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A120426T1541-79501-SWE-5A. FLUENZ A Live Attenuated Influenza Vaccine (LAIV). Agenda. FLUENZ Product characteristics Indication Mode of Action Others Efficacy Safety Practical information. Product characteristics. FLUENZ. FLUENZ nasal spray, suspension

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agenda
Agenda
  • FLUENZ
    • Product characteristics
      • Indication
      • Mode of Action
      • Others
    • Efficacy
    • Safety
    • Practical information.
fluenz
FLUENZ
  • FLUENZ nasal spray, suspension
  • Influenza vaccine (live attenuated nasal)
  • Trivalent (A/H1N1, A/H3N2, B)
  • 0.2 mLintranasal spray (0.1 mL pernostril)
  • Contains no preservatives (e.g., no thimerosal) or adjuvants (e.g. alum or squalene)
  • Storage at 2-8 ºC
  • Approved in U.S., Hong Kong, South Korea, Israel, UAE, Macau for 2-49 years, Canada for 2-59 years, Europe for 2-17 years.
  • FLUENZ /FluMist has been used in the US since 2003.

Ref. SmPC FLUENZ

5

fluenz smpc
FLUENZ SmPC

Therapeutic indication

FLUENZ is indicated for the prophylaxis of influenza in individuals 24 months to less than 18 year of age

The use of FLUENZ should be based on official recommendations

Ref. SmPC FLUENZ

special warnings precautions
FLUENZ SmPCSpecial warnings & precautions

Contraindications

Should not be administered to children

  • with severe asthma or active wheezing as not adequately studied

Vaccine recipients should attempt to avoid close association with severely immunocompromised individuals

Children and adolescents:

hypersensitivity to:

the active substances, any of the excipients, gentamicin or to egg proteins

Children and adolescents:

clinically immunodeficient due to conditions or immunosupp. therapy

receiving salicylate therapy

For additional information, see SmPC

Ref. SmPC FLUENZ

extensive documentation behind ema approval
Extensive documentation behind EMA approval
  • Clinical efficacy or immunogenicity data from 43 studies
      • > 64.000 subjects
      • 31 studies includedpaediatricsubjects
  • Efficacy in paediatricsubjectswereassessed in 9 studies:
      • > 20.000 children
      • 6 placebo-controlled
      • 3 TIV (trivalentinactivatedinfluenzavaccine) controlled
  • Safety data
      • > 28,500 subjects 2 to 17 years of age from clinical studies
      • > 52,500 children and adolescents from post authorisationsafety studies
  • Flumist on the US market since 2003. > 39 million doses have been distributed

Fluenz Summary of Product Characteristics, http://www.ema.europa.eu, 2011-03-17

Assessment report Fluenz, 2011-09-26

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/

human/001101/WC500103711.pdf

AstraZeneca

mode of administration
Mode of administration
  • LAIV vaccine is sprayed directly into the nasal cavity1
    • Needle-free
    • Active inhalation/sniffingnot required
  • Intranasal administration enables induction of immunity at the site of virus entry2
    • Induces a broad innate, mucosal and systemic response2
    • Designed to more closely mimic the immune response generated by wild-type influenza2
  • FLUENZ SmPC
  • Tosh P et al. Mayo Clin Proc 2008; 83: 77–84.
types of influenza vaccine approved in the eu
TIV

Trivalent inactivated influenza vaccine, intramuscular

HA is the only standardised component; other antigens may be present1,2*

Types of influenza vaccine approved in the EU

LAIV

Live attenuated influenza vaccine, intranasal

Attenuated vaccine with multiple antigens3,4*

HA

NA

HA

HA

HA

NP

HA: haemagglutinin; M1, M2: matrix proteins; NA: neuraminidase; NP: nucleoprotein.

*Image adapted from: Clinical Virology. 6th ed. 1997:911–942.4

Please refer to the specific prescribing information for each manufacturer’s influenza vaccine as not all influenza vaccines are indicated for all ages

1. Fluarix [Summary of Product Characteristics]. GlaxoSmithKline plc.

2. Fluvirin [Summary of Product Characteristics]. Novartis Vaccines and Diagnostics Ltd.

3. FLUENZ SmPC

4. Hayden FG et al. Clinical Virology. 6th ed. 1997;911–942.

CONFIDENTIAL – For Internal Use Only

laiv is engineered to prevent influenza infection
LAIV is engineered to prevent influenza infection

Attenuated virus: disease-causing properties removed so as not to cause illness

Cold-adapted: replicates efficiently only in the cooler areas of the nasopharynx

Temperature-sensitive: does not replicate efficiently in warmer areas of the lower respiratory tract where influenza viruses typically replicate

  • Cox RJ, et al. Scand J Immunol. 2004;59:1-15
  • SmPC FLUENZ
  • 3. Assessment report Fluenz, 2011-09-26
  • 4. Maassab HF, DeBorde DC. Vaccine. 1985b;3(5):355-369
fluenz creates a broad immune response
FLUENZ creates a broad immune response.

