Influenza affects elderly patients

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1 INFORMATION FOR THE PHARMACIST This artile was sponsored y Seqirus In. FLUAD (influenza vaine, adjuvanted) to Help Protet Elderly Patients Against Influenza Influenza affets elderly patients disproportionately, with an estimated 50% to 70% of hospitalizations and 80% to 90% of deaths from influenza ourring in adults 65 years or older. 1 Among patients with underlying hroni omorid onditions, suh as aute ishemi heart disease, stroke, or pneumonia, influenza is the most ommon ause of mortality during the winter months. 2 Symptoms of influenza in older adults may inlude anorexia, malaise, weakness, dizziness, profuse sweating, and mottled extremities. 3 Annual vaination, whih is reommended y the CDC for everyone 6 months or older, an help redue severe outomes in patients at risk, suh as those 65 years or older. 1,4 Unique Challenges in Elderly Patients The elderly population is unique eause of age-related delines in immune funtion. These omplex hanges, known as immunosenesene, an result in poorer response to influenza vaination in adults older than 65 years. 5,6 oth the initial and long-term immune responses to vainations are ompromised in these patients. 6 Sientists have developed strategies for improving vaine-mediated protetion against influenza in the elderly population. One produt is the highdose influenza vaine, whih ontains 4 times as muh antigen as the standard influenza vaine. Other produts have attempted to augment loal immunity y administering the influenza vaine intradermally. 7 FLUAD (influenza vaine, adjuvanted) ontains the proprietary adjuvant MF59, whih has demonstrated a strong immune response in a standard dose and whih is hypothesized to inrease immune Figure 1: Noninferiority Estalished ased on Seroonversion Rates at Day 22 10,a Seroonversion (%) % ell reruitment at the injetion site and augment the proess of antigen presentation. 8 Until the 1997 approval of FLUAD in Italy, early 20th entury aluminumased produts were the only availale adjuvanted vaines on the market. 8,9 Sine then, the immunogeniity of the MF59-adjuvanted influenza vaine has een onfirmed in a pivotal trial (N = in the FLUAD group) in adults 65 years or older. To date, more than 81 million doses of FLUAD have een distriuted in more than 30 ountries where it is approved. 8,10,11 Clinial Study of Immunogeniity of FLUAD In the pivotal linial trial for FLUAD, adults 65 years or older, with a mean age of 72 years, reeived FLUAD (N = 3545) or AGRIFLU (influenza vaine) (N = 3537), a US-liensed nonadjuvanted influenza vaine. Clinial 73% 58% 58% Vaine Strain Differenes in seroonversion rate d (95% CI) 33% 29% FLUAD AGRIFLU 9.8% (7.5%-12.1%) Seroonversion defined as prevaination H1 titer <10 and postvaination H1 titer 40 or at least a 4-fold inrease in H1 from prevaination H1 titer % (11.7%-16.1%) 3.2% (1.1%-5.3%) ªResults otained following vaination with influenza vaine formulated for the season. N = , the numer of vainated partiipants with availale data for the immunologi end point listed. N = , the numer of vainated partiipants with availale data for the immunologi end point listed. d FLUAD met noninferiority riteria ased on seroonversion rate differenes if the lower limit of the 95% CI [FLUAD- AGRIFLU] for eah strain was 10%. immunogeniity was assessed in 91% of sujets reeiving FLUAD and 92% of sujets reeiving AGRIFLU at day 22 after the vaination. In an analysis designed to assess noninferiority, researhers assessed seroonversion rates and geometri mean antiody titer ratios. Noninferiority was estalished for oth outome measures (Figures 1 and 2). 10 Safety Considerations for FLUAD Key safety onsiderations with FLUAD inlude its ontraindiation for use in patients who have previously experiened an allergi reation to any vaine omponent, inluding egg protein. Consideration of the enefits and risks of administering the influenza vaine should e made in any patient who experiened Guillain-arré Syndrome within 6 weeks of reeiving a previous influenza vaine. eause the tip ap of the prefilled FLUAD syringe on- Please see rief Summary of full Presriing Information on following pages. May 2016 PharmayTimes.om Pharmay Times

