Focetria - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Focetria suspension for injection in pre-filled syringe

Influenza vaccine H1N1v (surface antigen, inactivated, adjuvanted)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

A/California/07/2009 (H1N1)-derived strain used NYMC X-181 7.5 micrograms** per 0.5 ml dose

• * propagated in eggs

• * * expressed in microgram haemagglutinin.

Adjuvant MF59C.1 containing:

squalene

polysorbate 80 sorbitan trioleate

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 caused by A (H1N1v) 2009 virus (see section 4.4).

Focetria should be used in accordance with Official Guidance.

4.2 Posology and method of administration

The dose recommendations take into account the safety and immunogenicity data from clinical studies

Posology

Adults (18–60 years):

One dose of 0.5 ml at an elected date.

Immunogenicity data obtained at three weeks after one dose of Focetria H1N1v suggest that a single dose may be sufficient.

If a second dose is administered there should be an interval of at least three weeks between the first and second dose.

Elderly (>60 years):

One dose of 0.5 ml at an elected date.

A second dose of vaccine should be given after an interval of at least three weeks. Paediatric population

Children and adolescents aged 3–17 years:

One dose of 0.5 ml at an elected date.

Immunogenicity data obtained at three weeks after one dose of Focetria H1N1v suggest that a single dose may be sufficient. If a second dose is administered there should be an interval of at least three weeks between the first and second dose.

Children aged 6 months to 35 months :

One dose of 0.5 ml at an elected date.

There is a further immune response to a second dose of 0.5 ml administered after an interval of three weeks.

Children aged less than 6 months:

No data are available in children aged less than 6 months (see sections 4.8 and 5.1).

Vaccination is not currently recommended in this age group.

It is recommended that subjects who receive a first dose of Focetria, should complete the vaccination course with Focetria H1N1v (see section 4.4).

The use of a second dose should take into consideration the information provided in

sections 4.4, 4.8 and 5.1.

Method of administration

Immunisation should be carried out by intramuscular injection preferably 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 (egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethy­lammonium bromide (CTAB)) of this vaccine.

See section 4.4 for special warnings and s

4.4 Special warnings and precautions for use

The vaccine can only be expected to protect against influenza caused by A/California/07/2009 (H1N1)v-like strains.

Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients and to residues (eggs and chicken protein, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethy­lammonium bromide (CTAB)).

ectable vaccines, appropriate medical treatment and supervision should always be le in case of a rare anaphylactic event following the administration of the vaccine.

Immunisation should be postponed in patients with severe febrile illness or acute infection.

Focetria should under no circumstances be administered intravascularly.

There are no data with Focetria using the subcutaneous route. Therefore, 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 bleedings.

Cases of convulsion with and without fever have been reported in subjects vaccinated with Focetria. 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).

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

A protective response may not be elicited in all vaccinees (see section 5.1).

In the event that a second dose is to be administered it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of Focetria with other H1N1v vaccines.

4.5 Interaction with other medicinal products and other forms of interaction

Focetria H1N1v may be co-administered with a non adjuvanted seasonal influenza vaccine. Data on co-administration of Focetria H1N1v with a non-adjuvanted seasonal influenza subunit vaccine in healthy adults aged 18–60 years of age did not suggest any interference in the immune response to Focetria. The immune response to the seasonal antigens was satisfactory.

Co-administration was not associated with higher rates of local or systemic reactions compared to administration of Focetria alone.

The same study demonstrated that previous administration of adjuvanted or unadjuvanted seasonal influenza vaccines to adults and elderly does not interfere with the immune response to Focetria. Therefore the data indicate that Focetria may be co-administered with non adjuvanted seasonal influenza vaccines (with injections made into opposite limbs).

There are no data on co-administration of Focetria with other 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.

Following influenza vaccination, false positive serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western Blot method is negative. These transitory false positive results may be due to IgM production in response to the vaccine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Safety data are available in pregnant women exposed to Focetria in particular during second and third trimesters. Postmarketing spontaneously reported adverse events, an interventional study and large observational studies do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy. Further, data from vaccinations with seasonal interpandemic inactivated trivalent vaccines in pregnant women do not indicate that adverse foetal and maternal outcomes were attributable to the vaccine. Health care providers need to assess the benefits and potential risks of administering Focetria vaccine to pregnant women, taking into consideration official recommendations.

Breast-feeding

Focetria may be administered to lactating women.

Fertility

An animal study with H5N1 mock-up vaccine did not indicate reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

• • Clinical trials

Adverse reactions reported are listed according to the following frequency:

Very common (>1/10),

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100),

Rare (>1/10,000 to <1/1,000),

Very rare (<1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

Adult and Elderly

In a clinical trial 131 adults and 123 elderly were exposed to two doses of the 7.5 ^g Focetria.

