Imvanex

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
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 x 107 Inf.U * 
 
*infectious units 
1 Produced in chick embryo cells 
 
This vaccine contains trace residues of gentamicin (see section 4.3). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Suspension for injection. 
 
Pale milky coloured homogeneous suspension. 
 
 
4. CLINICAL PARTICULARS 
 
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. 
 



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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 and gentamicin). 
 
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/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 
4 weeks should be avoided. 
 



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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 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. 
 
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) 



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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) 

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) 
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 

Ear and labyrinth 
disorders 

- - - Vertigo 

Cardiac disorders - - - Tachycardia 
Respiratory, thoracic 
and mediastinal 
disorders 

- - Pharyngolaryngeal 
pain 
Rhinitis 
Cough 

Oropharyngeal pain 

Gastrointestinal 
disorders 

Nausea - Diarrhoea 
Vomiting 
 

 Dry mouth 
Abdominal Pain 

Skin and 
subcutaneous 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 

General disorders 
and administration 
site conditions 

Injection 
site pain 

Rigor/Chills 
Injection site nodule 

Underarm swelling 
Malaise 

Axillary pain 
Injection site 
exfoliation 



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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) 
Injection 
site 
erythema 
Injection 
site 
swelling 
Injection 
site 
induration 
Injection 
site pruritus 
Fatigue 

Injection site 
discolouration 
Injection site 
haematoma 
Injection site warmth 

Injection site 
haemorrhage 
Injection site 
irritation 
Flushing 
Chest pain 
 

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 

 
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 



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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. PHARMACOLOGICAL PROPERTIES 
 
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-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 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: 
 

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) 

POX-MVA-0083 
Healthy 194 12.5  (8.1, 18.2) 

85.4  
(79.6, 90.1) 

98.5  
(95.5, 99.7) 

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) 

POX-MVA-0112 
Healthy 88 29.6  (20.0, 40.8) 

83.7  
(74.2, 90.8) 

98.7  
(93.1, 100) 

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) 
  



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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) 

POX-MVA-0083 
Healthy 194 5.4  (2.6, 9.8) 

24.5  
(18.6, 31.2) 

86.6  
(81.0, 91.1) 

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) 

POX-MVA-0112 
Healthy 88 11.1  (5.2, 20.0) 

20.9  
(12.9, 31.0) 

77.2  
(66.4, 85.9) 

HIV 351 15.7  (11.9, 20.1) 
22.5  

(18.1, 27.4) 
60.3  

(54.7, 65.8) 

POX-MVA-0132 Healthy 21196 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; 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 1-3 
 
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. 
 

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 

POX-MVA-
0112 

Healthy 9 - 62.5  (24.5, 91.5) 
100  

(63.1, 100) 
100  

(59.0, 100.0) 

HIV 131 - 57.3  (48.1, 66.1) 
76.6  

(68.2, 83.7) 
92.7  

(86.6, 96.6) 
 

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 

POX-MVA-
0112 

Healthy 9 - 75.0  (34.9, 96.8) 
62.5  

(24.5, 91.5) 
85.7  

(42.1, 99.6) 

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); 
 



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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 PRNT 
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; 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, induced by either licensed smallpox vaccines a long time ago or two years after 
IMVANEX. 
 

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; PRNT = plaque reduction neutralization 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 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. 



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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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Trometamol 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
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. 



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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 and other handling 
 
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) 
 
EU/1/13/855/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 31 July 2013 
Date of the last renewal: 23 April 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



12 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 



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A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) of the biological active substance(s) 

Bavarian Nordic A/S 
Hejreskovvej 10 A, Kvistgård, 3490, Denmark 
 
Name and address of the manufacturer(s) responsible for batch release 

Bavarian Nordic A/S 
Hejreskovvej 10 A, Kvistgård, 3490, Denmark 

 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

Medicinal product subject to medical prescription. 
 
• Official batch release 
 

In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be 
undertaken by a state laboratory or a laboratory designated for that purpose. 

 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
any subsequent updates published on the European medicines web-portal. 

 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk management plan (RMP) 
 

The marketing authoristion holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
 



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E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of 
Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following 
measures: 
Description Due date 
To ensure adequate monitoring of safety and/or effectiveness, the applicant 
should perform the following studies to collect data where IMVANEX is used 
as a prophylactic vaccine and/or use in case of re-emergence of circulating 
smallpox. 
 

• Non-interventional post-authorisation safety study (PASS)  
POX-MVA-038: An observational, non-interventional post-
authorisation safety study for the prophylactic vaccination with 
IMVANEX for [insert description of target vaccinee population] 

• Non-interventional post-authorisation efficacy study (PAES)  
POX-MVA-039: An observational, non-interventional post-
authorisation safety and efficacy study for the prophylactic 
vaccination with IMVANEX following re-emergence of circulating 
smallpox infections 

 

Status to be reported 
annually within each 
annual re-
assessment 
application 

 
 

  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PACK OF 20 VIALS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IMVANEX suspension for injection 
Smallpox vaccine (Live Modified Vaccinia Virus Ankara) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 dose (0.5 ml) has a titre of no less than 5 x 107 Inf.U (Inf.U = infectious units) 
 
 
3. LIST OF EXCIPIENTS 
 
Trometamol 
Sodium chloride 
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Suspension for injection. 
 
