Pandemic influenza vaccine H5N1 AstraZeneca (previously Pandemic influenza vaccine H5N1 Medimmune) - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Pandemic influenza vaccine H5N1 AstraZeneca nasal spray, suspension

Pandemic influenza vaccine (H5N1) (live attenuated, nasal)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

• 1 dose (0.2 ml) contains:

Reassortant influenza virus* (live attenuated) of the following strain**:

A/Vietnam/1203/2004 (H5N1) strain

(A/Vietnam/1203/200­4, MEDI 0141000136)     107.0±0.5 FFU***

• * propagated in fertilised hens’ eggs from healthy chicken flocks.

• * * produced in VERO cells by reverse genetic technology. This product contains a genetically modified organism (GMO).

• * ** fluorescent focus units

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

The vaccine may contain residues of the following substances: egg proteins (e.g. ovalbumin) and gentamicin. The maximum amount of ovalbumin is less than 0.024 micrograms per 0.2 ml dose (0.12 micrograms per ml).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, suspension

The suspension is colourless to pale yellow, clear to opalescent with a pH of approximately 7.2. Small white particles may be present.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Prophylaxis of influenza in an officially declared pandemic situation in children and adolescents from 12 months to less than 18 years of age.

Pandemic influenza vaccine H5N1 AstraZeneca should be used in accordance with official guidance.

4.2 Posology and method of administration

Posology

Children and adolescents from 12 months to less than 18 years of age

0.2 ml (administered as 0.1 ml per nostril).

Two doses are recommended for all children and adolescents. The second dose should be administered after an interval of at least 4 weeks.

Children less than 12 months

Pandemic influenza vaccine H5N1 AstraZeneca should not be used in infants below 12 months of age because of safety concerns regarding increased rates of hospitalisation and wheezing in this population (see section 4.8).

Method of administration

Immunisation must be carried out by nasal administration.

Do not inject Pandemic influenza vaccine H5N1 AstraZeneca.

Pandemic influenza vaccine H5N1 AstraZeneca is administered as a divided dose in both nostrils. After administering half of the dose in one nostril, administer the other half of the dose in the other nostril immediately or shortly thereafter. The patient can breathe normally while the vaccine is being administered – there is no need to actively inhale or sniff.

See section 6.6 for administration instructions.

4.3 Contraindications

History of an anaphylactic (i.e. life-threatening) reaction to the active substance or to any of the excipients listed in section 6.1 (e.g. gelatin), or to gentamicin (a possible trace residue), to eggs or to egg proteins (e.g. ovalbumin). However, in a pandemic situation, it may be appropriate to give the vaccine, provided that facilities for resuscitation are immediately available in case of need.

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 administering this vaccine to individuals with a known hypersensitivity (other than anaphylactic reaction) to the active substance, or to any of the excipients listed in section 6.1, or to trace residues (gentamicin, eggs or egg proteins, ovalbumin). Appropriate medical treatment and supervision should always be readily available in case ofan anaphylactic event or hypersensitivity event following administration of the vaccine.

There are no data with Pandemic influenza vaccine H5N1 AstraZeneca in children and adolescents younger than 18 years of age receiving salicylate therapy. Due to the association of Reye’s syndrome with salicylates and wild-type influenza infection, healthcare providers should assess the potential risks of administering the vaccine with the potential benefits in a pandemic situation (see section 4.5).

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

No data are available for individuals with significant clinical immunodeficiency. In a pandemic situation, healthcare providers need to assess the potential benefits, alternatives, and risks of administering the vaccine to children and adolescents with significant clinical immunodeficiency due to conditions or immunosuppressive therapy such as: acute and chronic leukaemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high-dose corticosteroids.

The safety of seasonal live attenuated influenza vaccine (LAIV) in children with severe asthma and active wheezing has not been adequately studied. Healthcare providers need to assess the benefits and potential risks of administering Pandemic influenza vaccine H5N1 AstraZeneca to these individuals.

In a study with the seasonal trivalent live attenuated influenza vaccine (T/LAIV), an increased incidence of medically significant wheezing was seen in children 12–23 months of age (see section 4.8).

