Foclivia - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Foclivia suspension for injection in pre-filled syringe

Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:

A/Vietnam/1194/2004 (H5N1) per 0.5 ml dose propagated in fertilised hens’ eggs from healthy chicken flocks expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

Squalene

Polysorbate 80

Sorbitan trioleate

Sodium citrate

Citric acid

This vaccine complies with the WHO recommendations and EU decision for the pandemic.

Excipient with known effect :

The vaccine contains 1.899 milligrams of sodium and 0.081 milligrams of potassium per 0.5 ml dose.

Foclivia may contain trace residues of egg and chicken proteins, ovalbumin, kanamycin sulphate, neomycin sulphate, formaldehyde and cetyltrimethy­lammonium bromide which are used during the manufacturing process (see section 4.3).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Suspension for injection in pre-filled syringe.

Milky-white liquid.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation.

Foclivia should be used in accordance with Official Guidance.

4.2 Posology and method of administration

Posology

Adults and elderly (18 years of age and above): 0.5 ml at an elected date.

A second dose of vaccine should be given after an interval of at least 3 weeks.

Foclivia was evaluated in adults (aged 18 to 60 years old) and elderly (over 60 years old) following a 1, 22 day primary vaccination schedule.

Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1).

Paediatric population

The safety and efficacy of Foclivia in subjects under 18 years of age have not yet been established. Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.

No data are available in children aged less than 6 months.

Method of administration

Immunisation should be carried out by intramuscular injection into the deltoid muscle or anterolateral thigh (depending on the muscle mass).

4.3 Contraindications

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 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.

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.

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 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.

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. In addition, antibody responses in patients with endogenous or iatrogenic immunosuppression may be insufficient to provide protection.

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).

Since a second dose is recommended, it should be noted that 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

4.6 Fertility, pregnancy and lactation

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. Male fertility has not been assessed in animals (see section 5.3).

4.7 Effects on ability to drive and use machines

Some of the effects mentioned under section 4.8 may affect the ability to drive or use machines.

4.8 Undesirable effects

Summary of safety profile

• • Clinical trials

Adverse reactions from clinical trial in adults and elderly (above 18 years old)

The incidence of adverse reactions has been evaluated in seven clinical trials in healthy subjects involving over 4300 adults and elderly receiving H5N1 vaccine combined with MF59C.1 adjuvant (at least 7.5 ^g haemagglutinin, HA) containing either the A/turkey/Turke­y/1/2005 or the A/Vietnam/1194/2004 strain. There were 3872 subjects 18–60 years of age, 365 subjects 61–70 years of age, and 89 subjects greater than 70 years of age. The safety profile across clinical trials using H5N1 vaccine containing either the A/turkey/Turke­y/1/2005 or the A/Vietnam/1194/2004 strain is comparable (see section 5.1). Clinical trials in 80 subjects receiving adjuvanted vaccine with an H5N3 or an H9N2 strain showed a similar safety profile.

Across all trials, there was a general trend towards decreased reports of solicited local adverse reactions after the second vaccination compared with the first.

Irrespective of antigen dose, almost all solicited systemic adverse reactions were reported on the day of vaccination (day 1) or during the 3 days immediately following.

Data on safety of a booster dose are limited to three trials performed with H5N1 MF59C.1 adjuvanted vaccine containing A/Vietnam/1194/2004 (V87P1, V87P2) or A/turkey/Turke­y/1/2005 (V87P1E1) that included 116 adults (18–60 years) and 56 elderly subjects (>61 years). No increase in solicited adverse reactions was reported when a booster dose was administered 6 or 18 months after the initial dosing series. A slight increase in solicited adverse reactions in adults was reported when a booster dose was administered 18 months after the initial dosing series. In the elderly, the reported solicited adverse reactions increased with the third booster dose only when compared with the second dose.

Tabulated list of adverse reactions

The adverse reaction rates reported after any vaccination dose (i.e. 1st, 2nd or booster) were similar and 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)	Rare (>1/10,000 to <1/1,000)
Nervous system disorders	Headache
Gastrointestinal disorders		Nausea
Skin and subcutaneous tissue disorders		Sweating
Musculoskeletal and connective tissue disorders	Myalgia	Arthralgia

General disorders and administration site conditions

Injection site swelling, Injection site pain, Injection site induration, Injection site redness, Fatigue, Chills, Malaise

Injection site ecchymosis, Fever

Anaphylaxis

The majority of these reactions usually disappear within 1–2 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.