Mucosal and systemic immune response

    • mucosal IgA, systemic IgG and influenza specific T-cells2)
  • Resembles natural response to infection- engineered not to cause disease1

1. Cox RJ, et al. Scand J Immunol 2004;59:1-15.

2. Tam JS, et al. Pediatr Infect Dis J 2007;26(7):619-628

3. Ambrose C, et al. Pediatri Infect Dis J 2008; 27:744-8.

4. Honolulo HI, Halloran ME, et al. Am J Epidemiol. 2003;158:305-311

5. Gaglani M, et al. Pediatr Infect Dis J 2001;20:1155-1160

6. Fluenz: EPAR – Public assessment report. Published: 17/03/2011

key studies conducted in children placebo controlled trials
Key studies conducted in children* – Placebo-controlled trials

*LAIV is not approved for children under 24 months of age

Ref. FLUENZ SmPC

summary of 6 randomized studies high fluenz efficacy in pediatric population
Summary of 6 randomized studies:High FLUENZ efficacy in pediatric population.

Efficacy of one and two doses of LAIV vs. placebo on

culture-confirmed influenza for antigenically similar subtypes

60% reduction

(95% CI: 51, 68)

77% reduction

(95% CI: 72, 80)

87% reduction

(95% CI: 81, 90)

16

14.6%

14.5%

14

12.6%

12

Placebo

LAIV

10

Incidence of influenza

(matched strains), %

8

5.7%

6

4

3.1%

1.6%

2

0

One dose in first season

(previously unvaccinated)

Two doses in first season

(previously unvaccinated)

Revaccination with one dose in second season(previously vaccinated)

*LAIV is not approved for children under 24 months of age

Rhorer J et al. Vaccine 2009; 27: 1101–1110.

key studies conducted in children tiv controlled trials
Key studies conducted in children* – TIV-controlled trials

*LAIV is not approved for children under 24 months of age

FLUENZ [Summary of Product Characteristics]. AstraZeneca Ltd.

higher efficacy relative to tiv for all strains regardless of match
Higher efficacy relative to TIV for all strains regardless of match

3 randomised studies: all strains regardless of match13,000 children 6 months to 17 years*

55% reduction

(95% CI: 45, 63)

52% reduction

(95% CI: 25, 71)

32% reduction

(95% CI: 1, 54)

10

9

8.6%

8

TIV

LAIV

7

6.6%

6

5.8%

Incidence of influenza

(matched strains), %

5

4.5%

3.9%

4

2.8%

3

2

1

0

6–59 months1

6–71 months2

6–17 years3

Age

*LAIV is not approved for children under 24 months of age

1. Belshe RB et al. New Engl J Med 2007; 356: 685–696.

2. Ashkenazi S et al. Pediatr Infect Dis J 2006; 25: 870–879.

3. Fleming D et al. Pediatr Infect Dis J 2006; 25: 860–869.

mismatched strains comparison of laiv vs placebo or tiv
Mismatched strains: Comparison of LAIV vs. placebo or TIV

Incidence of culture-confirmed influenza in children aged 6–85 months* in

2 randomised studies

86% reduction

in attack rate

(95% CI: 75, 92)

79% reduction

in attack rate

(95% CI: 71, 86)

6% reduction

in attack rate

(95% CI: −32, 33)

14

11.6%

12

Placebo recipients

LAIV recipients

TIV recipients

10

8

Incidence of culture-confirmed influenza, %

4.5%

6

4

1.8%

1.7%

1.6%

2

0.9%

0

Mismatched

A/H3N2 (1997/1998)

Study AV006

Mismatched

A/H3N2 (2004/2005)

Study CP111

Mismatched B

(2004/2005)

Study CP111

26–85 months1

6–59 months2

6–59 months2

  • *LAIV is not approved for children under 24 months of age
  • Belshe RB et al. J Pediatr 2000; 136: 168–175.
  • Belshe RB et al. N Eng J Med 2007; 356: 685–696.
cochrane review efficacy laiv and tiv
Cochrane reviewEfficacy LAIV and TIV.

Children > 2 år

Cochrane review: Jefferson et al. Vaccines for preventing influenza in healthy children.