20 single dose vials. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
Thaw at room temperature. Gently swirl for at least 30 seconds. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
Exp. (-20°C +/-5°C): 
Exp. (-50°C +/-10°C): 
Exp. (-80°C +/-10°C): 
 
 



18 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a freezer (at -20°C +/-5°C or -50°C +/-10°C or -80°C +/-10°C) protected from light. Expiry 
date depends on storage temperature. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Dispose of in accordance with local requirement. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bavarian Nordic A/S 
Philip Heymans Allé 3 
DK-2900 Hellerup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/855/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
IMVANEX® suspension for injection 
Smallpox vaccine 
 
 
2. METHOD OF ADMINISTRATION 
 
Subcutaneous use 
 
 
3. EXPIRY DATE 
 
Exp. (-20°C +/-5°C): 
Exp. (-50°C +/-10°C): 
Exp. (-80°C +/-10°C): 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 dose (0.5 ml) 
 
 
6. OTHER 
 
Store in a freezer (at -20°C +/-5°C or -50°C +/-10°C or -80°C +/-10°C) protected from light. 
 
 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



21 

Package leaflet: Information for the user 
 

IMVANEX suspension for injection 
Smallpox vaccine (Live Modified Vaccinia Virus Ankara) 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you receive this vaccine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What IMVANEX is and what it is used for 
2. What you need to know before you receive IMVANEX 
3. How IMVANEX is given 
4. Possible side effects 
5. How to store IMVANEX 
6. Contents of the pack and other information 
 
 
1. What IMVANEX is and what it is used for 
 
IMVANEX is a vaccine used to prevent smallpox infection in adults. 
 
When a person is given the vaccine, the immune system (the body’s natural defence system) will 
produce its own protection in the form of antibodies against the smallpox virus. 
IMVANEX does not contain smallpox virus (Variola) and cannot spread or cause smallpox. 
 
 
2. What you need to know before you receive IMVANEX 
 
You must not receive IMVANEX: 
 
• if you have previously had a sudden life-threatening allergic reaction to any ingredient of 

Imvanex (these are listed in section 6) or chicken protein, benzonase or gentamicin which may 
be present in the vaccine in very small amounts. 
 

• if you are ill with a high temperature. In this case, your doctor will postpone the vaccination 
until you are feeling better. The presence of a minor infection, such as a cold, should not require 
postponement of the vaccination, but talk to your doctor or nurse first. 

 
Warnings and precautions 
 
Talk to your doctor or nurse before receiving IMVANEX: 

• if you have atopic dermatitis (see section 4). 
• if you have HIV infection or any other condition or treatment leading to a weakened immune 

system. 
 
The protective efficacy of IMVANEX against smallpox has not been studied. 
 
IMVANEX may not fully protect all people who are vaccinated. 



22 

 
Prior vaccination with IMVANEX may modify the cutaneous response (‘take’) to subsequently 
administered replication-competent smallpox vaccine resulting in a reduced or absent take. 
 
Other medicines or vaccines and IMVANEX 
 
Tell your doctor or nurse if you are taking or have recently taken any other medicines or if you have 
recently received any other vaccine. 
 
Pregnancy and breast-feeding 
 
If you are a pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask 
to your doctor for advice. The use of this vaccine during pregnancy and breast-feeding is not 
recommended. However, your doctor will assess whether the possible benefit in terms of preventing 
smallpox would outweigh the potential risks of giving you this vaccine. 
 
Driving and using machines 
 
There is no information on the effect of IMVANEX on your ability to drive or use machines. 
However, it is possible that if you experience any of the side effects listed in section 4, then some of 
these may affect your ability to drive or use machines (e.g. dizziness). 
 
IMVANEX contains sodium 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say 
essentially ’sodium-free’. 
 
 
3. How IMVANEX is given 
 
You can be given this vaccine whether or not you have received smallpox vaccination in the past. 
 
The vaccine will be injected under the skin, preferably into the upper arm, by your doctor or a nurse. It 
must not be injected into a blood vessel. 
 
If you have never been vaccinated against smallpox: 

• You will receive two injections. 
• The second injection will be given no less than 28 days after the first. 
• Make sure you complete the vaccination course of two injections. 

 
If you have previously been vaccinated against smallpox: 

• You will receive one injection. 
• If your immune system is weakened you will receive two injections with the second injection 

no less than 28 days after the first. 
 
If you forget to receive IMVANEX 
 
If you miss a scheduled injection, tell your doctor or nurse and arrange another visit. 
 
If you have any further questions on the use of this vaccine, ask your doctor or nurse. 
 
 



23 

4. Possible side effects 
 
Like all medicines, this vaccine can cause side effects, although not everybody gets them. 
 