2 INFORMATION FOR THE PHARMACIST Figure 2: Noninferiority Estalished ased on GMTs and GMT Ratios at Day GMT tains natural ruer latex, allergi reations may our in individuals with latex sensitivity who reeive the vaine. The most ommon loal adverse reations in the pivotal linial trial inluded injetion site pain (25%) and tenderness (21%), whereas systemi adverse reations inluded myalgia (15%), headahe (13%), and fatigue (13%). These adverse events (AEs) were soliited, and while higher rates of soliited AEs were noted with FLUAD, they were typially mild to moderate in severity. 10 Role of the Pharmaist Data show that a growing numer of elderly patients reeive their annual influenza vaine from their pharmaist. Influenza vainations are availale in pharmaies in all 50 states, whih has resulted in improved influenza vaination rates in the elderly population. 12,13 Patients an look to their pharmaist to provide a vaine with harateristis that will est serve them. y providing eduation aout the important harateristis of FLUAD, pharmaists an potentially provide their patients 65 years or older with an influenza vaine speifially designed for their needs to help protet them against influenza Vaine Strain GMT ratio (95% CI) ( ) FLUAD a AGRIFLU 1.61 ( ) 1.15 ( ) GMT = geometri mean antiody titer. a N = ; this is the numer of vainated partiipants with availale data for the immunologi end point listed. N = ; this is the numer of vainated partiipants with availale data for the immunologi end point listed. FLUAD met noninferiority riteria ased on GMT ratios if the lower limit of the 95% CI [FLUAD: AGRIFLU] for eah strain was >0.67. Important Safety Information INDICATIONS FLUAD is an inativated influenza vaine indiated for ative immunization against influenza disease aused y influenza virus sutypes A and type ontained in the vaine. FLUAD is approved for use in persons 65 years of age and older. CONTRAINDICATIONS Severe allergi reation to any omponent of the vaine, inluding egg protein, or after a previous dose of any influenza vaine. WARNINGS AND PRECAUTIONS If Guillain-arré Syndrome (GS) has ourred within six weeks of previous influenza vaination, the deision to give FLUAD should e ased on areful onsideration of the potential enefits and risks. The tip aps of the prefilled syringes ontain natural ruer latex whih may ause allergi reations in latex sensitive individuals. ADVERSE REACTIONS The most ommon ( 10%) loal (injetion site) adverse reations oserved in linial studies were injetion site pain (25%) and tenderness (21%). The most ommon ( 10%) systemi adverse reations oserved in linial studies were myalgia (15%), headahe (13%) and fatigue (13%). Referenes 1. CDC. What should you know and do this flu season if you are 65 years and older. CDC wesite. Updated August 17, Aessed Feruary 29, Lang PO, Mendes A, Soquet J, Assir N, Govind S, Aspinall R. Effetiveness of influenza vaine in aging and older adults: omprehensive analysis of the evidene. Clin Interv Aging. 2012;7: doi: /CIA.S Cohen YZ, Dolin R. Influenza. In: Kasper D, ed. Harrison s Priniples of Internal Mediine. 19th ed. New York, NY: MGraw-Hill; &ookid=1130&jumpsetionID= & Resultlik=&q=influenza+pathogenesis. Aessed Marh 3, Goodwin K, Vioud C, Simonsen L. Antiody response to influenza vaination in the elderly: a quantitative review. Vaine. 2006;24(8): MElhaney JE, Zhou X, Talot HK, et al. The unmet need in the elderly: how immunosenesene, CMV infetion, o-moridities and frailty are a hallenge for the development of more effetive influenza vaines. Vaine. 2012;30(12): doi: /j.vaine Weinerger, Herndler-randstetter D, Shwanninger A, Weiskopf D, Gruek-Loeenstein. iology of immune responses to vaines in elderly persons. Clin Infet Dis. 2008;46(7): doi: / Haq K, MElhaney JE. Immunosenesene: influenza vaination and the elderly. Curr Opin Immunol. 2014;29: doi: /j.oi O Hagan DT, Ott GS, Nest GV, Rappuoli R, Giudie GD. The history of MF59 adjuvant: a phoenix that arose from the ashes. Expert Rev Vaines. 2013;12(1): doi: /erv O Hagan DT, Ott GS, De Gregorio E, Seuert A. The mehanism of ation of MF59 - an innately attrative adjuvant formulation. Vaine. 2012;30(29): doi: /j.vaine Fluad [pakage insert]. Camridge, MA: Novartis Vaines and Diagnostis, In.; Seqirus data on file. Novartis Vaines and Diagnostis In. Development Safety Update Report ah AT, Goad JA. The role of ommunity pharmay-ased vaination in the USA: urrent pratie and future diretions. IPRP. 2015;4: Steyer TE, Ragui KR, Pearson WS, Mainous AG 3rd. The role of pharmaists in the delivery of influenza vainations. Vaine. 2004;22(8): Please see rief Summary of full Presriing Information on following pages. GMCC-804_ Pharmay Times PharmayTimes.om May 2016

