Prophylaxis of influenza in an officially declared pandemic situation. Foclivia should be used in accordance with Official Guidance.

Posology Individuals 6 months of age and older: administer two doses (0.5 ml each), 21 days apart. Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1). Paediatric population No data are available in children aged less than 6 months. Method of administration The vaccine is administered by intramuscular injection, preferably in the anterolateral aspect of the thigh in infants or in the deltoid muscle region of the upper arm in older individuals.

History of an anaphylactic (i.e. life threatening) reaction to any of the constituents or trace residues (eggs, chicken proteins, ovalbumin, kanamycin sulphate, neomycin sulphate, formaldehyde, hydrocortisone and cetyltrimethylammonium bromide) of this vaccine. However, in a pandemic situation, it may be appropriate to give this vaccine to individuals with a history of anaphylaxis as defined above, provided that facilities for resuscitation are immediately available in case of need. See section 4.4.

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. Caution is needed when administrating this vaccine to persons with a known hypersensitivity to the active substance, to any of the excipients listed in section 6.1 and to residues (eggs, chicken proteins, ovalbumin, kanamycin sulphate, neomycin sulphate, formaldehyde, hydrocortisone and cetyltrimethylammonium bromide). As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. If the pandemic situation allows, immunisation should be postponed in patients with febrile illness until the fever is resolved. Immunocompromised individuals Immunocompromised individuals, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced immune response to active immunisation. The vaccine should under no circumstances be administered intravascularly or intradermally. There are no data with Foclivia using the subcutaneous route of administration. Healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleeding. Protection against influenza There is no immune correlate of protection established for influenza A (H5N1). A protective immune response may not be elicited in all vaccine recipients. Some degree of cross-reactive immunity has been observed against H5N1 viruses of clades different to that of the vaccine strain. However, the degree of protection that may be elicited to H5N1 strains of other clades is unknown (see section 5.1). There are no safety, immunogenicity or efficacy data to support interchangeability of Foclivia with other H5N1 monovalent vaccines. While no data are available from the use of Foclivia, cases of convulsion with and without fever have been reported in subjects vaccinated with Focetria, an MF59.1 adjuvanted H1N1 pandemic vaccine similar to Foclivia. The majority of febrile convulsions occurred in paediatric subjects. Some cases were observed in subjects with a history of epilepsy. Particular attention should be given to subjects suffering from epilepsy and the physician should inform the subjects (or parents) about the possibility to experience convulsion. (see section 4.8). Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints. Excipients with known effect Sodium This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’ Potassium This vaccine contains potassium, less than 1 mmol (39 mg) per dose, that is to say essentially ‘potassium-free’.

Foclivia may be co-administered with non-adjuvanted seasonal influenza vaccines, and immunisation should be carried out on separate limbs. There are no data on co-administration of Foclivia with vaccines other than non- adjuvanted seasonal influenza vaccines. If co-administration with another vaccine is considered, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

Pregnancy Limited data obtained from women who became pregnant during the course of clinical trials with Foclivia or other pandemic vaccines adjuvanted with MF59C.1 were insufficient to inform vaccine-associated risks in pregnancy. However, it is estimated that during the 2009 H1N1 pandemic more than 90,000 women were vaccinated during pregnancy with Focetria (an H1N1 pandemic vaccine similar to Foclivia) which contains the same amount of MF59C.1 as Foclivia. Post-marketing spontaneously reported adverse events and an interventional study do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy. In addition, two large observational studies designed to assess the safety of Focetria exposure in pregnancy showed no increase in the rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birth weight, prematurity, neonatal deaths, and congenital malformations among almost 10,000 vaccinated pregnant women and their offspring compared with unvaccinated controls. Health care providers need to assess the benefits and potential risks of administering Foclivia vaccine to pregnant women, taking into consideration official recommendations. Breast-feeding There are no data regarding the use of Foclivia during breast-feeding. The potential benefits and risks to the mother and infant should be considered before administering Foclivia. Fertility There are no data concerning human fertility. A study in female rabbits did not indicate reproductive or developmental toxicity of Foclivia (see section 5.3). Male fertility has not been assessed in animals.