Cochrane Database Syst Rev. 200816;(2):CD004879

fluenz has shown to protect over time
FLUENZ has shown to protect over time
  • FLUENZ gave 73% efficacy against matched influenza strains over a 12 months period1,2
  • FLUENZ protected against late influenza outbreaks 2

1. Ambrose C, et al. Pediatri Infect Dis J 2008;27:744-748

2. Tam J, et al. Pediatr Infect Dis J 2007;26:619-628

3. Fluenz SmPC

laiv shows an increase in efficacy over time relative to tiv
LAIV shows an increase in efficacy over time relative to TIV

Efficacy by time post-vaccination versus placebo; matched strains

  • In 3 TIV-controlled studies, the relative efficacy of LAIV versus TIV for matched strains increased with time in each study
  • Results are best explained by a decline in TIV efficacy over time

4

0–4 months

Relative efficacy (95% CI):34% (3, 55)

>4–8 months

Relative efficacy (95% CI):62% (42, 76)

3

TIV

LAIV

Incidence, %

2

1

0

0

1

2

3

4

5

6

7

8

Time from first vaccination to influenza illness (months)

Adapted from Ambrose CS et al, 2010

Ambrose CS et al. Pediatr Infect Dis J 2010; 29: 806–811.

comparable safety to placebo in children aged 2 17 years of age
Comparable safety to placebo in children aged 2–17 years of age†

Solicited reactogenicity events days 0–10

post-vaccination in year 1 of placebo-controlled studies

70

*

60

LAIV dose 1

Placebo dose 1

LAIV dose 2

Placebo dose 2

50

40

Incidence, %

30

*

20

*

*

10

0

Chills

Cough

≥38.0C

≥39.0C

≥40.0C

Vomiting

Irritability

Headache

Sore throat

Muscle ache

Abdominal pain

Decreased activity/tiredness

Runny/stuffy nose

Decreased appetite

Fever

Adapted from Ambrose CS et al, 2011

†Data available from 14 placebo-controlled studies.

*Statistically significant difference (p<0.05).

Ambrose CS et al. Influenza Other Respi Viruses 2011; DOI: 10.1111/j.1750-2659.2011.00243.x.

comparable safety to tiv in children aged 2 17 years of age
Comparable safety to TIV in children aged 2–17 years of age†

Solicited reactogenicity events days 0–10

post-vaccination in year 1 of TIV studies

70

*

60

LAIV dose 1

TIV dose 1

LAIV dose 2

TIV dose 2

50

*

40

Incidence, %

30

20

*

10

0

Chills

Cough

≥38.0C

≥40.0C

≥39.0C

Vomiting

Irritability

Headache

Sore throat

Muscle ache

Abdominal pain

Decreased activity/tiredness

Runny/stuffy nose

Decreased appetite

Fever

Adapted from Ambrose CS et al, 2011

†Data available from six TIV-controlled studies.

*Statistically significant difference (p<0.05).

Ambrose CS et al. Influenza Other Respi Viruses 2011; DOI: 10.1111/j.1750-2659.2011.00243.x.

study p515 asthma exacerbations within 42 days of vaccination with laiv or tiv
Increased

Asthma

Unscheduled

medication

exacerbations

clinic visits

Study P515: asthma exacerbations within 42 days of vaccination with LAIV or TIV
  • The incidence of asthma exacerbations were comparable between groups
  • No significant differences were observed between treatment groups in mean PEFR findings, asthma symptoms scores, or night-time awakening scores

Asthma exacerbations occurring

within 42 days of vaccination with LAIV or TIV

TIV

LAIV

14

12.0

11.8

11.6

11.4

12

10

8.3

7.7

8

Incidence (%)

6

4

2

0.3

0.3

0

Hospitalisation

Adapted from Fleming D et al, 2006

PEFR: Peak expiratory flow rate.

Fleming D et al. Pediatr Infect Dis J 2006; 25: 860–869.

summary
Summary
  • Offer a novel administration well suited for children
  • Superior efficacy vs traditional influenza vaccines among pediatric populations.
    • Both during match and mismatch seasons.
    • Shown protection over time (12 months).
  • Protects at the site entry of influenza virus. Designed to trigger a broad immunity: IgA, IgG antibodies and T-cellular immune response.
  • Well documented with safety aligned with traditional influenza vaccine.
    • Used in US since 2003 with > 39 million doses distributed.
    • Experience from seasonal and pandemic setting within pediatric population without safety issues.
administration others
Administration & others

FLUENZ is supplied as a single-use, pre-filled intranasal spray device, containing a 0.2 ml dose. 10-pack.