Vaccine recipients should be informed that Pandemic influenza vaccine H5N1 AstraZeneca is an attenuated live virus vaccine and has the potential for transmission to immunocompromised contacts. Vaccine recipients should attempt to avoid, whenever possible, close association with severely immunocompromised individuals (e.g. bone marrow transplant recipients requiring isolation) for 1–2 weeks following vaccination. Shedding of the H5N1 vaccine virus in adults was extremely limited. Peak incidence of vaccine virus recovery occurred 1–2 days post-vaccination in clinical studies with Pandemic influenza vaccine H5N1 AstraZeneca. In circumstances where contact with severely immunocompromised individuals is unavoidable, the potential risk of transmission of the influenza vaccine virus should be weighed against the risk of acquiring and transmitting wild-type influenza virus.

Vaccine recipients under treatment with influenza antiviral agents should not receive Pandemic influenza vaccine H5N1 AstraZeneca until 48 hours after the cessation of influenza antiviral therapy.

No data exist regarding the safety of intranasal administration of Pandemic influenza vaccine H5N1 AstraZeneca in children with unrepaired craniofacial malformations.

4.5 Interaction with other medicinal products and other forms of interaction

Children and adolescents under 18 years of age receiving salicylate therapy should avoid vaccination with Pandemic influenza vaccine H5N1 AstraZeneca (see section 4.4). Use of salicylates in children and adolescents for 4 weeks after vaccination should be avoided unless medically indicated as Reye’s syndrome has been reported following the use of salicylates during wild-type influenza infection.

The co-administration of Pandemic influenza vaccine H5N1 AstraZeneca with inactivated vaccines or with the seasonal vaccine Fluenz Tetra has not been studied.

Data regarding co-administration of the seasonal trivalent influenza vaccine live, intranasal (T/LAIV) with live attenuated vaccines (measles, mumps, and rubella vaccine (MMR), varicella vaccine, and orally-administered poliovirus) are available and suggest that concomitant admininstration of Pandemic influenza vaccine H5N1 AstraZeneca with these live vaccines may be acceptable.

Based upon the potential for influenza antiviral agents to reduce the effectiveness of Pandemic influenza vaccine H5N1 AstraZeneca, it is recommended not to administer the vaccine until 48 hours after the cessation of influenza antiviral therapy. Administration of influenza antiviral agents within two weeks of vaccination may affect the response of the vaccine.

If influenza antiviral agents and Pandemic influenza vaccine H5N1 AstraZeneca are administered concomitantly, timing and the need for revaccination should be considered based on clinical judgement.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data available on the use of Pandemic influenza vaccine H5N1 AstraZeneca in pregnant women.

There are a moderate amount of data from the use of T/LAIV and the seasonal Fluenz Tetra vaccine in pregnant women. There was no evidence of significant maternal adverse outcomes in 138 pregnant women who had a record of receiving the seasonal T/LAIV vaccine in a US-based health insurance claims database.

In more than 300 case reports in the AstraZeneca safety database of vaccine administration in pregnant women, no unusual patterns of pregnancy complications or foetal outcomes were observed.

Similarly from the VAERS, in 113 reports of pregnant women who had received AstraZeneca’s (H1N1) 2009 Monovalent Vaccine Live, Intranasal, no unusual patterns of pregnancy complications or foetal outcomes were observed.

Animal developmental toxicity studies conducted with T/LAIV and Fluenz Tetra do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Post-marketing data from occasional inadvertent gestational use of the seasonal vaccines offer some reassurance.

Healthcare providers need to assess the benefit and potential risks of administering Pandemic influenza vaccine H5N1 AstraZeneca to pregnant women.

Breast-feeding

It is not known whether Pandemic influenza vaccine H5N1 AstraZeneca is excreted in human milk. Therefore, as some viruses are excreted in human milk, the vaccine should not be used during breastfeeding.

Fertility

No data exist regarding the possible effects of Pandemic influenza vaccine H5N1 AstraZeneca on male and female fertility.

4.7 Effects on ability to drive and use machines

Pandemic influenza vaccine H5N1 AstraZeneca has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The assessment of the safety profile for Pandemic influenza vaccine H5N1 AstraZeneca is based on a limited number of adult subjects.

In clinical studies, the safety profile of Pandemic influenza vaccine H5N1 AstraZeneca was comparable to the safety profile of the seasonal vaccines T/LAIV and Fluenz Tetra (see section 5.1 for more information).