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

Summary of safety profile The safety of H5N1 vaccine combined with MF59C.1 adjuvant (7.5 or 15 micrograms haemagglutinin, HA) containing either the A/turkey/Turkey/1/2005 or the A/Vietnam/1194/2004 strain has been evaluated in nine clinical trials in healthy subjects involving 5055 adults, elferly and children. There were 4041 adult subjects 18 to 60 years of age and 540 elderly subjects 61 years of age and above. In the paediatric population, there were 214 subjects 6 to 35 months of age, 167 subjects 3 to 8 years of age and 93 subjects 9 to 17 years of age. The overall safety profile was similar across the adult, elderly and paediatric populations. Clinical trials in 80383 subjects receiving MF59C.1 adjuvanted vaccine with an H1N1, H5N3 or H9N2 strain showed a similar safety profile to the H5N1 trials. Irrespective of antigen dose, antigen subtype or age group, most local and systemic adverse reactions after administration were of short duration, with onset close to the time of vaccination, and were mild or moderate in severity. Across all trials, there was a general trend towards decreased reports of local adverse reactions after the second vaccination compared with the first. Tabulated list of adverse reactions In adults 18 to 60 years, the most frequently reported (=10%) adverse reactions were injection site pain (59%), myalgia (34%), headache (26%), injection site redness (24%), fatigue (24%), injection site induration (21%), injection site swelling (15%), chills (13%) and maliase (13%). In elderly subjects (= 61 years), the most frequently reported (=10%) adverse reactions were injection site pain (35%), myalgia (24%), injection site redness (17%), headache (16%), chills (12%), fatigue (10%) and malaise (10%). In children and adolescents 3 to 17 years of age, the most frequently reported (=10%) adverse reactions were injection site pain (95%), headache (61%), myalgia (60%), fatigue (41%), injection site redness (60%), injection site induration (34%), injection site swelling (34%), malaise (32%), nausea (25%), sweating (18%), chills (19%), diarrhoea (18%) and injection site ecchymosis (16%). In infants and children 6 to 35 months of age, the most frequently reported (=10%) adverse reactions were injection site redness (62%), irritability (57%), tenderness (55%), unusual crying (48%), sleepiness (45%), injection site induration (38%), injection site swelling (37%) change in eating habits (36%), diarrhoea (34%), fever (27%), injection site ecchymosis (19%), vomiting (10%), sweating, (10%) and unusual sweating (10%). The solicited and unsolicited adverse reactions reported after any vaccination dose (i.e. first, second or booster) across subjects age, are listed according to the following MedDRA frequency convention and 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); Very rare (<1/10,000). 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) Immune system disorders Anaphylaxis Metabolism and nutrition disorders Change in eating habits1 Loss of appetite Nervous system disorders Headache Gastrointestinal disorders Nausea2, Diarrhoea2, Vomiting2 Skin and subcutaneous tissue disorders Sweating2, Unusual sweating1 Urticaria Musculoskeletal and connective tissue disorders Myalgia Arthralgia General disorders and administration site conditions Injection site swelling, Injection site pain, Injection site tenderness1 , Injection site induration, Injection site Injection site hemorrhage 1 Reported only in paediatric subjects 6-35 months 2 Reported as Common in adults (18-60 years) and elderly (= 61 years) 3 Reported as Very common only in paediatric subjects 6 months-8 years. Reported as Common in adolescents and adults 9-60 years of age and Uncommon in eldery (= 61 years) The majority of these reactions usually disappear within 3 days without treatment. Clinical trials in special populations Adverse reactions in special populations have been evaluated in two clinical trials, V87_25 and V87_26, involving adult (18-60 years) and elderly (= 61 years) subjects who were either healthy or with underlying medical conditions or immunosuppressive conditions. Across studies V87_25 and V87_26, the safety of H5N1 A/turkey/Turkey/1/2005 in healthy adult and elderly subjects was consistent with existing safety data from previous clinical trials. However, in immunocompromised subjects 18 to60 years of age, slightly higher rates of nausea (13.0%) were reported. In addition, higher rates of arthralgia (up to 23.3%) were reported in both adult and elderly subjects, who were immunocompromised or with underlying medical conditions. The following solicited adverse reactions were additionally collected in these two studies and reported with the following frequencies across subjects who received H5N1 A/turkey/Turkey/1/2005 irrespective of age or health status: diarrhoea (up to 11.9%), loss of appetite (up to 10.9%) and vomiting (up to 1.7%). In both studies, subjects with underlying medical and immunosuppressive conditions reported higher frequencies of diarrhoea, loss of appetite and vomiting compared to healthy subjects (irrespective of age). • Post-marketing surveillance No post-marketing experience exists for Foclivia. In addition to the adverse events listed from clinical studies, the following adverse events were reported from post-marketing surveillance with H1N1v Focetria vaccine (licensed for use from 6 months of age during the 2009 influenza pandemic, and containing the same MF59 adjuvant and manufactured with the same process as Foclivia). Blood and lymphatic system disorders Lymphadenopathy. redness, Injection site ecchymosis2 , Fatigue, Chills/ Shivering, Malaise, Sleepiness1, Irritability1, Unusual crying1, Fever3 Immune system disorders Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock,. Nervous system disorders Dizziness, somnolence, syncope , presyncope, neuralgia, paraesthesia, convulsions and neuritis. Cardiac disorders Palpitation, tachycardia. Respiratory, thoracic and mediastinal disorders Cough. Gastrointestinal disorders Abdominal pain Skin and subcutaneous tissue disorders Generalised skin reactions including pruritus, non-specific rash, angioedema. Musculoskeletaland connective tissue disorders Muscular weakness, pain in extremities. General disorders and administration site conditions Asthenia. The following additional adverse events were reported from post-marketing surveillance with seasonal non-adjuvanted trivalent vaccines in all age groups and a seasonal trivalent MF59-adjuvanted subunit influenza vaccine approved for use in elderly subjects 65 years of age and older: Blood and lymphatic system disorders Thrombocytopenia (in some cases reversible platelet counts less than 5000 mm3). Nervous system disorders Neurological disorders, such as encephalomyelitis and Guillain Barré syndrome. Vascular disorders Vasculitis which may be associated with transient renal involvement. Skin and subcutaneous tissue disorders Erythema multiforme. General disorders and administration site conditions Extensive swelling of injected limb lasting more than one week, injection-site cellulitis- like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week). 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