The safety profile of Focetria was similar to that of the H5N1 mock up vaccines. Most of the reactions were mild in nature and of short duration. The incidence of symptoms observed in subjects over 60 years of age was generally lower as compared to the 18–60 years old population.

Very common: pain, induration and erythema, myalgia, headache, sweating, malaise and fatigue

In clinical trials with different formulations (H5N3, H9N2 and H5N1) approximately 3400 subjects were exposed to the mock-up vaccines.

Most of the reactions were mild in nature, of short duration and qualitatively similar to those induced by conventional seasonal influenza vaccines. It is widely accepted that the adjuvant effect leading to increased immunogenicity is associated with a slightly higher frequency of local reactions (mostly mild pain) compared with conventional, nonadjuvanted influenza vaccines. There were fewer reactions after the second vaccination compared with the first.

Adverse reactions from clinical trials with the mock-up vaccine are listed below.

The incidence of symptoms observed in subjects over 60 years of age was lower as compared to the 18–60 years old population.

Nervous system disorders

Very common: he Rare: convulsions

Muscoskeletal, connective tissue and bone disorders

Very common: myalgia

Common: arthralgia

Gastrointestinal disorders

Common: nausea

General disorders and administration site conditions

Very common: injection site swelling, injection site pain, injection site induration, injection site redness, fatigue, malaise and shivering

Common: injection site ecchymosis and fever

Uncommon: influenza like illness

Rare: anaphylaxis

The common reactions usually disappear within 1–2 days without treatment.

Paediatric population

Children and adolescents 6 months to 17 years of age

Clinical trials with Focetria H1N1v

Safety data after the first and second dose in children and adolescents suggest a comparable safety profile with that reported for the H5N1 mock-up vaccine formulation.

Adverse reactions in the week following vaccination from 87 children 3–8 years old and 95 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=87		N=85
Any adverse reaction	67%		61% \
Local	56%		49% or
Systemic	32%		31%
Fever > 38°C to 38.9°C	3%		1%
Fever 39°C to 39.9°C	0%		r1%
Fever > 40° C	0%		0%
Any other AE	13%		15%
Adolescents (9 to 17 years of age)	N=95		xjXZ N=94
Any adverse reaction	67%        ,		O 55%
Local	60%		49%
Systemic	38%		26%
Fever >38°C to 38.9°C	2% y	>9)	1%
Fever 39°C to 39.9°C	0%		0%
Fever> 40° C	0% '		0%
Any other AE	11%		9%

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:

, myalgia, headache and fatigue.

Adverse reactions in the week following vaccination from 80 infants 6–11 months old and 82 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=80	N=75
Any adverse reaction	79%	65%
Local a. (&	44%	29%
Systemic^	69%	55%
Fever >38°C to 38.9°C	9%	6%
Fever 39°C to 39.9°C	2%	4%
Fever> 40° C	0%	0%
Any other AE	29%	28%
Toddlers (12 to 35 months of age)	N=82	N=81
Any adverse reaction	70%	70%
Local	50%	48%
Systemic	55%	44%
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%	22%

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 233 infants and toddlers 6 to 35 months of age:

Tenderness, erythema, irritability, unusual crying, sleepiness, diarrhoea and change in eating habits.

Induration was a common reaction in toddlers but was less common in infants.

• • Post-marketing surveillance

Focetria H1N1v

In addition to the adverse reactions reported in the clinical trials, the following have been reported during post-marketing experience with Focetria H1N1v:

Blood and lymphatic system disorders Lymphadenopathy.

Cardiac disorders

Palpitation, tachycardia.

General disorders and administration site conditions Asthenia.

Muscoskeletal, connective tissue and bone disorders Muscular weakness, pain in extremities.

Respiratory disorders Cough.

Skin and subcutaneous tissue disorders

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

Gastrointestinal disorders

Gastrointestinal disorders such as

Nervous system disorders

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

Immune system disorders

Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases

om Post-marketing surveillance with seasonal trivalent vaccines in all age groups and with the MF59 adjuvanted seasonal trivalent vaccine with the similar composition of Focetria (surface antigen, inactivated, adjuvanted with MF59C.1), licensed for use in elderly subjects above 65 years of age, the following adverse events have been reported:

Rare:

Transient thrombocytopenia.

Very rare:

Vasculitis with transient renal involvement and exudative erythema multiforme.

Neurological disorders, such as encephalomyelitis and Guillain Barré syndrome.

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vaccines. Influenza vaccine, ATC Code: J07BB02

Clinical efficacy and safety

Clinical studies with Focetria H1N1v currently provide:

• • Safety and immunogenicity data obtained after administration of one or two doses of Focetria H1N1v

to healthy children and adolescents aged 6 months-17 years and to healthy adults, including the elderly.

