AFLURIA, Influenza Vaccine Suspension for Intramuscular Injection Formula Initial U.S. Approval: 2007

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not inlude ll the informtion needed to use sfely nd effetively. See full presriing informtion for., Influenz Vine Suspension for Intrmusulr Injetion Formul Initil U.S. Approvl: 2007 RECENT MAJOR CHANGES Dosge nd Administrtion (2) 08/2014 INDICATIONS AND USAGE is n intivted influenz vine indited for tive immuniztion ginst influenz disese used y influenz virus sutypes A nd type B present in the vine. (1) is pproved for use in persons 5 yers of ge nd older. (1) DOSAGE AND ADMINISTRATION For intrmusulr (IM) injetion only, y needle nd syringe (5 yers of ge nd older) or y PhrmJet Strtis NeedleFree Injetion System (18 through 64 yers of ge). A single dose is 0.5 ml. (2) Age Shedule 5 yers through 8 yers One dose or two doses t lest 1 month prt 9 yers nd older One dose 1 or 2 doses depends on vintion history s per Advisory Committee on Immuniztion Prties nnul reommendtions on prevention nd ontrol of influenz with vines. (2.1) DOSAGE FORMS AND STRENGTHS is suspension for injetion supplied in two presenttions: 0.5 ml prefilled syringe (single dose) (3, 11) 5 ml multidose vil (ten 0.5 ml doses) (3, 11) CONTRAINDICATIONS Severe llergi retion (e.g., nphylxis) to ny omponent of the vine inluding egg protein, or to previous dose of ny influenz vine. (4, 11) WARNINGS AND PRECAUTIONS Administrtion of CSL s 2010 Southern Hemisphere influenz vine ws ssoited with inresed rtes of fever nd ferile seizures in hildren predominntly elow the ge of 5 yers s ompred to previous yers. Ferile events were lso oserved in hildren 5 through 8 yers of ge. (5.1) If GuillinBrré Syndrome (GBS) hs ourred within 6 weeks of previous influenz vintion, the deision to give should e sed on reful onsidertion of the potentil enefits nd risks. (5.2) Approprite medil tretment nd supervision must e ville to mnge possile nphylti retions following dministrtion of the vine. (5.3) Immunoompromised persons my hve diminished immune response to. (5.4) ADVERSE REACTIONS In hildren 5 through 17 yers of ge, the most ommon injetionsite dverse retions when dministered y needle nd syringe were pin ( 60%), redness ( 20%) nd swelling ( 10%). The most ommon systemi dverse events were hedhe, mylgi ( 20%), irritility, mlise nd fever ( 10%). (6.1) In dults 18 through 64 yers of ge, the most ommon injetionsite dverse retions when dministered y needle nd syringe were tenderness ( 60%), pin ( 40%), swelling ( 20%), nd redness, ithing ( 10%). The most ommon systemi dverse events were musle hes ( 30%) nd hedhe, mlise ( 20%). (6.1) In dults 18 through 64 yers of ge, the most ommon injetionsite dverse retions when dministered y the PhrmJet Strtis NeedleFree Injetion System up to 7 dys postvintion were tenderness ( 80%), swelling, pin, redness ( 60%), ithing ( 20%) nd ruising ( 10%). The most ommon systemi dverse events within this period were mylgi, mlise ( 30%), nd hedhe ( 20%). (6.1) In dults 65 yers of ge nd older, when dministered y needle nd syringe the most ommon injetionsite dverse retions were tenderness ( 30%) nd pin ( 10%). No systemi dverse events ourred in 10% of sujets in this ge group (6.1) To report SUSPECTED ADVERSE REACTIONS, ontt iocsl In. t or VAERS t or USE IN SPECIFIC POPULATIONS Sfety nd effetiveness of hve not een estlished in pregnnt women or nursing mothers. (8.1, 8.3) Antiody responses were lower in geritri sujets thn in younger sujets. (8.5) is not pproved for use in hildren less thn 5 yers of ge euse of inresed rtes of fever nd ferile seizures. One omprtorontrolled tril demonstrted higher rtes of fever in reipients of s ompred to trivlent intivted influenz vine ontrol. (8.4) See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Fever nd Ferile Seizures 5.2 GuillinBrré Syndrome 5.3 Preventing nd Mnging Allergi Retions 5.4 Altered Immunoompetene 5.5 Limittions of Vine Effetiveness 6 ADVERSE REACTIONS 6.1 Clinil Trils Experiene 6.2 Postmrketing Experiene 6.3 Adverse Retions Assoited With Influenz Vintion 7 DRUG INTERACTIONS 7.1 Conurrent Use With Other Vines 7.2 Conurrent Use With Immunosuppressive Therpies 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnny 8.3 Nursing Mothers 8.4 Peditri Use 8.5 Geritri Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mehnism of Ation 13 NONCLINICAL TOXICOLOGY 13.1 Crinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Effiy Aginst LortoryConfirmed Influenz 14.2 Immunogeniity in Children Administrtion vi Needle nd 14.3 Immunogeniity in Adults nd Older Adults Administrtion vi Needle nd 14.4 Immunogeniity in Adults Administrtion vi PhrmJet Strtis NeedleFree Injetion System 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION * Setions or susetions omitted from the full presriing informtion re not listed

