IMVANEX SUSPENSION FOR INJECTION SMALLPOX VACCINE (LIVE MODIFIED VACCINIA VIRUS ANKARA) - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

IMVANEX suspension for injection

Smallpox vaccine (Live Modified Vaccinia Virus Ankara)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One dose (0.5 ml) contains:

Modified Vaccinia Ankara – Bavarian Nordic Live virus1 no less than

5 × 107 Inf.U

infectious units

1 Produced in chick embryo cells

This vaccine contains trace residues of chicken protein, benzonase, gentamicin and ciprofloxacin (see section 4.3).

For the full list of excipients, see section 6.1.

Suspension for injection.

Light yellow to pale white, milky suspension.

4.1

Therapeutic indications

Active immunisation against smallpox in adults (see sections 4.4 and 5.1).

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

4.2 Posology and method of administration

Posology

Primary vaccination (individuals previously not vaccinated against smallpox): A first dose of 0.5 ml should be administered on an elected date.

A second dose of 0.5 ml should be administered no less than 28 days after the first dose.

See sections 4.4 and 5.1.

Booster vaccination (individuals previously vaccinated against smallpox): There are inadequate data to determine the appropriate timing of booster doses. If a booster dose is considered necessary then a single dose of 0.5 ml should be administered.

See sections 4.4 and 5.1.

Special population:

Immunocompromised patients (e.g. HIV infected, patients under immunosuppressive therapy) who have been previously vaccinated against smallpox should receive two booster doses. The second booster vaccination should be given no less than 28 days after the first dose.

Paediatric population

The safety and efficacy of IMVANEX in children below 18 years have not been established.

Method of administration

Immunisation should be carried out by subcutaneous injection, preferably into the upper arm (deltoid).

For instructions on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or trace residues (chicken protein, benzonase, gentamicin and ciprofloxacin).

4.4 Special warnings and precautions for use

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.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

Immunisation should be postponed in individuals suffering from an acute severe febrile illness or acute infection. The presence of a minor infection and/or low-grade fever should not result in the deferral of vaccination.

IMVANEX should not be administered by intravascular injection.

The protective efficacy of IMVANEX against smallpox has not been studied. See section 5.1.

A protective immune response may not be elicited in all vaccinees.

There are inadequate data to determine the appropriate timing of booster doses.

Prior vaccination with IMVANEX may modify the cutaneous response (‘take’) to subsequently administered replication-competent smallpox vaccine resulting in a reduced or absent take. See section 5.1.

Individuals with atopic dermatitis developed more local and general symptoms after vaccination (see section 4.8)

Data have been generated in HIV infected individuals with CD4 counts > 100 cells/Lil and < 750 cells/^l. Lower immune response data have been observed in HIV infected individuals compared to healthy individuals (see section 5.1). There are no data on the immune response to IMVANEX in other immunosuppressed individuals.

Two doses of IMVANEX given at a 7-day interval showed lower immune responses and slightly more local reactogenicity than two doses given at a 28-day interval. Therefore, dose intervals of less than 4 weeks should be avoided.

Sodium content

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

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies with other vaccines or medicinal products have been performed. Therefore, concomitant administration of IMVANEX with other vaccines should be avoided.

The concomitant administration of the vaccine with any immunoglobulin including Vaccinia Immune Globulin (VIG) has not been studied and should be avoided.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data (less than 300 pregnancy outcomes) from the use of IMVANEX in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure the use of IMVANEX should be avoided during pregnancy unless it is considered that the possible benefit in terms of preventing smallpox would outweigh the potential risk.

Breast-feeding

It is not known whether IMVANEX is excreted in human milk.

IMVANEX should be avoided during breastfeeding unless it is considered that the possible benefit in terms of preventing smallpox would outweigh the potential risk.

Fertility

Animal studies did not reveal any evidence of impaired female and male fertility.

4.7 Effects on ability to drive and use machines

Some of the undesirable effects mentioned in section 4.8 may affect the ability to drive or use machines (e.g. dizziness).