Clinical studies in which a version of Focetria containing HA derived from

A/Vietnam/1194/2004 (H5N1) was administered at day 1 and at day 22 provide:

• • Safety and immunogenicity data in healthy children and adolescents aged from 6 months to 17 years and in adults, including the elderly

Immune response to Focetria H1N1v

• • Studies in adults and elderly:

Immunogencity results with two doses of 7.5 ^g

trial in adults and elderly are shown below.

The seroprotection rate*, seroconversion rate* and the seroconversion factor ** for anti-HA antibody to A/H1N1v in adult and elderly subjects by HI assay after administration of 7.5 ^g of Focetria were as follows:

	Adults (18–60 years)
Anti-HA antibody	21 days after 1st dose(day 22)		21 days after 2nd dose (day 43)
	Total N=I2O	Seronegative at baseline N=46	Total N=120	Seronegative at baseline N=46
Seroprotection rate (95% CI)	96% (91–99)	98% (88–100)	100% (97–100)	100% (92–100)
GMR (95% CI)	17 (13–23)	44 (24–80)	23 (17–30)	75 (45–124)
Seroconversion or Significant Increase (95% CI)	88% (81–93)	98% (88–100)	95% (89–98)	100% (92–100)

* measured by HI assay

** geometric mean ratios of HI

	Elderly (>60 years)
Anti-HA antibody	21 days after 1st dose(day 22)		21 days after 2nd dose (day 43)
	Total N=117	Seronegative at baseline N=25	Total N=117	Seronegative at baseline N=25
Seroprotection rate (95% CI)	73% (64–80)	60% (39–79)	88% (81–93)	84% (64–95)
GMR (95% CI)	4.02 (3.1–5.2)	5.48 (2.82–11)	6.85 (5.36–8.75)	18 (8.9–35)
Seroconversion or Significant Increase (95% CI)	43% (34–52)	60% (39–79)	62% (53–71)	84% (64–95)

Paediatric population

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H1N1v in children and adolescents aged 9–17 years by HI assay after administration of 7.5 ^g of Focetria were as follows:

overall GMT from 319 to 702 (N=70) and an increase in GMT from 247 to 726 in children who were seronegative at baseline (N=48).

The seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to

H1N1v in children aged 12–35 months by HI assay after administration of 7.5 ^g of Focetria were as follows:

Children 12–35 months
Anti-HA antibody	21 days after 1st dose(day 22)		21 days after 2nd dose (day 43)
	Total N=66	Seronegative at baseline N=45	Total N=66	Seronegative at baseline N=45
Seroprotection rate (95% CI)	100% (95–100)	100% (92–100)	100% (95–100)	100% (92–100)
GMR (95% CI)	33 (21–51)	48 (29–79)	93 (54–159)	145 (88–238)
Seroconversion or Significant Increase (95% CI)	100% (95–100)	100% (92–100)	100% (95–100)	100% (92–100)

* measured by HI assay

** geometric mean ratios of HI

Data on responses to a second dose administered after an interval of three weeks showed an increase in overall GMT from 307 to 873 (N=66) and an increase in GMT from 243 to 733 in children who were seronegative at baseline (N=45).

The seroprotection rate*, seroconversion rate* and the seroconversion fa ctor** for anti-HA antibody to H1N1v in infants aged 6–11 months by HI assay after administration of 7.5 ^g of Focetria were as follows:

Infants 6–11 months Ö
Anti-HA antibody	21 days after 1st dose(day 22)		21 days after 2nd dose (day 43)
	Total N=57	Seronegative at baseline N=37	Total N=57	Seronegative at baseline N=37
Seroprotection rate (95% CI)	100% (94–100)	100% (91–100)	100% (94–100)	100% (91–100)
GMR (95% CI)	21 (14–30) O	32 (18–55)	128 (74–221)	274 (196–383)
Seroconversion or Significant Increase (95% CI)	96% (88–100)	100% (91–100)	98% (91–100)	100% (91–100)

* measured by HI assay

** geometric mean ratios of HI

econd dose administered after an interval of three weeks showed an increase in to 1700 (N=57) and an increase in GMT from 162 to 1399 in children who t baseline (N=37).

Additional information is available from the studies conducted with a vaccine similar in composition to Focetria but containing antigen derived from H5N1 viruses. Please consult the Product Information of:

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

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data obtained with the mock-up vaccine (MF59C.1-adjuvanted H5N1 vaccine) and with seasonal vaccine containing MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of efficacy, repeated dose toxicity, and reproductive and developmental toxicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.6 Special precautions for disposal and other handling

7. MARKETING AUTHORISATION HOLDER

Novartis Vaccines and Diagnostics S.r.l. – Via Fiorentina, 1 – Siena, Italy.

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/385/001

EU/1/07/385/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12 August 2010