Active immunisation against smallpox, mpox and disease caused by vaccinia virus in adults (see sections 4.4 and 5.1). 2 The use of this vaccine should be in accordance with official recommendations.

Posology Primary vaccination (individuals previously not vaccinated against smallpox, mpox or vaccinia viruses) 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, mpox or vaccinia viruses) 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, mpox or vaccinia viruses should receive two booster doses. The second booster vaccination should be given no less than 28 days after the first booster dose. Paediatric population The safety and efficacy of IMVANEX in children below 18 years have not been established. No data are available. Method of administration Immunisation should be carried out by subcutaneous injection, preferably into the upper arm. For instructions on administration, see section 6.6.

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).

3 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 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. Concurrent illness 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. General recommendations IMVANEX should not be administered by intravascular injection. Limitations of vaccine effectiveness The protective efficacy of IMVANEX against smallpox, mpox and disease caused by vaccinia virus has not been studied in humans, 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 Individuals with atopic dermatitis developed more local and general symptoms after vaccination (see section 4.8) Immunocompromised individuals Data have been generated in HIV infected individuals with CD4 counts = 100 cells/µl and = 750 cells/µl. 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 28 days should be avoided. Anxiety-related reactions Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stressrelated 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. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ’sodium-free’. 4

No

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, it is preferable to avoid the use of IMVANEX during pregnancy. Administration of IMVANEX in pregnancy should only be considered when the potential benefits outweigh any potential risk to the mother and fetus. Breast-feeding It is not known whether IMVANEX is excreted in human milk. As a precautionary measure, it is preferable to avoid the use of IMVANEX during breast-feeding. Administration of IMVANEX during breast-feeding should only be considered when the potential benefits outweigh any potential risks to the mother and baby. Fertility Animal studies did not reveal any evidence of impaired female and male fertility.

There is no information on the effect of IMVANEX on the ability to drive or use machines. However, some of the

mentioned in section 4.8 may affect the ability to drive or use machines (e.g. dizziness). 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 x 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. 5 Tabulated list 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) Unknown (cannot be estimated from the available data) Table 1 Adverse reactions reported in completed clinical trials (N = 7 082 subjects) and post-authorisation experience with IMVANEX MedDRA System Organ Class 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) Unknown (cannot be estimated from the available data) Infections and infestations - - Nasopharyngitis Upper respiratory tract infection Sinusitis Influenza Conjunctivitis Blood and lymphatic system disorders - - Lymphadenopathy - Metabolism and nutrition disorders - Appetite disorder - - Psychiatric disorders - - Sleep disorder - Nervous system disorders Headache - Dizziness Paresthesia Migraine Peripheral sensory neuropathy Somnolence Acute peripheral facial paralysis (Bell’s palsy) Ear and labyrinth disorders - - - Vertigo Cardiac disorders - - - Tachycardia Respirator y thoracic and mediastina l disorders - - Pharyngolaryngeal pain Rhinitis Cough Oropharyngeal pain Gastrointestinal disorders Nausea - Diarrhoea Vomiting Dry mouth Abdominal Pain 6 MedDRA System Organ Class 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) Unknown (cannot be estimated from the available data) Skin and subcutaneou s tissue disorders - - Rash Pruritus Dermatitis Urticaria Skin discolouration Hyperhidrosis Ecchymosis Night sweats Subcutaneous nodule Angioedema Musculoskeletal and connective tissue disorders Myalgia Pain in extremity Arthralgia Musculoskeletal stiffness Back pain Neck pain Muscle spasms Musculoskeletal pain Muscular Weakness 7 MedDRA System Organ Class 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) Unknown (cannot be estimated from the available data) General disorders and administration site conditions Injection site pain Injection site erythema Injection site swelling Injection site induration Injection site pruritus Fatigue Rigor/Chills Injection site nodule Injection site discolouration Injection site haematoma Injection site warmth Underarm swelling Malaise Injection site haemorrhage Injection site irritation Flushing Chest pain Axillary pain Injection site exfoliation Injection site inflammation Injection site paraesthesia Injection site reaction Injection site rash Oedema peripheral Asthenia Injection site anesthesia Injection site dryness Injection site movement impairment Influenza like illness Injection site vesicles Investigations - Body temperature increased Pyrexia Troponin I increased Hepatic enzyme increased White blood cell count decreased Mean platelet volume decreased White blood cell count increased Injury, poisoning and procedural complications - - - Contusion 8 Description of selected adverse reactions 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 a Yellow card. Reporting forms and information can be found on the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or App Store and include batch/Lot number if available.