Clinical studies have evaluated the incidence of adverse reactions in 59 adults from 18 to 49 years of age receiving at least one dose of Pandemic influenza vaccine H5N1 AstraZeneca. Additional data are provided from 289 adults enrolled in studies of vaccine candidates for an additional 7 influenza subtypes and from 240 adults and 259 children enrolled in studies of the monovalent 2009 H1N1 pandemic vaccine.

The most common adverse reactions observed in clinical studies conducted with the Pandemic influenza vaccine H5N1 AstraZeneca in healthy adults was headache (25.4%) and upper respiratory infection (10.2%).

Paediatric population

List of adverse reactions

From clinical studies and post-marketing surveillance with T/LAIV and Fluenz Tetra in over 110,000 children and adolescents 2 to 17 years of age, the following adverse reaction frequencies are reported: 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)

Immune system disorders

Uncommon: Hypersensitivity reactions (including facial oedema, urticaria and very rare anaphylactic reactions)

Metabolism and nutrition disorders

Very common: Decreased appetite

Nervous system disorders

Common: Headache

Respiratory, thoracic and mediastinal disorders

Very common: Nasal congestion/rhi­norrhoea

Uncommon: Epistaxis

Skin and subcutaneous tissue disorders

Uncommon: Rash

Musculoskeletal and connective tissue disorders

Common: Myalgia

General disorders and administration site conditions

Very common: Malaise

Common: Pyrexia

Description of selected adverse reactions

Children less than 12 months of age

Pandemic influenza vaccine H5N1 AstraZeneca is not indicated for use in infants younger than 12 months of age (see section 4.2). The safety and efficacy of the vaccine in this population has not been established. No data are available.

In an active-controlled clinical study (MI-CP111) conducted with T/LAIV in comparison to the injectable influenza trivalent vaccine, an increased rate of hospitalisations (for any cause) through 180 days after final vaccination dose was observed in infants 6–11 months of age (6.1% T/LAIV versus 2.6% injectable influenza vaccine). Most hospitalisations were due to gastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. The rate of hospitalisations was not increased in T/LAIV recipients 12 months and older and the rates for infants and toddlers 12–23 months of age were 3.2% T/LAIV versus 3.5% injectable influenza vaccine.

Wheezing in children below 24 months of age

In the same study, an increased rate of wheezing through 42 days was observed in infants and toddlers 6–23 months of age (5.9% T/LAIV versus 3.8% injectable influenza vaccine). Corresponding rates for infants and toddlers 12–23 months of age were 5.4% and 3.6% for T/LAIV and injectable influenza vaccine, respectively. A total of 20 subjects (12 T/LAIV, 0.3%; 8 injectable influenza vaccine, 0.2%) were hospitalised in association with medically significant wheezing. No deaths resulted from these events, and none of the hospitalised children required mechanical ventilation or admission to an intensive care unit. The rate of wheezing was not increased in T/LAIV recipients 24 months of age and older.

Chronic conditions

Although safety in children and adolescents with mild to moderate asthma has been established for T/LAIV, data in children with other pulmonary diseases or with chronic cardiovascular, metabolic or renal diseases are limited.

In a study (D153-P515) of children 6 to 17 years of age with asthma (seasonal T/LAIV: n=1,114, seasonal injectable influenza vaccine: n=1,115), there were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate, asthma symptom scores, or night-time awakening scores. The incidence of wheezing within 15 days after vaccination was lower in T/LAIV recipients relative to seasonal inactivated vaccine recipients (19.5% vs. 23.8%, P=0.02).

In a study (AV010) of children and adolescents 9 to 17 years of age with moderate to severe asthma (seasonal T/LAIV: n=24, placebo: n=24), the primary safety criterion, change in percent predicted forced expiratory volume in 1 second (FEV1) measured before and after vaccination, did not differ between treatment arms.

Other special populations:

Immunocompromised

Overall, the safety profile of T/LAIV in a limited number of subjects with mildly to moderately nonHIV related compromised immune function, asymptomatic or mildly symptomatic HIV infection, or cancer (solid tumors and haematological malignancies) was comparable to that in healthy individuals and does not indicate any untoward effect. No data are available for individuals with severe immunosuppression (see section 4.4). In a pandemic situation, the use of Pandemic influenza vaccine H5N1 AstraZeneca in mildly to moderately immunosuppressed individuals may be considered after weighing the anticipated benefits against the potential risks for the individual.