	H5N1 MF59C.1 adjuvanted A/turkey/Turke­y/1/2005 vaccine
	Study V87 25				Study V87 26
	Medical conditions		Healthy		Immunocompromi sed		Healthy
	Adults (20–60 years)	Elderly (61–84 years)	Adults (19–60 years)	Elderly (61–79 years)	Adults (20–60 years)	Elderly (61–84 years)	Adults (18–59 years)	Elderly (61–91 years)
No. of subjects	N=145	N=149	N=59	N=58	N=147	N=148	N=58	N=62

*actual age range of population enrolled

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 through 60 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).

Adverse reactions from clinical trial in children aged 6 months to 17 years

A clinical trial (Study V87P6) was conducted with a H5N1 A/Vietnam/1194/2004 vaccine combined with MF59C.1 adjuvant (N=334) vs seasonal influenza vaccine (N=137).

Regardless of age, reactogencity was higher after the first dose than after the second vaccination. Reactogenicity after the third dose, administered 12 months following the second dose, was higher than after both first and second doses. The percentages of subjects reporting local adverse reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers, erythema and tenderness were the most frequently reported solicited local adverse reactions; irritability and unusual crying were the most frequently reported solicited systemic adverse reactions. In children and adolescents, pain was the most frequently reported solicited local adverse reaction, and fatigue and headache were the most frequently reported solicited systemic adverse reactions. Across all ages, the frequency of fever after any dose was not more than 6%.

	Study V87P6 H5N1 MF59C.1 adjuvanted A/Vietnam/1		194/2004 vaccine
	First dose	Second dose (21 days after first dose)	Third dose (12 months after second dose)
Toddlers (6 to 35 months)	N=145	N=138	N=124
Any	76%	68%	80%
Local	47%	46%	60%
Systemic	59%	51%	54%
Fever > 38°C (> 40°C)	0%	0%	0%
Any Other Adverse Event	54%	49%	35%
Children (3 to 8 years)	N=96	N=93	N=85
Any	72%	68%	79%
Local	66%	58%	74%
Systemic	32%	33%	45%
Fever > 38°C (> 40°C)	4%	2%	6%
Any Other Adverse Event	36%	31%	19%
Adolescents(9 to 17 years)	N=93	N=91	N=83
Any	91%	82%	89%
Local	81%	70%	81%
Systemic	69%	52%	69%
Fever > 38°C (> 40°C)	0%	1%	2%
Any Other Adverse Event	30%	27%	22%

Focetria (an MF59.1 adjuvanted H1N1 pandemic vaccine similar to Foclivia).

Adverse reactions in the week following vaccination with Focetria H1N1v from 77 children 3–8 years old and 80 children and adolescents 9–17 years old receiving the 7.5 ^g formulation were reported as follows:

	Injection 1	Injection 2
Children (3 to 8 years of age)	N= 77	N= 75
Any adverse reaction	74%	69%
Local	62%	56%
Systemic	39%	35%
Fever > 38°C to 38.9°C	4%	1%
Fever 39°C to 39.9°C	0%	1%
Fever > 40° C	0%	0%
Any other AE	14%	17%
Adolescents (9 to 17 years of age)	N= 80	N= 79
Any adverse reaction	79%	66%
Local	70%	58%
Systemic	45%	30%
Fever > 38°C to 38.9°C	3%	1%
Fever 39°C to 39.9°C	0%	0%
Fever > 40° C	0%	0%
Any other AE	13%	10%

Data in children and adolescents 3–17 years suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in children and adolescents 3 to 17 years of age: Pain, induration and erythema, malaise, myalgia, headache and fatigue.

Adverse reactions in the week following vaccination with Focetria H1N1v from

73 infants 6–11 months old and 73 toddlers 12–35 months old, receiving the 7.5 ^g formulation were reported as follows:

	Injection 1	Injection 2
Infants (6 to 11 months of age)	N= 73	N= 68
Any adverse reaction	79%	65%
Local	44%	26%
Systemic	70%	56%
Fever > 38°C to 38.9°C	11%	9%
Fever 39°C to 39.9°C	3%	4%
Fever > 40° C	0%	0%
Any other AE	32%	31%
Toddlers (12 to 35 months of age)	N= 73	N= 71
Any adverse reaction	70%	71%
Local	51%	49%
Systemic	60%	49%
Fever > 38°C to 38.9°C	10%	11%
Fever 39°C to 39.9°C	4%	1%
Fever > 40° C	1%	0%
Any other AE	21%	24%

Data in infants and toddlers 6–35 months of age suggest a slight decrease in reactogenicity after the second dose, with no increase in rates of fever.

Very common reactions reported in 146 infants and toddlers 6 to 35 months of age:

Tenderness, erythema, irritability, unusual crying, sleepiness, diarrhoea, vomiting and change in eating habits. Induration and ecchymosis were very common reactions in toddlers but were less common in infants.