4.8 Undesirable effects

Summary of the safety profile

The safety of IMVANEX has been assessed in 20 clinical trials in which 5,261 Vaccinia-naïve individuals received two doses of no less than 5 × 107 Inf.U four weeks apart while 534 Vaccinia- and IMVANEX-experienced individuals received a single booster dose.

The most common adverse reactions observed in clinical trials were injection site reactions and common systemic reactions typical for vaccines which were mild to moderate in intensity and resolved without intervention within seven days following vaccination.

Adverse reaction rates reported after either vaccination dose (1st, 2nd or booster) were similar.

Tabulated summary of adverse reactions

Adverse reactions from all clinical trials are listed according to the following frequency:

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)

Table 1:      Adverse Reactions Reported in Completed Clinical Trials with IMVANEX (N = 7,082

subjects)

Individuals with atopic dermatitis (AD)

In a non-placebo controlled clinical trial that compared the safety of IMVANEX in individuals with AD to healthy individuals, individuals with AD reported erythema (61.2%) and swelling (52.2%) at the injection site with a higher frequency than healthy individuals (49.3% and 40.8%, respectively). The following general symptoms were reported more frequently in individuals with AD compared to healthy individuals: headache (33.1% vs. 24.8%), myalgia (31.8% vs. 22.3%), chills (10.7% vs. 3.8 %), nausea (11.9% vs. 6.8%), and fatigue (21.4% vs. 14.4%).

7% of the individuals with AD in clinical trials with IMVANEX experienced a flare-up or worsening of their skin condition during the course of the trial.

Rash

IMVANEX may trigger local rashes or more widespread eruptions. Events of rash after vaccination (related cases observed in 0.4% of subjects) with IMVANEX tend to occur within the first days after vaccination, are mild to moderate in intensity and usually resolve without sequelae.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

No case of overdose has been reported.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vaccine, other viral vaccines, ATC code: J07BX

Efficacy in animals

Non-human primate (NHP) studies have demonstrated that vaccination with IMVANEX induced a comparable immune response and protective efficacy to traditional smallpox vaccines used to eradicate smallpox and protected NHP from severe disease associated with a lethal challenge of monkeypox virus. As seen with traditional smallpox vaccines, a significant reduction in both mortality and morbidity (viral load, weight loss, number of pox lesions, etc.) compared to non-vaccinated controls was demonstrated for NHP vaccinated with IMVANEX.

Immunogenicity

Seroconversion rates in Vaccinia-naive healthy and special populations

The Vaccinia-naive study population included healthy individuals as well as individuals with HIV infection and AD who received 2 doses of IMVANEX 4 weeks apart. Seroconversion rates in Vaccinia-naive individuals were defined as appearance of antibody titers equal or greater than the assay cut-off value following receipt of two doses of IMVANEX. Seroconversion by ELISA and PRNT were as follows:

1Day 7/14 corresponding to 1 or 2 weeks after the first IMVANEX dose (analysis time point at Day 7 only in studies POX-MVA-008 and POX-MVA-011; POX-MVA-005 had the first post vaccination analysis at Day 14); Day 28 corresponding to 4 weeks after the first IMVANEX dose; Day 42 corresponding to 2 weeks following the second dose of IMVANEX;

SCR = Seroconversion rate; 2 Full Analysis Set (FAS) (for POX-MVA-013: Immunogenicity Analysis Set; IAS); 3 Per Protocol Analysis Set (PPS), 4 seropositivity rates, 5 no immunogenicity sample taken, 6 combined Groups 13

Seroconversion rates in Vaccinia-experienced healthy and special populations

Seroconversion in Vaccinia-experienced individuals was defined as at least a two-fold increase in base titres following a single vaccination with IMVANEX.