3 FLUAD (Influenza Vaine, Adjuvanted) Suspension for Intramusular Injetion Formula Initial U.S. Approval: 2015 RIEF SUMMARY: See pakage insert for full presriing information. 1 INDICATIONS AND USAGE FLUAD is an inativated influenza vaine indiated for ative immunization against influenza disease aused y influenza virus sutypes A and type ontained in the vaine. FLUAD is approved for use in persons 65 years of age and older. Approval is ased on the immune response eliited y FLUAD. Data demonstrating a derease in influenza disease after vaination with FLUAD are not availale. [see Clinial Studies (14)] 4 CONTRAINDICATIONS Do not administer FLUAD to anyone with a history of severe allergi reation (e.g. anaphylaxis) to any omponent of the vaine, inluding egg protein [see Desription (11)], or to a previous influenza vaine. 5 WARNINGS AND PRECAUTIONS 5.1 Guillain-arré Syndrome If Guillain-arré syndrome (GS) has ourred within 6 weeks of reeipt of prior influenza vaine, the deision to give FLUAD should e ased on areful onsideration of the potential enefits and risks. The 1976 swine influenza vaine was assoiated with an elevated risk of GS. Evidene for a ausal relationship of GS with other influenza vaines is inonlusive; if an exess risk exists, it is proaly slightly more than 1 additional ase per 1 million persons vainated. [see Referenes (1)] 5.2 Preventing and Managing Allergi Reations Appropriate medial treatment and supervision must e availale to manage possile anaphylati reations following administration of the vaine. 5.3 Latex The tip aps of the prefilled syringes ontain natural ruer latex whih may ause allergi reations in latex sensitive individuals. [see Desription (11)] 5.4 Altered Immunoompetene The immune response to FLUAD in immunoompromised persons, inluding individuals reeiving immunosuppressive therapy, may e lower than in immunoompetent individuals. [see Conurrent Use With Immunosuppressive Therapies (7.2)] 5.5 Synope Synope (fainting) may our in assoiation with administration of injetale vaines inluding FLUAD. Ensure proedures are in plae to avoid injury from falling assoiated with synope. 5.6 Limitations of Vaine Effetiveness Vaination with FLUAD may not protet all vaine reipients against influenza disease. 6 ADVERSE REACTIONS 6.1 Clinial Trials Experiene eause linial trials are onduted under widely varying onditions, the adverse reation rates oserved in the linial trials of a vaine annot e diretly ompared to rates in the linial trials of another vaine and may not reflet rates oserved in linial pratie. Soliited adverse reations were assessed in a multienter, oserver-lind, randomized ontrolled study (Study 1) onduted in the United States, Colomia, Panama and the Philippines. The safety analysis set inluded 3545 FLUAD reipients and 3537 AGRIFLU (Influenza Vaine) reipients. The enrolled sujet population in Study 1 was 65 to 97 years of age (mean 72 years) and 64% were female. Within eah treatment group, 53% were Asian, 28% were Cauasian, 18% were Hispani, 1% were lak, and fewer than 1% eah were Native Amerian/ Alaskan, Paifi Islander/Hawaiian, or Other. Soliited loal (injetion site) and systemi adverse reations were olleted from sujets in Study 1 who ompleted a symptom diary ard for seven days following vaination. The reported frequenies of soliited loal and systemi adverse events from Study 1 are presented in Tale 1. Tale 1. Perentages of Sujets 65 Years of Age With Soliited Loal and Systemi Adverse Reations in Days 1-7 After Administration of FLUAD or AGRIFLU (a U.S. Liensed Comparator) NCT Loal Injetion site Pain Tenderness Erythema Induration Swelling Study 1 FLUAD (N a = ) Perentage AGRIFLU (N a = ) Perentage Any Moderate Severe Any Moderate Severe Any to 50 mm to 100 mm 0.2 <0.1 > 100 mm Any to 50 mm to 100 mm > 100 mm Any to 50 mm to 100 mm 0.2 <0.1 > 100 mm <