• • Post-marketing surveillance

No post-marketing surveillance data are available following Foclivia administration.

The following adverse events were reported from post-marketing surveillance with Focetria (an H1N1 pandemic vaccine similar to Foclivia) which contains the same amount of adjuvant MF59C.1 as Foclivia, approved for use in children 6 months of age and above, adults and the elderly:

Blood and lymphatic system disorders

Lymphadenopathy.

Immune system disorders

Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock, angioedema.

Nervous system disorders

Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.

Cardiac disorders

Palpitation, tachycardia.

Respiratory disorders

Cough.

Gastrointestinal disorders

Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.

Skin and subcutaneous tissue disorders

Generalised skin reactions including pruritus, urticaria or non-specific rash.

Musculoskeletal, connective tissue and bone 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 national reporting system listed in Appendix V

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 ^g

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 ^g 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 ^g 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)

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 >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

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/1194/2004 booster after 2nd dose	Study V87P2 Adults A/Vietnam/1194/2004 booster after 2nd dose	Study V87P1 Elderly A/Vietnam/1194/2004 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 factor (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 pg 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 pg 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 pg 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 pg 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 2nd 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
SR H	Seroprotectio n rate (95%CI)	70% (58–80)	65% (52–77)	90% (73–98)	59% (52–66)
	Seroconversio n rate (95%CI)	NAI	65% (52–77)	86% (68–96)	49% (42–56)
	Seroconversio n factor(95%CI)	NAI	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
HI	Seroprotectio n rate (95%CI)°	36% (25–49)	28% (17–41)	24% (10–44)	23% (18–30)
	Seroconversio n rate (95%CI)°	NAI	28% (17–41)	21% (8–40)	19% (14–25)
	Seroconversio n factor (95%CI)°°	NAI	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

I 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 2nd 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
SRH	Seroprotection rate (95%CI)	57% (39–73)	20% (18–23)
	Seroconversion rate (95%CI)	NA	48% (41–55)

	Seroconversion factor (95%CI)	NA	1.74 (1.57–1.94)
		N=36	N=208
HI	Seroprotection rate (95%CI)°	36% (21–54)	25% (19–32)
	Seroconversion rate (95%CI)°	NA	19% (14–25)
	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 2nd 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=186		V87P11 Elderly (>61–89 years)a N=142
		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 6–8 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 18–65 years primed 6–8 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 2nd 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 2nd 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 2nd dose were as follows:

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
Geometrie 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)	Immunocompromised N=143	Healthy N=57	Immunocompromised N=139	Healthy N=62
Geometrie 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)

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 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).

Available data in paediatric populations

A clinical trial (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 pg were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6–35 months, 3–8 years and 9–17 years) achieved high levels of antibodies to A/Vietnam/1194/2004 as evaluated with SRH and HI assays as presented in table below. In this trial no vaccine related SAEs were observed.

		Toddlers (6 to 35 months)	Children (3 to 8 years)	Adolescents (9 to 17 years)
		N=134	N=91	N=89
HI	Seroprotection 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)
	Seroconversion rate (95% CI) Day 43	97% (92–99)	97% (91–99)	89% (80–94)
SRH		N=133	N=91	N=90
	Seroprotection rate (95% CI) Day 43	100% (97–100)	100% (96–100)	100% (96–100)
	Seroconversion factor (95% CI) Day 43 to Day 1	16 (14–18)	15 (13–17)	14 (12–16)
	Seroconversion rate (95% CI) Day 43	98% (95–100)	100% (96–100)	99% (94–100)

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).

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 ^g doses of Focetria was evaluated in 70 children and adolescents (9–17 years), 60 children (3–8 years), 58 children (12–35 months) and 49 infants (6–11 months). CHMP immunogenicity criteria set for adults (18–60 years) were met both after the 1st and the 2nd 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.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

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).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

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.

6.2 Incompatibilities

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

6.3 Shelf life

1 year.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

0.5 ml in pre-filled syringe (type I glass) with plunger-stopper (bromo-butyl rubber). Packs of 1 and 10 with or without needle. Syringes without needle are fitted with a Luer Lock system.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

When using a pre-filled syringe without needle supplied with a Luer Lock system, remove the tip cap by unscrewing it in a counter-clockwise direction. Once the tip cap is removed, attach a needle to the syringe by screwing it on in a clockwise direction until it locks. Once the needle is locked in place, remove the needle protector and administer the vaccine.

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

7. MARKETING AUTHORISATION HOLDER

Seqirus S.r.l.

Via del Pozzo 3/A, S. Martino

53035 Monteriggioni (SI)

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/577/001–002

EU/1/09/577/005–006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 October 2009

Date of latest renewal: 19 October 2014