No case of has been reported.

Pharmacotherapeutic group: Vaccines, 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 mpox 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. Mouse studies have demonstrated that vaccination with IMVANEX protected mice from a lethal challenge of replicating vaccinia virus. Immunogenicity 9 Seroconversion to vaccinia in Vaccinia-naïve healthy and special populations The Vaccinia-naïve 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-naïve individuals were defined as appearance of vaccinia antibody titres equal or greater than the assay cut-off value following receipt of two doses of IMVANEX. Seroconversion by ELISA and PRNT were as follows: Table 2 Seroconversion rates by ELISA in Vaccinia-naïve healthy and special populations SCR - ELISA Day 7/141 Day 281 Day 421 Study Health status N SCR % (95% CI) SCR % (95% CI) SCR % (95% CI) POX-MVA- 0052 Healthy 183 70.9 (63.7, 77.4) 88.9 (83.4, 93.1) 98.9 (96.0, 99.9) Healthy 194 12.5 (8.1, 18.2) 85.4 (79.6, 90.1) 98.5 (95.5, 99.7) POX-MVA- 0083 AD 257 22.9 (17.8, 28.6) 85.4 (80.5, 89.5) 97.3 (94.5, 98.9) POX-MVA- 0094 Healthy 66 69.7 (57.1, 80.4) 72.2 (60.4, 83.0) 96.8 (89.0, 99.6) Healthy 88 29.6 (20.0, 40.8) 83.7 (74.2, 90.8) 98.7 (93.1, 100) POX-MVA- 0112 HIV 351 29.2 (24.3, 34.5) 67.5 (62.1, 72.5) 96.2 (93.4, 98.0) POX-MVA-0132 Healthy 2,1196 N/A5 N/A5 99.7 (99.4; 99.9) Table 3 Seroconversion rates by PRNT in Vaccinia-naïve healthy and special populations SCR - PRNT Day 7/141 Day 281 Day 421 Study Health Status N SCR % (95% CI) SCR % (95% CI SCR % (95% CI) POX-MVA- 0052 Healthy 183 45.1 (37.7, 52.6) 56.7 (49.1, 64.0) 89.2 (83.7, 93.4) Healthy 194 5.4 (2.6, 9.8) 24.5 (18.6, 31.2) 86.6 (81.0, 91.1) POX-MVA- 0083 AD 257 5.6 (3.1, 9.3) 26.8 (21.4, 32.7) 90.3 (86.0, 93.6) POX-MVA- 0094 Healthy 66 12.1 (5.4, 22.5) 10.6 (4.4, 20.6) 82.5 (70.9, 90.9) Healthy 88 11.1 (5.2, 20.0) 20.9 (12.9, 31.0) 77.2 (66.4, 85.9) POX-MVA- 0112 HIV 351 15.7 (11.9, 20.1) 22.5 (18.1, 27.4) 60.3 (54.7, 65.8) POX-MVA- 0132 Healthy 2119 6 N/A5 N/A5 99.8 (99.5; 99.9) 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; PRNT = plaque reduction neutralisation test; ELISA = enzyme-linked immunosorbent assay using MVA as an antigen 2 2 Full Analysis Set (FAS) (for POX-MVA-013: Immunogenicity 10 Analysis Set; IAS); 3 Per Protocol Analysis Set (PPS), 4 seropositivity rates, 5 no immunogenicity sample taken, 6 combined Groups 1- 3 Seroconversion to vaccinia 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. Table 4 Seroconversion rates by ELISA in Vaccinia-experienced healthy and special populations SCR - ELISA Day 01 Day 7/141 Day 281 Day 421 Study Health status N SCR % SCR % (95% CI) SCR % (95% CI) SCR % (95% CI) POX- MVA- 0052 Healthy 200 - 95.5 (91.6, 97.9) 93.0 (88.5, 96.1) NA POX- MVA- 0242 Healthy 61 - 83.6 (71.9, 91.8) 79.7 (67.2, 89.0) NA Healthy 9 - 62.5 (24.5, 91.5) 100 (63.1, 100) 100 (59.0, 100.0) POX- MVA- 0112 HIV 131 - 57.3 (48.1, 66.1) 76.6 (68.2, 83.7) 92.7 (86.6, 96.6) Table 5 Seroconversion rates by PRNT in Vaccinia-experienced healthy and special populations SCR - PRNT Day 01 Day 7/141 Day 281 Day 421 Study Health status N SCR % SCR % (95% CI) SCR % (95% CI) SCR % (95% CI) POX- MVA- 0052 Healthy 200 - 78.5 (72.2, 84.0) 69.8 (63.0, 76.1) NA POX- MVA- 0242 Healthy 61 - 73.8 (60.9, 84.2) 71.2 (57.9, 82.2) NA Healthy 9 - 75.0 (34.9, 96.8) 62.5 (24.5, 91.5) 85.7 (42.1, 99.6) POX- MVA- 0112 HIV 131 - 46.0 (37.0, 55.1) 59.7 (50.5, 68.4) 75.6 (67.0, 82.9) 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); ); PRNT = plaque reduction neutralisation test; ELISA = enzyme-linked immunosorbent assay using MVA as an antigen. Long-term immunogenicity to vaccinia 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: Table 6 Seroconversion rates by ELISA and PRNT in Vaccinia-naïve healthy over a period of 24 months ELISA PRNT 11 Month N SCR % (95% CI) GMT (95% CI) SCR % (95% CI) GMT (95% CI) 2 178 98.9 (96.0, 99.9) 328.7 (288.5, 374.4) 86.0 (80.0, 90.7) 34.0 (26.4, 43.9) 6 178 73.0 (65.9, 79.4) 27.9 (20.7, 37.6) 65.2 (57.7, 72.1) 7.2 (5.6, 9.4) 24* 92 71.7 (61.4, 80.6) 23.3 (15.2, 35.9) 5.4 (1.8, 12.2) 1.3 (1.0, 1.5) ELISA = enzyme-linked immunosorbent assay using MVA as an antigen; 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 pre- existing immunological memory response to vaccinia, induced by either licensed smallpox vaccines a long time ago or two years after IMVANEX. Table 7 Seroconversion rates by ELISA and PRNT after a booster dose Primary immunisation N Day 01 N Day 71 Day 141 ELISA S+ % GMT S+ % GMT S+ % GMT 2 doses of IMVANEX 92 72 23 75 100 738 100 1,688 Licensed smallpox vaccine 200 79 39 195 - - 98 621 PRNT S+ % GMT S+ % GMT S+ % GMT 2 doses of IMVANEX 92 5.4 1 75 92 54 99 125 Licensed smallpox vaccine 200 77 22 195 - - 98 190 1Day 0 corresponding to day of booster vaccination with IMVANEX (pre- booster); 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 using MVA as an antigen; PRNT = plaque reduction neutralisation test; S+ = Seropositivity rate; GMT = geometric mean titre. Immunogenicity and attenuation of take of ACAM2000 in healthy subjects IMVANEX was compared to ACAM2000 (a 'second generation' live attenuated smallpox vaccine produced in cell culture and licensed 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 randomised 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 titre (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 12 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). Vaccine effectiveness In real-world observational studies conducted in vaccine-eligible individuals (according to local recommendations), vaccine effectiveness against mpox disease was demonstrated at least 14 days after vaccinationa, with adjusted vaccine effectiveness estimates ranging from 35% (95% CI, -2-59) to 89% (95% CI, 76-95) after one IMVANEX dose and from 66% (95% CI, 47-78) to 90% (95% CI, 86- 92) after two IMVANEX doses. Table 8 Vaccine effectiveness at least 14 days after vaccinationa Country Study Design, Period Vaccination strategy 1-dose effectiveness % [95% CI] 2-dose effectiveness % [95% CI] Case-control Aug 2022-Mar 2023 PrEP/PEP 77% (60-87) 89% (56-97) Case-control Aug 2022-Nov 2022 PrEP 36% (22-47)* 66% (47-78)* Retrospective cohort May 2022-Dec 2022 PrEP/PEP 81% (64-90)* 83% (28-96)* Case-coverage Jul 2022-Oct 2022 PrEP/PEP 86% (83-89)* 