4 Systemi Myalgia Fatigue Headahe Arthralgia Chills Diarrhea Fever Nausea Vomiting Any Moderate Severe Any Moderate Severe PLT d 0.0 <0.1 Any Moderate Severe PLT 0.0 <0.1 Any Moderate Severe Any Moderate Severe Any Moderate Severe PLT <0.1 <0.1 Any C to 38.4 C 38.5 C to 38.9 C 39.0 C to 40.0 C C Any Moderate Severe Any Moderate Severe < a N = numer of sujets with safety data. Moderate: pain, tenderness, myalgia, fatigue, headahe, arthralgia, hills, nausea, vomiting defined as some limitation in normal daily ativity, diarrhea defined as 4 to 5 stools a day. Severe: pain, tenderness, myalgia, fatigue, headahe, arthralgia, hills, nausea, vomiting defined as unale to perform normal daily ativity, diarrhea defined as 6 or more watery stools a day. d Potentially life threatening (PLT) reation defined as requiring emergeny room visit or hospitalization. Unsoliited Adverse Events (AEs): The linial safety of FLUAD was assessed in fifteen (15) randomized, ontrolled studies. The total safety population in these trials inluded 10,952 adults 65 years of age and older, omprising 5,754 who reeived FLUAD and 5,198 who reeived other US liensed influenza vaines. The perentage of sujets with an unsoliited AE within 30 days following vaination was similar etween vaine groups (16.9% FLUAD vs. 18.0% ative omparator). Serious Adverse Events (SAEs) and Deaths: In Study 1, in whih sujets were followed for SAEs and deaths for one year following vaination (N=3,545 FLUAD, N=3,537 AGRIFLU), the perentages of sujets with an SAE were similar etween vaine groups (7% FLUAD vs. 7% AGRIFLU). Four SAEs (1 FLUAD and 3 AGRIFLU) were assessed as related to study vaination over one year of oservation and 2 of these ourred (1 FLUAD and 1 AGRIFLU) within 21 days following study vaination. There were 98 deaths (n=52 FLUAD, n=46 AGRIFLU) over one year of whih none ourred within the first 21 days following vaination. In 14 additional randomized, ontrolled studies, SAEs were olleted over a 3 to 4-week period in 4 studies, over a 8-week period in 1 study, and over a 6-month period in 9 studies (N= 2,209 FLUAD, N=1,661 US liensed influenza vaines). The perentages of sujets with an SAE within 30 days (1.1% FLUAD vs. 1.8% AGRIFLU) or within 6 months (4.3% FLUAD vs. 5.9% AGRIFLU) were similar etween vaine groups. The perentages of deaths within 30 days (0.3% FLUAD vs. 0.6% ative omparator) or within 6 months (1.0% FLUAD vs. 1.5% ative omparator) were also similar. Adverse Events of Speial Interest (AESIs): Rates of new onset neuroinflammatory and immune mediated diseases were assessed in a post ho analysis of the 15 randomized ontrolled studies over the time periods speified aove for SAEs. The perentage of sujets with an AESI at any time after vaination was similar etween vaine groups (0.9% FLUAD vs. 0.9% ative omparator). There were no notale imalanes for speifi AESIs. Safety of Annual Revaination: In 5 of the randomized, ontrolled trials, sujets were followed for SAEs and deaths for 6 months following revaination (N=492 FLUAD, N=330 US liensed and non-us liensed influenza vaines). After the seond annual vaination, the perentages of sujets with an SAE were similar etween vaine groups (6.1% FLUAD vs. 5.5% omparator influenza vaines); 23 deaths (n=17 FLUAD, n=6 omparator influenza vaines) were reported. Causes of death inluded ardiovasular events, malignany, trauma, gastrointestinal disorders, and respiratory failure. Clinial harateristis of the deaths, inluding the variale auses, timing sine vaination, and underlying medial onditions, do not provide evidene for a ausal relationship with FLUAD. 6.2 Postmarketing Experiene The following adverse events have een spontaneously reported during post-approval use of FLUAD in Europe and other regions sine eause these events are reported voluntarily from a population of unertain size, it is not always possile to relialy estimate their frequeny or estalish a ausal relationship to the vaine.

