IXCHIQ 1 vial/1 pack Powder and solvent for solution for injection

IXCHIQ is indicated for active immunisation for the prevention of disease caused by chikungunya virus (CHIKV) in individuals 18 years and older.

The use of this vaccine should be in accordance with official recommendations.

Posology

IXCHIQ is administered as a single dose of 0.5 mL. The need for revaccination has not been established.

Paediatric population

The safety and immunogenicity of IXCHIQ in children and adolescents aged 0 to 17 years have not yet been established. Only limited safety (see section 4.8) and immunogenicity data in adolescents 12 years of age and older are available.

Method of administration

For intramuscular injection only, after reconstitution.

IXCHIQ should be administered intramuscularly in the deltoid muscle within 2 hours of reconstitution.

The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Immunodeficient or immunosuppressed individuals due to disease or medical therapy (e.g., from hematologic and solid tumors, receipt of chemotherapy, congenital immunodeficiency, long-term immunosuppressive therapy or patients with HIV infection who are severely immunocompromised).

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.

Hypersensitivity and anaphylaxis

Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine. Close observation for at least 15 minutes is recommended following vaccination.

Anxiety-related reactions

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stressLrelated 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.

Concurrent illness

Vaccination should be postponed in individuals suffering from acute severe febrile illness or acute infection. The presence of a minor infection and/or low-grade fever should not delay vaccination.

Thrombocytopenia and coagulation disorders

The vaccine should be given with caution to individuals receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as haemophilia) because bleeding or bruising may occur following an intramuscular injection in these individuals.

Limitations of vaccine effectiveness

The ability of IXCHIQ to prevent disease due to chikungunya virus was based on a serological surrogate endpoint (see section 5.1). As with any vaccine, a protective immune response may not be elicited after vaccination in all persons. It is recommended to continue personal protection measures against mosquito bites after vaccination.

Pregnancy

A decision to administer IXCHIQ during pregnancy should take into consideration the individual's risk of wild-type CHIKV infection, gestational age, and risks to the foetus or neonate from vertical transmission of wild-type CHIKV (see section 4.6).

Blood donation

Vaccine viraemia was detected in 90% of subjects 3 days after vaccination, proportions of vaccinees with detectable virus declined to 17% by 7 days after administration of IXCHIQ and no vaccine viraemia was detected 15 days after vaccination. See sections 4.6 and 4.8.

Individuals administered IXCHIQ should not donate blood for at least 4 weeks post- vaccination.

Chikungunya-like Adverse Reactions

IXCHIQ may cause severe or prolonged chikungunya-like adverse reactions (see section 4.8).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Potassium

This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium-free'.

Concomitant administration with other vaccines

IXCHIQ is not recommended to be co-administered with other vaccines because there are no data on the safety and immunogenicity following concomitant administration of IXCHIQ with other vaccines.

Administration of immune globulins, blood or plasma transfusions 3 months before or up to 1 month after IXCHIQ administration may interfere with the expected immune response.

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 IXCHIQ in pregnant women. These data are not sufficient to conclude on the absence of potential effects of IXCHIQ on pregnancy, embryo-foetal development, parturition and post-natal development.

Vertical transmission of wild-type CHIKV from pregnant individuals with viraemia at delivery is common and can cause potentially fatal CHIKV disease in neonates.

Vaccine viraemia occurs in the first week following administration of IXCHIQ, with resolution of viraemia by 14 days after vaccination. It is not known if the vaccine virus can be vertically transmitted and cause foetal or neonatal adverse reactions.

Decisions to administer IXCHIQ during pregnancy should take into consideration the individual's risk of exposure to wild-type CHIKV, gestational age, and risks to the foetus or neonate from vertical transmission of wild-type CHIKV.

Breast-feeding

It is unknown if IXCHIQ is excreted in human milk. A risk to the breastfed child cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IXCHIQ and any potential adverse effects on the breastfed child from IXCHIQ.

Animal studies did not indicate any direct or indirect harmful effects with respect to lactation (see section 5.3).

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).

IXCHIQ has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 may temporarily affect the ability to drive or use machines.

Summary of the safety profile

The overall safety of IXCHIQ is based on an analysis of the pooled safety data from three completed phase I and III clinical studies conducted in the US on 3 610 participants ≥18 years old who received one dose of IXCHIQ with a follow-up of 6 months.

The most common vaccination site reactions were tenderness (10.8%) and pain (6.1%). The most common systemic adverse reactions were headache (32%), fatigue (29.4%), myalgia (23.7%), arthralgia (16.6%), fever (13.8%) and nausea (11.4%).