Post-marketing experience with seasonal T/LAIV

Very rare reports of Guillain-Barré syndrome and exacerbation of symptoms of Leigh syndrome (mitochondrial encephalomyopathy) have also been observed.

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

Administration of a higher than recommended dose of Pandemic influenza vaccine H5N1 AstraZeneca has not been reported in the small number of subjects who received the vaccine during pre-licensure clinical studies. Based on experience with the live attenuated seasonal influenza vaccine, administration of a higher than recommended dose is expected to result in an adverse reaction profile that is comparable to that observed with the recommended dose of Pandemic influenza vaccine H5N1 AstraZeneca.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccines, influenza live attenuated; ATC Code: J07BB03

The influenza virus strain in Pandemic influenza vaccine H5N1 AstraZeneca is (a) cold-adapted (ca) ; (b) temperature-sensitive (ts) ; and © attenuated (att). The virus must infect and replicate in cells lining the nasopharynx of the vaccine recipient in order to induce protective immunity.

Clinical studies

This section describes the clinical experience observed in three pivotal studies conducted with the Pandemic influenza vaccine H5N1 AstraZeneca in adults. In addition, studies conducted with AstraZeneca’s 2009 H1­N1 pandemic LAIV and seasonal T/LAIV vaccine are also considered supportive because all these vaccines are manufactured using the same process, administered through the same route, and studied primarily in naive individuals.

Paediatric studies

H1N1 pandemic LAIV vaccine in children aged 2 to 17 years

In clinical study MI-CP217, the safety and descriptive immunogenicity of a live attenuated monovalent influenza virus vaccine (derived from A/California/7/2009) developed for the 2009 H1N1 pandemic were evaluated in a total of 326 randomised subjects (259 subjects monovalent vaccine; 65 subjects placebo) and 324 subjects received one dose of investigational product. Of these subjects, 319 received a second dose (256 subjects monovalent vaccine; 63 subjects placebo).

For children regardless of baseline serostatus, seroresponse rates after receipt of monovalent vaccine were 7.8% and 11.1% for Days 15 and 29, respectively, and 32.0% on Day 57. For placebo recipients regardless of baseline serostatus, seroresponse rate was 6.3% on Days 15 and 29 and 14.5% on Day 57. Seroresponse rates were slightly higher among subjects who were seronegative at baseline. In a surveillance study conducted by the US CDC (Griffin, et al, 2011) the effectiveness of the H1N1 pandemic LAIV vaccine in children 2 through 9 years of age was estimated at 81.9% (95% CI:13.6, 96.2).

T/LAIV efficacy

T/LAIV’s efficacy data in the paediatric population consist of 9 controlled studies comprising over 20,000 infants and toddlers, children and adolescents, conducted during 7 influenza seasons. Four placebo-controlled studies included second season revaccination. T/LAIV has demonstrated superiority in 3 active-controlled studies with injectable influenza vaccine. See Table 1 and 2 for a summary of efficacy results in the paediatric population.

Table 1 T/LAIV efficacy in placebo controlled paediatric studies

aM = months

bNumber of study participants for year 1 or year 2 primary efficacy analysis.

cReduction in culture-confirmed influenza illness relative to placebo.

dData presented for clinical trial D153-P504 are for study participants who received two doses of study vaccine or placebo. In previously unvaccinated study participants who received one dose in year 1, efficacy was 57.7% (95% CI: 44.7, 67.9) against matched strains and 56.3% (95% CI: 43.1, 66.7) against all strains regardless of match, respectively, thus supporting the need for two doses of vaccine in previously unvaccinated children.

eIn study participants who received 2 doses in year 1 and placebo in year 2, efficacy in year 2 was 56.2% (95% CI: 30.5, 72.7) against matched strains and 44.8% (95% CI: 18.2, 62.9) against all strains regardless of match, respectively, in D153-P501, thus supporting the need for second-season revaccination.

fThe primary circulating strain was antigenically dissimilar from the H3N2 strain represented in the vaccine; efficacy against the mismatched A/H3N2 strain was 85.9% (95% CI: 75.3, 91.9).