No case of has been reported.

Pharmacotherapeutic group: Influenza vaccine, ATC Code: J07BB02 Clinical efficacy and safety Pandemic preparedness vaccines contain influenza antigens that are different from those in the currently circulating influenza viruses. These antigens can be considered as ‘novel’ antigens and simulate a situation where the target population for vaccination is immunologically naïve. Data obtained with a pandemic preparedness vaccine will support a vaccination strategy that is likely to be used for the pandemic vaccine: clinical efficacy and safety data obtained with pandemic preparedness vaccines are relevant for the pandemic vaccines. Immune response to H5N1 vaccine combined with MF59C.1 adjuvant containing A/Vietnam/1194/2004 or A/turkey/Turkey/1/2005 strain. Adults (18-60 years) A Phase II clinical trial (V87P1) was conducted with H5N1 MF59C.1 adjuvanted vaccine containing A/Vietnam/1194/2004 in 312 healthy adults. Two doses of vaccine containing 7.5 micrograms Haemagglutinin(HA)/dose were administered three weeks apart to 156 subjects. Immunogenicity was assessed in 149 subjects. In a phase III clinical trial (V87P13), 2693 adult subjects were enrolled and 2566 received two doses of H5N1 MF59C.1 adjuvanted vaccine containing A/Vietnam/1194/2004 7.5 micrograms HA/dose administered three weeks apart. Immunogenicity was assessed in a subset (N=197) of subjects. In a third clinical trial (V87P11) 194 adult subjects received two doses of H5N1 MF59C.1 adjuvanted vaccine containing A/turkey/Turkey/1/2005 7.5 micrograms HA/dose administered three weeks apart. Immunogenicity was assessed in 182 subjects. The seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 and to H5N1 A/turkey/Turkey/1/2005 in the adults measured by Single Radial Haemolysis (SRH) assay was as follows: Anti-HA antibody (SRH) Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=149 Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=197 Study V87P11 A/turkey/Turkey/1/2005 21 days after 2nd dose N=182 Seroprotection rate (95%CI)* 85% (79-91) 91% (87-95) 91% (85-94) Seroconversion rate (95%CI)** 85% (78-90) 78% (72-84) 85% (79-90) Seroconversion factor (95%CI)*** 7.74 (6.6-9.07) 4.03 (3.54-4.59) 6 (5.2-6.93) Anti-HA antibody (SRH) Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=69 Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=128 - Baseline Serostatus < 4 mm2 = 4 mm2 - Seroprotection rate (95%CI)* 87% (77-94) 94% (88-97) - Seroconversion rate (95%CI)** 87% (77-94) 73% (65-81) - Seroconversion factor (95%CI)*** 8.87 (7.09-11) 2.71 (2.38-3.08) - * Seroprotection: SRH area =25 mm2 ** Seroconversion was defined as an SRH area =25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) *** geometric mean ratios (GMRs) of SRH MicroNeutralization (MN) results against A/Vietnam/1194/2004 (Studies V87P1 and V87P13) indicate a seroprotection and seroconversion rate ranging from 67% (60-74) to 85% (78-90) and 65% (58-72) to 83% (77-89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH. In Study V87P11 MN results against homologous A/turkey/Turkey/1/2005 indicate a seroprotection and seroconversion rate of 85% (79-90) and 93% (89-96), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH. Persistence of antibodies after primary vaccination in this population was assessed by Hemagglutination Inhibition (HI), SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels. Elderly (=61 years) The seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibody to H5N1 MF59C.1 adjuvanted vaccine (A/Vietnam/1194/2004 and A/turkey/Turkey/1/2005) in subjects aged 61 years and older (limited number of subjects were above 70 years of age; N=123) measured by SRH assay assessed in two clinical studies were as follows: Anti-HA antibody (SRH) Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=84a Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=210b Study V87P11 A/turkey/Turkey/1/2005 21 days after 2nd dose N=132c Seroprotection rate (95%CI)* 80% (70-88) 82% (76-87) 82% (74-88) Seroconversion rate (95%CI)** 70% (59-80) 