5 lood and lymphati system disorders: Thromoytopenia (some ases were severe with platelet ounts less than 5,000 per mm 3 ), lymphadenopathy General disorders and administration site onditions: Extensive swelling of injeted lim lasting more than one week, injetion site ellulitis-like reations (some ases of swelling, pain, and redness extending more than 10 m and lasting more than 1 week) Immune system disorders: Allergi reations inluding anaphylati shok, anaphylaxis and angioedema Musuloskeletal and onnetive tissue disorders: Musular weakness Nervous system disorders: Enephalomyelitis, Guillain-arré Syndrome, onvulsions, neuritis, neuralgia, paraesthesia, synope, presynope Skin and suutaneous tissue disorders: Generalized skin reations inluding erythema multiforme, urtiaria pruritus or non-speifi rash Vasular disorders: Vasulitis with transient renal involvement 7) and later in pregnany (gestation day 20), 0.5 ml (45 mg)/rait/oasion (approximately 15-fold exess relative to the adult human dose ased on ody weight). No adverse effets on mating, female fertility, pregnany, emryo-fetal development, or post-natal development were oserved. There were no vaine-related fetal malformations or other evidene of teratogenesis. 8.4 Pediatri Use The safety and effetiveness of FLUAD in the pediatri population has not een estalished. 8.5 Geriatri Use Safety and immunogeniity of FLUAD have een evaluated in adults 65 years of age and older. [See Adverse Reations (6.1) and Clinial Studies (14)] FLUAD is a registered trademark of Novartis Vaines and Diagnostis, In. Manufatured y: Novartis Vaines and Diagnostis Limited. An affiliate of: Novartis Vaines and Diagnostis, In., 350 Massahusetts Avenue, Camridge, MA USA DRUG INTERACTIONS 7.1 Conomitant Use With Other Vaines There are no data to assess the onomitant administration of FLUAD with other vaines. If FLUAD is to e given at the same time as other injetale vaine(s), the vaine(s) should e administered at different injetion sites. Do not mix FLUAD with any other vaine in the same syringe. 7.2 Conurrent Use With Immunosuppressive Therapies Immunosuppressive or ortiosteroid therapies may redue the immune response to FLUAD. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnany Pregnany Category : A reprodutive and developmental toxiity study has een performed in raits with a dose level that was approximately 15 times the human dose ased on ody weight. The study revealed no evidene of impaired female fertility or harm to the fetus due to FLUAD. There are, however, no adequate and well-ontrolled studies in pregnant women. eause animal reprodution studies are not always preditive of human response, this vaine should e used during pregnany only if learly needed. In a reprodutive and developmental toxiity study, the effet of FLUAD on emryo-fetal and postnatal development was evaluated in pregnant raits. Animals were administered FLUAD y intramusular injetion twie prior to gestation, during the period of organogenesis (gestation day