Table 2 T/LAIV relative efficacy in active-controlled paediatric studies with seasonal injectable influenza vaccine

aM = months. Y = years. Age range as described in the protocol for the study.

bReduction in culture-confirmed influenza illness relative to injectable influenza vaccine.

cT/LAIV demonstrated 55.7% (39.9, 67.6) fewer cases than injectable influenza vaccine in 3,686 infants and toddlers 6–23 months of age and 54.4% (41.8, 64.5) fewer cases in 4,166 children 24–59 months of age.

dT/LAIV demonstrated 64.4% (1.4, 88.8) fewer cases than injectable influenza vaccine in 476 infants and toddlers 6–23 months of age and 48.2% (12.7, 70.0) fewer cases in 1,609 children 24–71 months of age.

P/LAIV H5N1 vaccine

The European Medicines Agency has deferred the obligation to submit the results of studies with Pandemic influenza vaccine H5N1 AstraZeneca in one or more subsets of the paediatric population in prevention of influenza infection. See section 4.2 for information on paediatric use.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review any new information on the product every year and this SmPC will be updated as necessary.

Adult studies

Adults aged 18 to 49 years

In clinical study CIR 217, the safety, infectivity and immunogenicity of a live attenuated vaccine derived from A/Vietnam/1203/2004 (H5N1) influenza isolate were evaluated in 21 subjects who received one 106.7 median tissue culture infectious dose (TCID50), with 18 of those subjects receiving a second dose 4–8 weeks later. Twenty-one additional subjects received one dose of the vaccine virus at 107.5 TCID50, with 19 of those subjects receiving a second dose 4–8 weeks later. After 1 or 2 doses of 106.7 TCID50 vaccine, haemagglutination inhibition (HAI) and IgA seroresponses were each detected in 10% subjects, and nasal wash IgA responses were detected in 24% subjects. After 1 or 2 doses of 107.5 TCID50 vaccine, HAI and IgA seroresponses were each detected in 10% and 52% of subjects and nasal IgA responses were detected in 19% of subjects.

In clinical study CIR 239, the safety, infectivity, and immunogenicity of a live attenuated vaccine derived from A/Hong Kong/213/2003 (H5N1) influenza isolate were evaluated in 17 subjects who received one dose of 107.5 TCID50 of the vaccine intranasally in isolation, with 16 of those subjects receiving a second dose 4–8 weeks later. HAI responses were not detected in any of the subjects after either the first or second dose of the vaccine. IgA seroresponse and nasal wash response were each detected in 18% of subjects.

Adults aged 22 to 54 years

Clinical study CIR 277 assessed whether prior recipients of pandemic live attenuated influenza H5N1 vaccines were primed or established long-lasting immunity that could be detected following the subsequent administration of an inactivated H5N1 vaccine. The study enrolled 69 subjects in 5 groups: Group 1 enrolled 11 subjects who had previously received 2 doses of the A/Vietnam/1203/2004 H5N1 pandemic live attenuated influenza vaccine (P/LAIV) in 2006–2007; Group 2 enrolled 10 subjects who had previously received 2 doses of the A/Hong Kong/213/2003 H5N1 P/LAIV in 2007; Group 3 enrolled 8 subjects who had previously received 2 doses of the A/British Columbia/CN-6/2004 H7N3 P/LAIV in 2010 (as a P/LAIV control group); Groups 4 and 5 each enrolled 20 subjects who had not been previously vaccinated with LAIV and were influenza H5 naïve. Subjects in Groups 1 to 4 received a single 45-gg dose of the A/Vietnam/1203/2004 pandemic inactivated influenza vaccine (P/IIV) while subjects in Group 5 received 2 doses, approximately 28 days apart.

P/LAIV H5N1-primed subjects developed vigorous antibody responses to wild-type H5N1 virus upon subsequent exposure to the inactivated H5N1 vaccine, although such antibody responses were not detectable after the primary 2 doses in the majority of the subjects. Subjects who were primed with either the A/Vietnam/1203/2004 P/LAIV or the A/Hong Kong/213/2003 P/LAIV had a significantly better response to a single dose of inactivated H5N1 vaccine than P/LAIV-naïve subjects. The antibody response in A/Vietnam/1203/2004 P/LAIV-primed subjects also exceeded that observed after 2 doses of inactivated vaccine in P/LAIV-naïve subjects (see Table 3).