63% (56-69) 70% (61-77) Seroconversion factor (95%CI)*** 4.96 (3.87-6.37) 2.9 (2.53-3.31) 3.97 (3.36-4.69) Anti-HA antibody (SRH) Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=66 Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=143 Baseline Serostatus < 4 mm2 = 4 mm2 Seroprotection rate (95%CI)* 82% (70-90) 82% (75-88) Seroconversion rate (95%CI)** 82% (70-90) 54% (45-62) Seroconversion factor (95%CI)*** 8.58 (6.57-11) 1.91 (1.72-2.12) a Ages 62-88 years; b Ages 61-68 years; c Ages 61-89 years * Seroprotection: SRH area =25 mm2 ** Seroconversion was defined as an SRH area =25mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) *** GMRs of SRH MN results against A/Vietnam/1194/2004 (Studies V87P1 and V87P13) indicate a seroprotection and seroconversion rate ranging from 57% (50-64) to 79% (68-87) and 55% (48-62) to 58% (47-69) respectively. MN results, similar to SRH results, demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects. In Study V87P11, MN results against homologous A/turkey/Turkey/1/2005 indicate a seroprotection and seroconversion rate of 68% (59-75) and 81% (74-87), respectively. Immune response to vaccination assessed by MN assay is similar to SRH results. Persistence of antibodies after primary vaccination in this population as assessed by HI, SRH, and MN tests reduced from 1/2 to 1/5 of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules as assessed by HI, SRH, and MN tests. Up to 50% (N=33) of the elderly subjects aged 62 to 88 years immunised with H5N1 MF59C.1 adjuvanted vaccine containing A/Vietnam/1194/2004 in trial V87P1 were seroprotected at six months. A third (booster) dose of H5N1 vaccine combined with MF59C.1 was administered 6 months after the primary vaccination series. Results are shown by SRH. The seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows: Study V87P1 Adults A/Vietnam/1194/200 4 booster after 2nd dose Study V87P2 Adults A/Vietnam/1194 /2004 booster after 2nd dose Study V87P1 Elderly A/Vietnam/1194/200 4 booster after 2nd dose SRH N=71 N=13 N=38 Seroprotection rate (95%CI)* 89% (79-95) 85% (55-98) 84% (69-94) Seroconversion rate (95%CI)** 83% (72-91) 69% (39-91) 63% (46-78) Seroconversion facto r (95%CI)*** 5.96 (4.72-7.53) 2.49 (1.56-3.98 ) 5.15 (3.46-7.66) * Seroprotection: SRH area =25 mm2 ** Seroconversion was defined as an SRH area =25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) *** GMRs of SRH • Supportive data in adult and elderly populations In two dose finding studies 80 adults received an adjuvanted pandemic preparedness vaccine (H5N3 or H9N2). Two doses of vaccine with H5N3 (A/Duck/Singapore/97) strain at 3 different dosages (7.5, 15 and 30 micrograms HA/dose) were administered three weeks apart. Serum samples were tested against the original H5N3 and also a number of H5N1 isolates. Serologic responses obtained with the SRH assay showed that 100% of subjects achieved seroprotection and 100% seroconverted after two 7.5 micrograms injections. The adjuvanted vaccine was also found to induce antibodies that cross-protected against the H5N1 strains isolated in 2003 and 2004, which exhibit some antigenic drift compared to the original strains. Two doses of vaccine containing H9N2 (A/chicken/Hong Kong/G9/97) strain at 4 different dosages (3.75, 7.5, 15 and 30 micrograms HA/dose), were administered four weeks apart. Serologic responses obtained with the HI assay showed that 92% of subjects achieved seroprotection and 75% seroconverted after two 7.5 micrograms injections. Cross reactivity Cross-reactive immune response elicited by H5N1 A/Vietnam/1194/2004 against A/turkey/Turkey/1/2005 and A/Indonesia/5/2005 Adults (18-60 years) Some heterologous immune response against A/turkey/Turkey/1/2005 (NIBRG23; clade 2.2.1) and A/Indonesia/5/2005 (clade 2.1) was detectable both after the second and third vaccinations, indicating cross-reactivity of the clade 1 vaccine against clade 2 strains. Seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibodies to H5N1 A/turkey/Turkey/1/2005 after the second dose in adults 