FLUENZ must be administered by a Healthcare Professional

    • The patient should breathe normally

There is no need to readminister if:

    • FLUENZ drips out of the nose
    • The patient sneezes
    • The patient blows their nose

Shelf life

  • 18 weeks from distribution date; expiration date is listed on the sprayers

Ref. SmPC FLUENZ

fluenz smpc contraindications
FLUENZ SmPCContraindications

FLUENZis contraindicated in children and adolescents with hypersensitivity to the active ingredients, any excipients, gentamicin, to eggs or to egg proteins

FLUENZis contraindicated for children and adolescents who are clinically immunodeficient due to conditions or immunosuppressive therapy such as: acute and chronic leukemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high dose corticosteriods

FLUENZ is not contraindicated for use in individuals with asymptomatic HIV infection; or individuals who are receiving topical/inhaled corticosteroids or low-dose systemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. for adrenal insufficiency

FLUENZis contraindicated in children and adolescents receiving salicylate (e.g. aspirin) therapy because of the association of Reyes syndrome with salicylates and wild-type influenza infection

Ref. SmPC FLUENZ

fluenz smpc special warnings and precautions
FLUENZ SmPCSpecial warnings and precautions

As with most vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of FLUENZ.

FLUENZ should not be administered to children and adolescents with severe asthma or active wheezing because these individuals have not been adequately studied in clinical studies.

Note: FLUENZ is NOT contraindicated for children mild or moderate asthma

Do not administer FLUENZ to infants and toddlers younger than 12 months. In a clinical study, an increase in hospitalisations was observed in children younger than 12 months after vaccination. It is not recommended to administer FLUENZ to infants and toddlers 12-23 months of age. In a clinical study, an increased rate of wheezing was observed in children 12-23 months of age after vaccination.

Vaccine recipients should be informed that FLUENZ 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.

No data exist regarding the safety of intranasal administration of FLUENZ in children with unrepaired

craniofacial malformations.

FLUENZ should under no circumstances be injected.

Ref. SmPC FLUENZ

asthma documentation
Asthma documentation

There are several studies in children with asthma.  

  • The Fleming study: LAIV vs TIV. N= 2 211 Children (6-17 y) with mild-moderate asthma.
    • Results: LAIV higher efficacy vs TIV with comparable safety.
  • The Ashkenazi study: LAIV vs TIV. N= 2187 . Young children (6-71 months) with history of wheezing (46%) and asthma (23%).
    • Results: LAIV higher efficacy vs TIV with comparable safety.
  • The Redding study: LAIV vs placebo. N= 48. Children (9 - 17 y) with moderate to severe asthma.
    • Results: comparable safety.
  • EMA: safety has been established in children of all ages with mild to moderate asthma.  Not sufficient data on children with sever asthma.

Ref:

Ashkenazi S et al Pediatr.Infect.Dis.J. 2006 Oct;25(10):870-879.

Fleming DM et al. Pediatr.Infect.Dis.J. 2006 Oct;25(10):860-869

Redding et al Pediatr Infect Dis J, 2002;21:44–8.

EMA Assessment report FKUENZ

fluenz smpc undesirable effects
FLUENZ SmPC Undesirable effects

Not indicated in children < 24 months of age due to increased risk of wheezing post vaccination

summary of adverse events in children aged 2 6 years
Summary of adverse events in children aged 2- 6 years

*Most common adverse reactions (≥10% in LAIV and at least 5% greater than in control) are runny nose or nasal congestion and fever >37,8°C in children 2-6 years of age

Studies reflect the data collected between 2 pooled studies and 1 active-controlled study

1. Belshe, et al. N Engl J Med, 338:1405, 1998. 2. Tam, et al. PediatrInfect Dis J, 26:619, 2007. 3. Belshe, et al. N Engl J Med, 356:685,2007.

rates of wheezing in children through 42 days following vaccination
Rates of wheezing in children* through 42 days following vaccination
  • A small but significant increase in wheezing after LAIV vs. TIV was observed in children aged 6–23 months, but there was no significant difference in children aged ≥2 years

Medically significant wheezing rates by age

Percentage of subjects with

medically significant wheezing

Adapted from Belshe R et al, 2008

  • *LAIV is not approved for children under 24 months of age
  • †Age at time of first vaccine dose
  • Belshe RB et al. Vaccine 2008; 26S: D10–D16.
increased hospitalizations observed in children 6 11 months of age through 180 days
Increased hospitalizations observed in children 6-11 months of age through 180 days
  • Rates of hospitalisation for any cause were only higher amongst LAIV recipients aged 6–11 months*

Hospitalisation rates by age

TIV

p=0.002

7

LAIV

6

5

4

Incidence (%)

3

2

1

0

6–11

12–23

24–35

36–47

48–59

Age (months)

Adapted from Belshe R et al, 2007

*LAIV is not approved for children under 24 months of age

Belshe RB et al. N Eng J Med 2007; 356: 685–696.

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