Laboratory parameters

The most common abnormal laboratory parameters were neutropenia (41.8%), leukopenia (31.2%), lymphopenia (22.3%), Alanine aminotransferase increased (ALT: 15.5%), and Aspartate aminotransferase increased (AST: 11.7%) (based on an immunogenicity subset of 372 IXCHIQ recipients).

Vaccine Viraemia and Shedding

Vaccine virus was demonstrated to be present in blood and urine and might be present in other body fluids. Vaccine viraemia and shedding (measured by genomic amplification methods) following vaccination with IXCHIQ was assessed in one clinical trial (VLA1553-101). Viraemia was detected in 90% of subjects 3 days after vaccination, proportions of vaccinees with detectable virus declined to 17% by 7 days after administration of IXCHIQ and no vaccine viraemia was detected 15 days after vaccination. A single participant shed vaccine virus in urine 7 days after vaccination.

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: (≥ 1/1 000 to < 1/100),

Rare: (≥ 1/10 000 to < 1/1 000),

Very rare: (<1/10 000).

Within each frequency grouping the adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse drug reaction

*includes: leukopenia (leukocyte decreased), neutropenia (neutrophil decreased) and lymphopenia (lymphocyte decreased).

**includes: Alanine aminotransferase increased (ALT) and Aspartate aminotransferase increased (AST).

Chikungunya-like Adverse Reactions

The occurrence of certain adverse event combinations, referred to as chikungunya- like adverse reactions, was retrospectively evaluated in the pooled safety data from phase I and III clinical studies (N=3 610). Chikungunya-like adverse reactions were broadly defined, i.e. occurrence of fever (≥38°C) and at least one other symptom also reported for acute-stage chikungunya illness, including arthralgia or arthritis, myalgia, headache, back pain, rash, lymphadenopathy, and certain neurological, cardiac or ocular symptoms; within 30 days after vaccination, regardless of time of onset, severity or duration of the individual symptoms.

Adverse event combinations qualifying as chikungunya-like adverse reactions were reported in 12.1% of participants. Among those, combinations of fever with headache, fatigue, myalgia or arthralgia were the most common, all other symptoms were reported in fewer than 10% of chikungunya-like adverse reactions. The reported symptoms were mostly mild, 1.8% of participants reported at least one severe symptom, most commonly fever or arthralgia. Median onset of chikungunya-like adverse reactions was 3 days after vaccination, and median time to resolution was 4 days. Longer-lasting symptoms ≥30 days occurred in 0.4% of participants.

Paediatric population

Safety in adolescent participants ≥12 years was assessed in 502 participants in Brazil who received one dose of IXCHIQ with a follow-up of 28 days. Approximately 20% of the participants had pre-existing antibodies against chikungunya virus. The proportion of participants that experienced solicited systemic AEs and Chikungunya- like adverse reactions was higher in seronegative participants at baseline vaccinated with VLA1553 (67.9% and 27.2%, respectively) than in seropositive participants at baseline vaccinated with VLA1553 (44.7% and 6.4%, respectively). The proportion of participants who experienced solicited local AEs and unsolicited AEs was similar in the VLA1553 arms of each stratum.”

Reporting of suspected adverse reactions

If you are concerned about an adverse event, it should be reported on a Yellow Card. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store and include the vaccine brand and batch/Lot number if available.

Alternatively, adverse events of concern in association with IXCHIQ can be reported to Valneva Austria GmbH on +43 1 20620 1444 or email to [email protected].

Please do not report the same adverse event(s) to both systems as all reports will be shared between Valneva Austria GmbH and the MHRA (in an anonymised form) and dual reporting will create unnecessary duplicates.

No case of overdose has been reported in clinical studies. In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended.

Pharmacotherapeutic group: Other viral vaccines, ATC code: J07BX07

Mechanism of action

IXCHIQ contains live-attenuated CHIKV of the ECSA/IOL genotype. The exact mechanism of protection against CHIKV infection and/or disease has not been determined. IXCHIQ elicits neutralising antibodies against CHIKV.

Immunogenicity

No efficacy data are available for IXCHIQ. The clinical efficacy of IXCHIQ was inferred from a post-vaccination CHIKV-specific neutralizing antibody titre threshold.

A threshold of CHIKV-specific neutralizing antibody µPRNT50 titre of ≥150 was selected as surrogate marker for protection, referred to as seroresponse. This threshold was determined from a non-human primate passive transfer study in which animals with titres ≥150 were protected against wild-type CHIKV infections and had undetectable virus in blood during 14 days after the challenge. In addition, the threshold was supported by data obtained from a prospective human sero- epidemiological study.

VLA1553-301 was a placebo-controlled study assessing the immunogenicity and safety in generally healthy individuals 18 years and above. Participants in this study were followed up for 6 months after immunization. The proportion of participants with CHIKV-specific antibody titers ≥150 µPRNT50, i.e. seroresponse rate, 28 days post-vaccination in the IXCHIQ arm was the primary endpoint.

Humoral immune response was evaluated in 362 participants (266 in the IXCHIQ arm and 96 in the Placebo arm). All these participants were negative at baseline (pre- vaccination) for CHIKV neutralizing antibodies. The study population included 82 participants 65 years of age or above (59 and 23 in the IXCHIQ and Placebo arm).

Antibody persistence is evaluated in study VLA1553-303 (follow up of a subset of participants of study of VLA1553-301). Data are available up to 2 years post- immunization.

Seroresponse rate

In the pivotal trial VLA1553-301, 98.9% of the participants who were administered IXCHIQ presented a CHIKV-specific neutralizing antibody titers ≥150 µPRNT50 at 28 days post-vaccination. This percentage was sustained up to 6 months post- vaccination (96.3%). Refer to Table 2. Only 1.6% (n=4/251) of the participants vaccinated with IXCHIQ had CHIKV-specific neutralizing antibody titers ≥150 µPRNT50 at Day 8. No participant had CHIKV-specific neutralizing antibody response ≥150 µPRNT50 in the placebo arm of VLA1553-301.

Table 2. Seroresponse rates over time, as determined by µPRNT₅₀ assay, in study VLA1553-301 (PP population)

Abbreviations: CI=confidence interval; µPRNT₅₀=50% micro plaque reduction neutralization test; PP=per-protocol (population)

Antibody persistence

Persistence of the immune response was evaluated 12 and 24 months post-vaccination in VLA1553-303. All the participants were negative at baseline (pre-vaccination) for CHIKV-specific neutralizing antibodies. Proportion of participants with a CHIKV- specific neutralizing antibody response ≥150 µPRNT50 was 99.5% (183/184) and 97.1% (268/276), respectively at 1 and 2 year post-vaccination.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with IXCHIQ Vaccine in one or more subsets of the paediatric population in active immunisation for the prevention of disease caused by chikungunya virus (CHIKV)(see section 4.2 for information on paediatric use).

Not relevant to vaccines.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity and reproduction and developmental toxicity conducted.

A reproductive toxicity trial studying in female rats showed that IXCHIQ administered prior and after mating did not affect the reproductive parameters, the delivery, the foetal or pup development. There was evidence of placental and milk transfer of IXCHIQ-specific antibodies (see section 4.6).

Powder

Sucrose

D-Sorbitol

L-Methionine

Trisodium Citrate Di-Hydrate

Magnesium Chloride

Di-Potassium- Hydrogen Phosphate

Potassium-Di- Hydrogen-Phosphate

recombinant Human Albumin (rHA) produced in yeast (Saccharomyces cerevisiae)

Solvent

Sterile water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

2 years.

Do not freeze.

After reconstitution

In-use stability of the reconstituted vaccine has been demonstrated for 2 hours when stored either refrigerated at (2°C - 8°C) or at room temperature (15°C - 25°C). After this time, the reconstituted vaccine must be discarded.

From a microbiological point of view, after first opening the vaccine should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C 8°C).

Do not freeze.

Store in the original package in order to protect from light.

Stability data indicate that the vaccine components are stable for 24 hours in unopened vials when stored at temperatures from 23°C to 27°C. At the end of this period IXCHIQ should be used immediately or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursion only, it is not a recommended storage or shipping condition.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

IXCHIQ is supplied in a carton containing:

• One single-dose vial (type I glass) containing lyophilized powder of the vaccine with a rubber stopper (bromobutyl) and an aluminium flip-off cap with polypropylene closure.

• One solvent consisting of 0.5 mL sterile water for injection in a prefilled syringe with a rubber stopper (Flurotec® ) and a tip cap (bromobutyl) (packaged without needles).

• Pack size: 1 vial of powder, 1 pre-filled syringe of solvent without needles.

Preparation for administration

The vaccine must be reconstituted only with the solvent provided prior to administration.

The reconstituted vaccine is a clear, colorless to slightly yellowish liquid solution. The vaccine should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, do not administer the vaccine.

A needle (22-25G) with appropriate length of preferably at least 40 mm (1 1/2") should be used for reconstitution of the vaccine.

The syringe is for one-time use only.

Disposal

This product contains genetically modified organisms (GMOs).

Any unused vaccine or waste material should be disposed of in accordance with local guidance for pharmaceutical waste. Potential spills should be cleaned up immediately and disinfected according to local policies. Dispose of the used syringe and needle in a sharps container such as a closeable, puncture resistant container.