18-60 years of age, measured by SRH and HI assays were as follows: Anti-HA antibody Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=70 Study V87P12 A/Vietnam/1194/2004 21 days after 2nd dose N=60 Study V87P3 A/Vietnam/1194/2004 21 days after 2nd dose N=30 Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=197 Seroprotection rate (95%CI)* 70% (58-80) 65% (52-77) 90% (73-98) 59% (52-66) Seroconversion rate (95%CI)** NA 65% (52-77) 86% (68-96) 49% (42-56) SRH Seroconversion factor(95%CI)*** NA 4.51 (3.63-5.61) 7.67 (6.09-9.67) 2.37 (2.1-2.67) N=69 N=60 N=30 N=197 Seroprotection rate (95%CI)° 36% (25-49) 28% (17-41) 24% (10-44) 23% (18-30) Seroconversion rate (95%CI)° NA 28% (17-41) 21% (8-40) 19% (14-25) HI Seroconversion factor (95%CI)°° NA 2.3 (1.67-3.16) 1.98 (1.22-3.21) 1.92 (1.64-2.25) * Seroprotection: SRH area =25 mm2 ** Seroconversion was defined as an SRH area =25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) *** GMRs of SRH  In V87P1: baseline not tested ° measured by HI assay =40 °° GMRs of HI MN results for the clinical studies V87P12, V87P3 and V87P13 in the Table above revealed a seroprotection rate and seroconversion rate against A/turkey/Turkey/2005 ranging from 10% (2-27) to 39% (32-46) and 10% (2-27) to 36% (29-43) respectively. MN results yielded a GMR against A/turkey/Turkey/2005 ranging from 1.59 to 2.95. Elderly (=61 years) Seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibodies to H5N1 A/turkey/Turkey/05 after the second dose in elderly subjects =61 years of age, measured by SRH and HI assays were as follows: Anti-HA antibody Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=37 Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=207 Seroprotection rate (95%CI)* 57% (39-73) 20% (18-23) Seroconversion rate (95%CI)* NA*** 48% (41-55) SRH Seroconversion factor (95%CI)** NA*** 1.74 (1.57-1.94) N=36 N=208 Seroprotection rate (95%CI)° 36% (21-54) 25% (19-32) Seroconversion rate (95%CI)° NA*** 19% (14-25) HI Seroconversion factor (95%CI)°° NA*** 1.79 (1.56-2.06) * measured by SRH assay =25 mm2 ** geometric mean ratios of SRH ° measured by HI assay =40 °° geometric mean ratios of HI *** In V87P1: baseline not tested MN results for the clinical studies in the Table above revealed a seroprotection rate against A/turkey/Turkey/05 ranging from 11% (3-25) (study V87P1) to 30% (24-37) (study V87P13) and seroconversion rate of 25% (19-31) for study V87P13. MN results in study V87P13 yielded a GMR against A/turkey/Turkey/05 of 2.01 (1.78-2.26). Cross-reactive immune response elicited by A/turkey/Turkey/1/2005 against A/Indonesia/5/2005 and A/Vietnam/1194/2004 Heterologous immune response against A/Indonesia/5/2005 (clade 2.1) was detectable in Study V87P11 after the second vaccination, indicating cross-reactivity of the clade 2.2.1 vaccine against clade 2.1 strains. Seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibodies to H5N1 A/Indonesia/5/2005 and A/Vietnam/1194/2004 after the second dose in adults (18-60 years) and elderly (> 61years), measured by SRH and HI assays were as follows: Anti-HA antibody V87P11 Adults (18-60 years) N=182 V87P11 Elderly (>61-89 years)a N=132 A/Indonesia/ 5/2005 A/Vietnam/ 1194/2004 A/Indonesia/ 5/2005 A/Vietnam/ 1194/2004 SRH Seroprotection rate (95%CI)* 83 (77-88) 62 (54-69) 61 (52-69) 45 (37-54) Seroconversion rate (95%CI)** 79 (72-85) 60 (53-68) 64 (56-73) 44 (35-53) Seroconversion factor (95%CI)*** 6.24 (5.44-7.16) 4.45 (3.85-5.14) 3.87 (3.31-4.53) 3.03 (2.56-3.58) N=194 N=148 HI Seroprotection rate (95%CI) ° 50 (43-57) 47 (40-55) 34 (26-42) 39 (31-48) Seroconversion rate (95%CI) ° 49 (42-56) 44 (37-51) 32 (25-41) 34 (26-42) Seroconversion factor (95%CI) °° 4.71 (3.74-5.93) 4.25 (3.36-5.37) 2.69 (2.18-3.32) 2.8 (2.2-3.55) a actual age range of population enrolled * Seroprotection: SRH area =25 mm2 ** Seroconversion was defined as an SRH area =25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) *** GMRs of SRH ° measured by HI assay =40 °° GMRs of HI MN results for A/Indonesia/5/2005 revealed a seroprotection rate