Serious side effects 
Contact a doctor immediately, or go immediately to the emergency department of your nearest 
hospital if you experience any of the following symptoms: 

• difficulty in breathing 
• dizziness 
• swelling of the face and neck. 

 
These symptoms may be a sign of a serious allergic reaction. 
 
Other side effects 
 
If you already have atopic dermatitis, you may experience more intense local skin reactions (such as 
redness, swelling and itching) and other general symptoms (such as headache, muscle pain, feeling 
sick or tired), as well as a flare-up or worsening of your skin condition. 
 
The most common side effects reported were at the site of injection. Most of them were mild to 
moderate in nature and resolved without any treatment within seven days. 
 
If you get any of the following side effects, tell your doctor. 
 
Very common (may affect more than 1 in 10 people): 

• headache, 
• aching muscles, 
• feeling sick, 
• tiredness, 
• pain, redness, swelling, hardness or itching at the injection site. 

 
Common (may affect up to 1 in 10 people): 

• chills, 
• fever, 
• joint pain, pain in extremities, 
• loss of appetite, 
• lump, discolouration, bruising or warmth at the injection site. 

 
Uncommon (may affect up to 1 in 100 people): 

• nose and throat infection, upper respiratory tract infection, 
• swollen lymph nodes, 
• abnormal sleep, 
• dizziness, abnormal skin sensations, 
• muscle stiffness,  
• sore throat, runny nose, cough, 
• diarrhea, vomiting,  
• rash, itch, skin inflammation,  
• bleeding, irritation,  
• underarm swelling, feeling unwell, flushing, chest pain, pain in the armpit, 
• increase of cardiac laboratory values (like Troponin I ), liver enzyme increased, white blood 

cell count decreased, mean platelet volume decreased. 
 



24 

Rare (may affect up to 1 in 1000 people): 
• sinus infection, 
• influenza, 
• pink eye, 
• hives (nettle rash), 
• skin discolouration, 
• sweating, 
• skin bruising, 
• night sweats, 
• lump in skin,  
• back pain,  
• neck pain, 
• muscle cramps, 
• muscle pain, 
• muscle weakness, 
• swelling of the ankles, feet or fingers, 
• faster heart beat, 
• ear and throat ache, 
• abdominal pain,  
• dry mouth, 
• spinning sensation (vertigo), 
• migraine, 
• nerve disorder causing weakness, tingling or numbness, 
• drowsiness, 
• scaling, inflammation, abnormal skin sensation, reaction at the injection site, rash, numbness, 

dryness, movement impairment, vesicles at the injection site, 
• weakness, 
• influenza like illness, 
• swelling of the face, mouth and throat, 
• white blood cell count increased, 
• bruising. 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store IMVANEX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this vaccine after the expiry date which is stated on the label after Exp. The expiry date 
refers to the last day of that month. 
 
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. Do not refreeze the vaccine once thawed. 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. 
 
Store in the original package to protect from light. 
 
 
6. Contents of the pack and other information 
 



25 

What IMVANEX contains 
One dose (0.5 ml) contains: 
The active substance is Modified Vaccinia Ankara – Bavarian Nordic Live virus1, no less than 
5 x 107 Inf.U* 
*infectious units 
1Produced in chick-embryo cells 
 
The other ingredients are: trometamol, sodium chloride, and water for injections. 
 
This vaccine contains trace residues of gentamicin and benzonase. 
 
What IMVANEX looks like and contents of the pack 
 
Once the frozen vaccine has been thawed, IMVANEX is a pale milky coloured homogeneous 
suspension for injection. 
 
IMVANEX is provided as a suspension for injection in a vial (0.5 ml). 
IMVANEX is available in pack containing 20 vials. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Bavarian Nordic A/S 
Philip Heymans Allé 3 
DK-2900 Hellerup 
Denmark 
tel +45 3326 8383 
e-mail regulatory@bavarian-nordic.com 
 
Manufacturer: 
Bavarian Nordic A/S 
Hejreskovvej 10A,  
3490 Kvistgaard 
Denmark 
 
 
This leaflet was last revised in {MM/YYYY} 
 
This medicine has been authorised under ‘exceptional circumstances’. 
This means that because of scientific reasons it has been impossible to get complete information on 
this medicine. 
The European Medicines Agency will review any new information on this medicine every year and 
this leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  
 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
Instructions for preparation and administration of the vaccine: 
 



26 

The vaccine should be allowed to reach room temperature before use. Swirl gently before use. 
Visually inspect the suspension prior to administration. In case of any particles and/or abnormal 
appearance, the vaccine should be discarded. 
 
A dose of 0.5 ml is withdrawn into a syringe for injection. 
 
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 refreeze the vaccine once thawed. 
 
In the absence of compatibility studies, this vaccine must not be mixed with other vaccines. 


	ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) ANDMANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURESFOR THE MARKETING AUTHORISATION UNDER EXCEPTIONALCIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET