIA have been performed among pregnant women. A limited number of cases of inadvertent exposure during pregnancy were reported during clinical studies. Isolated adverse pregnancy outcomes (e.g., stillbirth, intrauterine death, spontaneous abortion, blighted ovum) have been observed for these exposed pregnancies, with similar frequency and nature in the vaccinated individuals compared to the control group, and with risk factors identified for all cases. Available data in pregnant women are not sufficient to determine the effects of DENGVAXIA on pregnancy, embryo-fetal development, parturition and postnatal development.

In two developmental toxicity studies, the effect of DENGVAXIA on embryo-fetal and postnatal development was evaluated in pregnant rabbits and mice. A developmental toxicity study was performed in female rabbits given a 5 log10 50% cell culture infectious dose (CCID50 ) of DENGVAXIA (full human dose ranging from 4.5 log10 to 6.0 log10 CCID50 ) by intravenous injection prior to mating and during gestation. The study revealed no evidence of harm to the fetus due to DENGVAXIA. In another study, female mice were administered a single dose of 5 log10 CCID50 , 6.5 log10 CCID50 (about 3 times the highest human dose) or 8 log10 CCID50 (about 100 times the highest human dose) of DENGVAXIA by intravenous injection during gestation. Fetal toxicities were observed at maternally toxic doses. [See Animal Data (8.1).]

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women are at increased risk of complications associated with dengue infection compared to non-pregnant women. Pregnant women with dengue may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery. Vertical transmission of dengue virus from mothers with viremia at delivery to their infants has been reported.

Fetal/neonatal adverse reactions

Vaccine viremia can occur 7 to 14 days after vaccination with a duration of <7 days [See Pharmacokinetics (12.3).]. The potential for transmission of the vaccine virus from mother to infant is unknown.

Animal Data

In two developmental toxicity studies, the effect of DENGVAXIA on embryo-fetal and postnatal development was evaluated in pregnant rabbits and mice.

Rabbits were administered a full human dose [0.5 mL (5 log10 CCID50 /animal/occasion)] of DENGVAXIA by intravenous injection 30 and 10 days before mating and on Days 6, 12 and 27 during gestation. No vaccine-related fetal malformation or variations and adverse effects on female fertility or preweaning development were reported in this study. Pregnant mice were administered a single dose of either 5 log10 CCID50 (full human dose ranging from 4.5 log10 to 6.0 log10 CCID50 ), 6.5 log10 CCID50 (about 3 times the highest human dose) or 8 log10 CCID50 (about 100 times the highest human dose) of DENGVAXIA by intravenous injection on Day 6, 9 or 12 of gestation. At doses of 6.5 log10 CCID50 or 8 log10 CCID50 of DENGVAXIA, maternal toxicity was observed which was associated with increased postimplantation loss and at doses of 8 log10 CCID50 with reduced fetal body weight. The significance of this observation for humans is unknown, especially considering the different route of administration (the human route of administration is subcutaneous) and dose levels which exceeded the intended human dose. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study.

8.2 Lactation

Risk Summary

Human data are not available to assess the impact of DENGVAXIA on milk production, its presence in breast milk, or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DENGVAXIA and any potential adverse effects on the breastfed child from DENGVAXIA or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine. A lactation study in which female mice were administered a single dose of DENGVAXIA on day 14 of lactation did not show the presence of DENGVAXIA in breast milk.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Vertical transmission of dengue virus, including potentially through breastmilk, has been reported.

Fetal/neonatal adverse reactions

Vaccine viremia can occur 7 to 14 days after vaccination with a duration of <7 days. [See Pharmacokinetics (12.3).] The potential for transmission of the vaccine virus from mother to infant through breastmilk is unknown.

Animal Data

A developmental toxicity study in which female mice were administered a single injection of 5 log10 CCID50 (full human dose ranging from 4.5 log10 to 6.0 log10 CCID50 ), 6.5 log10 CCID50 or 8 log10 CCID50 of DENGVAXIA by intravenous injection on Day 14 of lactation did not show the presence of DENGVAXIA in breast milk in mice when measured 24 hours after vaccine administration.

8.4 Pediatric Use

Safety and effectiveness of DENGVAXIA in children younger than 9 years of age have not been established.

8.5 Geriatric Use

Safety and effectiveness of DENGVAXIA in adults 65 years of age and older have not been established.

11 DESCRIPTION

DENGVAXIA (Dengue Tetravalent Vaccine, Live) is a sterile suspension for subcutaneous injection. DENGVAXIA is supplied as a vial of lyophilized vaccine antigen, which must be reconstituted at the time of use with 0.6 mL from the accompanying vial of diluent (0.4% sodium chloride). After reconstitution, DENGVAXIA is a clear, colorless suspension (trace amounts of white to translucent proteinaceous particles may be present). [See Dosage and Administration (2.3).]

After reconstitution, each 0.5 mL dose of DENGVAXIA contains 4.5 – 6.0 log10 CCID50 of each of the chimeric yellow fever dengue (CYD) virus serotypes 1, 2, 3, and 4. Each 0.5 mL dose is formulated to contain 2 mg sodium chloride and the following ingredients as stabilizers: 0.56 mg essential amino acids (including L-phenylalanine), 0.2 mg non-essential amino acids, 2.5 mg L-arginine hydrochloride, 18.75 mg sucrose, 13.75 mg D-trehalose dihydrate, 9.38 mg D-sorbitol, 0.18 mg trometamol, and 0.63 mg urea.

Each of the four CYD viruses (CYD-1, CYD-2, CYD-3, and CYD-4) in DENGVAXIA was constructed using recombinant DNA technology by replacing the sequences encoding the pre-membrane (prM) and envelope (E) proteins in the yellow fever (YF) 17D204 vaccine virus genome with those encoding for the homologous sequences of dengue virus serotypes 1, 2, 3, and 4, respectively. Each CYD virus is cultured separately in Vero cells (African Green Monkey kidney) under serum-free conditions, harvested from the supernatant of the Vero cells and purified by membrane chromatography and ultrafiltration. The purified and concentrated harvest of each CYD virus is then diluted in a stabilizer solution to produce the four monovalent drug substances. The final bulk product is a mixture of the four monovalent drug substances diluted in the stabilizer solution. The final bulk product is sterilized by filtration at 0.22 µm, filled into vials and freeze-dried.

DENGVAXIA does not contain preservative.

The vial stoppers for the Lyophilized Vaccine Antigen and Diluent vials of DENGVAXIA are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Following administration, DENGVAXIA elicits dengue-specific immune responses against the four dengue virus serotypes. The exact mechanism of protection has not been determined.

12.3 Pharmacokinetics

Viremia

In studies that evaluated the occurrence of vaccine viremia systematically at pre-specified timepoints, vaccine viremia (measured by genomic amplification methods) was observed following vaccination with DENGVAXIA in 5.6% of subjects, with 90% of these occurrences documented after the first injection. Vaccine viremia was observed 7 to 14 days after DENGVAXIA vaccination with a duration of <7 days.

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