of 38% (31-45) in adults (18-60 years) and 14% (8-20) in elderly (>61 years); a seroconversion rate of 58% (50-65) in adults and 30% (23-38) in elderly and finally a GMR of 4.67 (3.95-5.56) in adults and 2.19 (1.86-2.58) in elderly. MN results for A/Vietnam/1194/2004 revealed a seroprotection rate of 10% (6-16) in adults (18-60 years) and 6% (3-11) in elderly (>61 years); a seroconversion rate of 19% (13-25) in adults and 7% (4-13) in elderly and finally a GMR of 1.86 (1.63-2.12) in adults and 1.33 (1.17-1.51) in elderly. Long term booster immune memory: A single vaccination with H5N1 MF59C.1 adjuvanted A/Vietnam/1194/2004 vaccine induced high and rapid serological response in subjects primed 6 to 8 years previously with two doses of a different vaccine, having the same formulation but using the H5N3 strain. In a phase I clinical trial (V87P3) adult subjects aged 18 to 65 years primed 6 to 8 years previously with 2 doses of MF59-adjuvanted H5N3 vaccine/A/Duck/Singapore/97, were administered 2 booster doses of H5N1 MF59C.1 adjuvanted A/Vietnam/1194/2004 vaccine. SRH results after the first dose, that mimic prepandemic priming plus single heterologous booster dose, revealed seroprotection and seroconversion rates of 100% (74- 100) and an 18-fold increase in SRH area (GMR). Alternative vaccination schedules: In a clinical trial evaluating 4 different vaccination schedules in 240 subjects 18 to 60 years of age, where the second dose occurred either 1, 2, 3 or 6 weeks after the first dose of H5N1 MF59C.1 adjuvanted A/Vietnam/1194/2004 vaccine, all vaccine schedule groups after 3 weeks from the second vaccination achieved high levels of antibodies as evaluated with SRH. SRH seroprotection rates ranged from 86% to 98%, seroconversion rates from 64% to 90%, and GMR ranged from 2.92 to 4.57. The magnitude of immune response was lower in the group who received the second dose 1 week later and higher in the groups with longer interval schedules. Subjects with underlying medical or immunosuppressive conditions: Immunogenicity of H5N1 A/turkey/Turkey/1/2005 in adults (18 to 60 years) and elderly (>61 years) subjects with underlying medical conditions (Study V87_25) or immunosuppressive conditions (mainly HIV-infected subjects) (Study V87_26) in comparison to healthy adults (18-60 years) and elderly (>61 years), was evaluated in two randomised, phase III controlled clinical trials (with a seasonal trivalent inactivated MF59-adjuvanted subunit influenza vaccine approved for use in elderly subjects 65 years of age and older as a comparator). In trial V87_25 and V87_26, 96 and 67 subjects, respectively, were over the age of 70 years. In both trials, immunogenicity of H5N1 A/turkey/Turkey/1/2005 was shown by HI, SRH and MN assays following both the first and second dose. Geometric mean area*, seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/turkey/Turkey/1/2005 measured by SRH assays 21 days after the seconddose were as follows: a actual age range of population enrolled * measured by SRH assay seroprotection: SRH area =25 mm2, seroconversion: SRH area =25 mm2 for subjects with a baseline SRH area =4 mm2 or a minimum 50% increase in SRH area for subjects with >4 mm2. ** geometric mean ratios of SRH HI results for the two clinical studies revealed lower values than those reported in previous studies. Seroconversion rates against homologous A/turkey/Turkey/1/2005 ranged from 37.50% to 43.10% in healthy adults, and from 19.18% to 26.47% in adults with immunosuppressive or underlying medical conditions, respectively; seroconversion rates ranged from 21.43% to 30.65% in healthy elderly subjects, and from 24.49% to 27.86% in elderly subjects with immunosuppressive or underlying medical conditions. Similar trends were observed for seroprotection rates in both studies. MN results against homologous A/turkey/Turkey/1/2005 indicate a seroconversion rate of 66.67% in healthy adults, and ranging from 33.57% to 54.14% in adults with Study V87_25 Adults (20- 60 years)a Adults (19- 60 years)a Elderly (61-84 years)a