1Day 0 corresponding to day of vaccination with IMVANEX; Day 7/14 corresponding to 1 or 2 weeks after vaccination with IMVANEX (first post vaccination analysis at Day 7 in study POX-MVA-011, and at Day 14 in studies POX-MVA-005 and POX-MVA-024); Day 28 corresponding to 4 weeks after vaccination with IMVANEX; SCR = Seroconversion rate; 2 Full Analysis Set (FAS);

Long-term immunogenicity in humans

Limited data on long-term immunogenicity covering a period of 24 months following primary vaccination of Vaccinia-naïve individuals with IMVANEX are currently available as shown below:

ELISA = enzyme-linked immunosorbent assay; GMT= geometric mean titre; N = number of subjects in the specific study group; PRNT = plaque reduction neutralisation test; SCR = seroconversion ra­te;

*represents seropositivity rates

Booster Dose

Two clinical studies have demonstrated that IMVANEX is able to boost a preexisting immunological memory response, induced by either licensed smallpox vaccines a long time ago or two years after IMVANEX.

1Day 0 corresponding to day of booster vaccination with IMVANEX (prebooster); Day 7 and 14 corresponding to 1 or 2 weeks after booster vaccination with IMVANEX; N = number of subjects in the specific study group; ELISA = enzyme-linked immunosorbent assay; PRNT = plaque reduction neutralization test; S+ = Seropositivity rate; GMT = geometric mean titre.

Imvanex was compared to ACAM2000 (a ‚second generation‘ live attenuated smallpox vaccine produced in cell culture and licenced in the United States of America) in a randomized, open-label non-inferiority clinical trial in healthy adults (US military personnel) aged 18 to 42 years and who were naïve to smallpox vaccine (Study POX-MVA-006).

A total of 433 subjects were randomized in a 1 : 1 ratio to receive either two doses of Imvanex followed by a single dose of ACAM2000 at four weeks intervals or to receive a single dose of ACAM2000. ACAM2000 was administered via scarification.

The first co-primary endpoint compared vaccinia-specific neutralizing antibody responses at the peak visits (Day 42 after first vaccination for Imvanex where the subjects received two doses according to the standard vaccination schedule and Day 28 for ACAM2000). Imvanex induced a peak neutralizing antibody geometric mean titer (GMT) of 153.5 (n = 185; 95% CI 134.3, 175.6), which was non-inferior to the GMT of 79.3 (n = 186; 95% CI 67.1, 93.8) obtained after scarification with ACAM2000.

The second co-primary endpoint evaluated if vaccination with Imvanex (n = 165) prior to administration of ACAM2000 results in an attenuation of the cutaneous reaction to ACAM2000 (n = 161) as measured by maximum lesion area in mm2. At day 13–15, the median maximum lesion area for subjects who were administered ACAM2000 was 75mm2 (95% CI 69.0, 85.0) and for those who received Imvanex it was 0.0 (95% CI 0.0, 2.0).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with IMVANEX in all subsets of the paediatric population for prevention of smallpox infection by active immunisation against smallpox infection and disease (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that because of the lack of smallpox disease in the world it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity, local tolerance, female fertility, embryo-foetal and postnatal toxicity.

6.1

Trometamol Sodium chloride

Water for injections

6.2

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

6.3 Shelf life

2 years at –20°C +/-5°C

5 years at –50°C +/-10°C

5 years at –80°C +/-10°C

After thawing, the vaccine should be used immediately or if previously stored at –20°C +/-5°C, the vaccine can be stored at 2°C-8°C in the dark for up to 8 weeks prior to use.

Do not re-freeze a vial once it has been thawed.

6.4 Special precautions for storage

Store in a freezer (at –20°C +/-5°C or –50°C +/-10°C or –80°C +/-10°C).

Expiry date depends on storage temperature.

If previously stored at –20°C +/-5°C, the vaccine can be stored short-term in a refrigerator at 2°C-8°C for up to 8 weeks prior to use.

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

6.5 Nature and contents of container

0.5 ml suspension in a vial (Type I glass) with stopper (bromobutyl rubber).

Pack size of 20.

6.6 Special precautions for disposal

The vaccine should be allowed to reach room temperature before use. Swirl the vial gently before use for at least 30 seconds.

The suspension should be visually inspected for particulate matter and discoloration before use. In the event of any damage to the vial, foreign particulate matter and/or variation of physical aspect being observed, discard the vaccine.

A dose of 0.5 ml is withdrawn into a syringe for injection.

Any unused vaccine or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Bavarian Nordic A/S

Philip Heymans Allé 3

DK-2900 Hellerup

Denmark

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 40365/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021