Table 3 Serum microneutralization (MN) and haemagglutination inhibition (HAI) assay antibody responses on Days 28 and 56 following administration of an inactivated H5N1 vaccine

Data for Group 3, subjects initially vaccinated with an H7N3 P/LAIV are not shown.

aDays are counted relative to the only P/IIV dose for Groups 1–4 and after the first of 2 P/IIV doses for Group 5.

bSerological response defined as a >4-fold rise in antibody titer (>1:20).

cSerum samples were available from 7 subjects in Group 3 on Day 28 and from 18 subjects in Group 5 on Day 56.

Antibody response developed rapidly in P/LAIV H5N1-primed subjects. Seven of 11 (64%) subjects in Group 1 (ca A/Vietnam/1204/2004 [H5N1]) had >4-fold rises in HAI antibody titer by Day 7 following receipt of the inactivated vaccine, with a geometric mean titer (GMT) of 165 and a titer range of 20 to 1280 in responders. Of the P/LAIV-naive subjects, only 10% had >4-fold rises by Day 7. Antibody responses in P/LAIV H5N1-primed subjects were also broader. H5N1 P/LAIV-primed subjects developed antibody responses that neutralised 2 or more clades of H5N1 viruses from the A/Goose/Guangdon­g/1996 H5N1 lineage, whereas few subjects even in the 2-dose inactivated H5N1 vaccine group developed cross-clade neutralising antibodies. The affinity of antibodies against the HA1 domain of the H5 HA in the H5N1 P/LAIV-primed groups was significantly higher than the 2-dose inactivated vaccine group, which correlated with cross-clade H5N1 neutralisation.

Similar responses were seen with P/LAIV H7N7– and H7N9-primed subjects who developed vigorous antibody responses to the corresponding wild-type viruses upon subsequent exposure to the inactivated vaccine from the same subtype. For the H7N7 P/LAIV, strong serum antibody responses were detected by both MN and HAI in 9 of 13 individuals, with peak titers achieved by Day 14. For the H7N9 P/LAIV, 8 of 14 individuals who received a single dose of vaccine and 13 of 16 individuals who received two doses of vaccine developed strong antibody responses; peak titers were again seen by Day 14.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data with the Pandemic influenza vaccine H5N1 AstraZeneca, and the seasonal vaccines T/LAIV and Fluenz Tetra reveal no special hazard for humans based on conventional non-clinical studies of repeated dose toxicity, reproduction and developmental toxicity, local tolerance, and neurovirulence.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sucrose

Dipotassium phosphate

Potassium dihydrogen phosphate

Gelatin (porcine, Type A)

Arginine hydrochloride

Monosodium glutamate monohydrate

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

18 weeks.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Keep the nasal applicator in the outer carton in order to protect from light.

Before use, the vaccine may be taken out of the refrigerator once for a maximum period of 12 hours at a temperature not above 25°C. Stability data indicate that the vaccine components are stable for 12 hours when stored at temperatures from 8°C to 25°C. At the end of this period, Pandemic influenza vaccine H5N1 AstraZeneca should be used immediately or discarded.

6.5 Nature and contents of container

Pandemic influenza vaccine H5N1 AstraZeneca is supplied as a 0.2 ml suspension in a single-use nasal applicator (Type 1 glass), with nozzle (polypropylene with polyethylene transfer valve), nozzle tip-protector cap (synthetic rubber), plunger rod, plunger-stopper (butyl rubber), and a dose-divider clip.

Pack size of 10.

6.6 Special precautions for disposal and other handling

Administration

Pandemic influenza vaccine H5N1 AstraZeneca IS FOR NASAL USE ONLY.

• • DO NOT USE WITH A NEEDLE. Do not inject.
• • Do not use Pandemic influenza vaccine H5N1 AstraZeneca if the expiry date has passed or if

the sprayer appears damaged, for example, if the plunger is loose or displaced from the sprayer or if there are any signs of leakage.

• • Check the appearance of the vaccine before administration. The suspension should be colourless

to pale yellow, clear to opalescent. Small white particles may be present.

• • Pandemic influenza vaccine H5N1 AstraZeneca is administered as a divided dose in both

nostrils.

• • After administering half of the dose in one nostril, administer the other half of the dose in the

other nostril immediately or shortly thereafter.

• • The patient can breathe normally while the vaccine is being administered – there is no need

to actively inhale or sniff.

• • Refer to the Pandemic influenza vaccine H5N1 AstraZeneca administration diagram (Figure 1)

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Sodertalje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1089/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 May 2016

Date of latest renewal: 16 March 2020