Elderly (61-79 years)a Anti-HA antibody (SRH) Medical Conditions N=140 Healthy N=57 Medical Conditions N=143 Healthy N=57 Geometric Mean Area (95%CI)* 31.07 (27.43-35.19) 58.02 (48.74-69.06) 29.34 (26.07-33.01) 27.78 (22.57-34.18) Seroprotection rate (95%CI)* 65.00 (56.5-72.9) 89.47 (78.5-96) 58.74 (50.2-66.9) 57.89 (44.1-70.9) Seroconversion rate (95%CI)* 72.86 (64.7-80) 98.25 (90.6-99.96) 64.34 (55.9-72.2) 66.67 (52.9-78.6) Seroconversion factor (95%CI)** 3.33 (2.94-3.77) 6.58 (5.53-7.83) 2.37 (2.10-2.66) 2.96 (2.41-3.64) Study V87_26 Adults (20- 60 years)a Adults (18-59 years)a Elderly (61-84 years)a Elderly (61-91 years)a Anti-HA antibody (SRH) Immuno- compromised N=143 Healthy N=57 Immuno- compromised N=139 Healthy N=62 Geometric Mean Area (95%CI)* 26.50 (22.49-31.22) 48.58 (40.01-58.99) 26.85 (23.01-31.33) 23.91 (18.89-30.26) Seroprotection rate (95%CI)* 60.84 (52.3-68.9) 87.72 (76.3-94.9) 58.99 (50.3-67.3) 53.23 (40.1-66) Seroconversion rate (95%CI)* 61.54 (53-69.5) 89.47 (78.5-96) 64.75 (56.2-72.7) 56.45 (43.3-69) Seroconversion factor (95%CI)** 3.16 (2.69-3.73) 7.10 (5.85-8.62) 3.15 (2.70-3.68) 2.83 (2.24-3.58) immunosuppressive or underlying medical conditions, respectively; seroconversion rates ranged from 24.39% to 29.03% in healthy elderly subjects, and from 31.65% to 39.42% in elderly subjects with immunosuppressive or underlying medical conditions. Similar trends were observed for seroprotection rates in both studies. In both studies V87_25 and V87_26, the lower levels of antibodies (as measured by HI, SRH and MN assays) and reduced seroprotection rates in adults and elderly (= 61 years old) subjects with underlying medical or immunosuppressive conditions, suggest that H5N1 A/turkey/Turkey/1/2005 may not elicit the same level of protection against A/H5N1 strain as compared to healthy adults (see section 4.4). These studies provided limited immunogenicity data in subjects with some underlying medical (in particular, renal impairment and peripheral cardiovascular disease) and immunosuppressive conditions (in particular, transplant recipients and patients under cancer treatment). In these trials, lower levels of antibodies and reduced seroprotection rates against homologous H5N1 A/turkey/Turkey/1/2005 were also measured in healthy elderly subjects, as compared to healthy adults, though previous studies showed induction of sufficiently immunogenic responses against H5N1 strains (see above for information on elderly). Paediatric populations The immunogenicity of aH5N1 in the paediatric population was assessed in Studies V87P6 and V87_30. V87P6 was conducted with a H5N1 A/Vietnam/1194/2004 vaccine combined with MF59C.1 adjuvant in 471 children from 6 months to 17 years of age. Two doses of 7.5 micrograms were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the second vaccination (day 43) all age groups (i.e. 6 to 35 months, 3 to 8 years and 9 to 17 years) achieved high levels of antibodies to A/Vietnam/1194/2004 as evaluated with SRH and HI assays as presented in table below. Children (6 to 35 months) Children (3 to 8 years) Adolescents (9 to 17 years) N=134 N=91 N=89 Seroprotection rate (95% CI)* Day 43 97% (92-99) 97% (91-99) 89% (80-94) HI Seroconversion rate (95% CI)** Day 43 97% (92-99) 97% (91-99) 89% (80-94) Seroconversion factor (95% CI)*** Day 43 to Day 1 129 (109-151) 117 (97-142) 67 (51-88) N=133 N=91 N=90 Seroprotection rate (95% CI) ° Day 43 100% (97-100) 100% (96-100) 100% (96-100) SRH Seroconversion rate (95% CI) °° Day 43 98% (95-100) 100% (96-100) 99% (94-100) Seroconversion factor (95% CI) °°° Day 43 to Day 1 16 (14-18) 15 (13-17) 14 (12-16) * Seroprotection defined as HI titre = 1:40 ** Seroconversion defined as non-detectable titre to =1:40, or 4-fold increase from a detectable Day 1 titre *** Geometric mean ratios of HI ° Seroprotection: SRH area =25 mm2 °° Seroconversion defined as an SRH area =25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area =4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2) °°° Geometric mean ratios of SRH MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94-100), a seroconversion rate ranging from 97% (95%CI: 91-99) to 99% (95%CI: 96-100) and a GMR ranging from 29 (95%CI: 25-35) to 50 (95%CI: 44-58). Study V87_30 was a randomised, observer-blind, multicentre study to measure the immunogenicity of several formulations of H5N1 A/turkey/Turkey/1/2005 and MF59 adjuvant. In this study, 420 paediatric subjects 6 months to 8 years of age were divided into two age cohorts: 6 to 35 months of age (N=210) and 3 to 8 years of age (N=210). The vaccine was administered in two separate injections given 3 weeks apart. Antibody levels against A/turkey/Turkey/1/2005 were measured by HI and MN assays three weeks after the second vaccination (Day 43). The immunological response for the approved formulation (7.5 micrograms HA with 100% MF59 adjuvant, 0.5 ml dose) and the study formulation with half the antigen content (3.75 micrograms HA with 100% MF59 adjvant, 0.5 ml dose), are presented below. Formulation 7.5 mcg HA/ 100% MF59 Adjuvant 3.75 mcg HA/ 100% MF59 Adjuvant Age groups 6 to 35 months 3 to 8 years 6 to 35 months 3 to 8 years N=31 N=36 N=36 N=33 Seroprotection rate (95% CI) * Day 43 87% (70-96) 86% (71-95) 86% (71-95) 88% (72-97) Seroconversion rate (95% CI)** Day 43 87% (70-96) 86% (71-95) 86% (71-95) 88% (72-97) HI Seroconversion factor (95% CI)*** Day 43 to Day 1 24 (14-40) 22 (14-34) 31 (19-51) 20 (13-31) % with Titre =1:40 (95% CI) Day 43 100% (89-100) 100% (90-100) 100% (90-100) 100% (89-100) Seroconversion rate (95% CI)** Day 43 100% (89-100) 100% (90-100) 100% (90-100) 100% (89-100) MN Seroconversion factor (95% CI)*** Day 43 to Day 1 165 (117-231) 125 (92-171) 214 (156-294) 132 (95-182) * Seroprotection defined as HI titre = 1:40 ** Seroconversion defined as non-detectable titre to =1:40, or 4-fold increase from a detectable Day 1 titre *** Geometric mean titre ratios Immunogenicity results with Focetria H1N1v (Study V111_03): The seroprotection rate and seroconversion rate measured by HI assay and the seroconversion factor expressed as geometric mean ratio of HI for anti-HA antibody to H1N1 after administration of one and two 7.5 micrograms doses of Focetria was evaluated in 70 children and adolescents (9 to 17 years), 60 children (3 to 8 years), 58 children (12 to 35 months) and 49 infants (6 to 11 months). CHMP immunogenicity criteria set for adults (18 to 60 years) were met both after the first and the second dose in all the above age strata (both in the overall population and in the subset seronegative at baseline). The European medicines Agency has deferred the obligation to submit the results of studies with Foclivia in one or more subsets of the paediatric populations in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use. Foclivia has been authorised under “Exceptional Circumstances”. This means that for scientific reasons, it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMA) will review any new information which may become available every year and this SmPC will be updated as necessary.

Not applicable.

Non-clinical data obtained with Foclivia and with seasonal influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period).

Sodium chloride, Potassium chloride, Potassium dihydrogen phosphate, Disodium phosphate dihydrate, Magnesium chloride hexahydrate, Calcium chloride dihydrate, Water for injections. For the adjuvant, see section 2.

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

1 year.

Store in a refrigerator (2°C - 8°C). Do not freeze. Discard if the vaccine has been frozen. Store in the original package in order to protect from light.

0.5 ml in single-dose vial (type I glass) with stopper (halo-butyl rubber). Packs of 10. Not all pack sizes may be marketed.

Gently shake before use. After shaking, the normal appearance of Foclivia is a milky-white suspension. Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded. Any unused vaccine or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

spc-doc_PLGB 47991-0010.pdf

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