90% (86-92)* US Case-control Jun 2022-Dec 2022 PrEP/PEP 68% (25-87)* 89% (44-98)* Retrospective cohort Jul 2022-Dec 2022 PrEP 79% (33-100)*,** - Spain Prospective cohort May 2022-Aug 2022 PEP 89% (76-95)a - Canada Case-control Jun 2022-Sep 2022 PrEP 35% (-2-59) 65% (1-87)*** - UK Case-coverage Jul 2022-Dec 2022 PrEP 78% (54-89)** - Note: all data are adjusted vaccine effectiveness, based on subcutaneous administration, unless indicated otherwise. *Covers both subcutaneous and intradermal administrations. **Crude vaccine effectiveness. ***Based on individual-level data supplemented with questionnaire responses on risk behaviour. a PEP administered = 14 days after exposure. Impact on hospitalisation In a surveillance study conducted from May 2022 to May 2023 in the US, IMVANEX was shown to reduce the risks of mpox-related hospitalisation. Compared with unvaccinated mpox patients, the odds of hospitalisation were 0.27 (95% CI, 0.08-0.65) after one IMVANEX dose, and 0.20 (95% CI, 0.01-0.90) after two IMVANEX doses. The estimated relative risk reduction was 73% after one IMVANEX dose and 80% after two IMVANEX doses. Paediatric population The licensing authority has deferred the obligation to submit the results of studies with IMVANEX in all subsets of the paediatric population for prevention of smallpox, mpox and disease caused by vaccinia virus by active immunisation against smallpox, mpox and disease caused by vaccinia virus infection and disease (see section 4.2 for information on paediatric use). Exceptional circumstances This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to 13 the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

Not applicable.

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

Trometamol Sodium chloride Water for injections

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

3 years at -20°C +/-5°C 5 years at -50°C +/-10°C 9 years at -80°C +/-10°C After thawing, the vaccine can be stored at 2°C–8°C in the dark for up to 2 months within the approved shelf-life prior to use. 14 Do not re-freeze a vial once it has been thawed.

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. The vaccine can be stored short-term in a refrigerator at 2°C–8°C for up to 2 months within the approved shelf-life prior to use. Store in the original package in order to protect from light.

0.5 ml suspension in a vial (Type I glass) with stopper (bromobutyl rubber). Pack sizes of 10 single dose vials or 20 single dose vials. 6.6.

The vial should be allowed to reach a temperature between 8°C and 25°C before use. Swirl the vial gently before use for at least 30 seconds. After thawing, IMVANEX is a light yellow to pale white colored, clear to milky suspension. It may contain light yellow to pale white flocculates. The suspension should be visually inspected for any extraneous particulate matter and discoloration before use. In the event of any damage to the vial, extraneous 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. Each vial is for single use. Any unused vaccine or waste material should be disposed of in accordance with local requirements. 4.

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