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A120426T1541-79501-SWE-5A

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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A120426T1541-79501-SWE-5A

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  1. A120426T1541-79501-SWE-5A

  2. FLUENZ A Live Attenuated Influenza Vaccine (LAIV)

  3. Agenda • FLUENZ • Product characteristics • Indication • Mode of Action • Others • Efficacy • Safety • Practical information.

  4. Product characteristics

  5. 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

  6. 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

  7. FLUENZ SmPC Special 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

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Efficacy

  14. Key studies conducted in children* – Placebo-controlled trials *LAIV is not approved for children under 24 months of age Ref. FLUENZ SmPC

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  21. 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.

  22. Safety

  23. 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.

  24. 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.

  25. 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.

  26. FLUENZ SmPC Adverse reactions

  27. 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.

  28. Practical Information

  29. 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

  30. Back up

  31. 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

  32. 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

  33. 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

  34. Recommendations in other countries.

  35. FLUENZ SmPC Undesirable effects Not indicated in children < 24 months of age due to increased risk of wheezing post vaccination

  36. 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.

  37. 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.

  38. 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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