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE is n intivted influenz vine indited for tive immuniztion ginst influenz disese used y influenz virus sutypes A nd type B present in the vine. is pproved for use in persons 5 yers of ge nd older. 2 DOSAGE AND ADMINISTRATION For intrmusulr (IM) injetion only, y needle nd syringe (5 yers of ge nd older) or y PhrmJet Strtis NeedleFree Injetion System (18 through 64 yers of ge). A single dose is 0.5 ml. The dose nd shedule for re presented in Tle 1. Tle 1: Shedule Age Shedule 5 yers through 8 yers One dose or two doses t lest 1 month prt 9 yers nd older One dose 1 or 2 doses depends on vintion history s per Advisory Committee on Immuniztion Prties nnul reommendtions on prevention nd ontrol of influenz with vines. Shke thoroughly nd inspet visully efore use. Prenterl drug produts should e inspeted visully for prtiulte mtter nd disolortion prior to dministrtion, whenever suspension nd ontiner permit. If either of these onditions exists, the vine should not e dministered. My e dministered y needle nd syringe (5 yers of ge nd older) or PhrmJet Strtis NeedleFree Injetion System (18 through 64 yers of ge only). When using the singledose prefilled syringe, shke the syringe thoroughly nd dminister the dose immeditely. When using the multidose vil, shke the vil thoroughly efore withdrwing eh dose, nd dminister the dose immeditely. Needle nd : Drw up the ext dose using seprte sterile needle nd syringe for eh individul ptient. It is reommended tht smll syringes (0.5 ml or 1 ml) e used to minimize ny produt loss. PhrmJet Strtis NeedleFree Injetion System: For instrutions on withdrwl of 0.5 ml dose nd use of the PhrmJet Strtis Needle Free Injetion System, refer to the Instrutions For Use for the PhrmJet Strtis NeedleFree Injetion System. The preferred site for intrmusulr injetion is the deltoid musle of the upper rm. Between uses, return the multidose vil to the reommended storge onditions etween 28 C (3646 F). Do not freeze. Disrd if the vine hs een frozen. 3 DOSAGE FORMS AND STRENGTHS is sterile suspension for intrmusulr injetion (see Desription [11]). is supplied in two presenttions: 0.5 ml prefilled syringe (single dose). 5 ml multidose vil (ten 0.5 ml doses). 4 CONTRAINDICATIONS is ontrindited in individuls with known severe llergi retions (e.g., nphylxis) to ny omponent of the vine inluding egg protein, or to previous dose of ny influenz vine (see Desription [11]). 5 WARNINGS AND PRECAUTIONS 5.1 FEVER AND FEBRILE SEIZURES Administrtion of CSL s 2010 Southern Hemisphere influenz vine ws ssoited with postmrketing reports of inresed rtes of fever nd ferile seizures in hildren predominntly elow the ge of 5 yers s ompred to previous yers; these inresed rtes were onfirmed y postmrketing studies. Ferile events were lso oserved in hildren 5 through 8 yers of ge. 5.2 GUILLAINBARRÉ SYNDROME If GuillinBrré Syndrome (GBS) hs ourred within 6 weeks of previous influenz vintion, the deision to give should e sed on reful onsidertion of the potentil enefits nd risks. The 1976 swine influenz vine ws ssoited with n inresed frequeny of GBS. Evidene for usl reltion of GBS with susequent vines prepred from other influenz viruses is unler. If influenz vine does pose risk, it is proly slightly more thn one dditionl se per 1 million persons vinted. 5.3 PREVENTING AND MANAGING ALLERGIC REACTIONS Approprite medil tretment nd supervision must e ville to mnge possile nphylti retions following dministrtion of the vine. 5.4 ALTERED IMMUNOCOMPETENCE If is dministered to immunoompromised persons, inluding those reeiving immunosuppressive therpy, the immune response my e diminished. 5.5 LIMITATIONS OF VACCINE EFFECTIVENESS Vintion with my not protet ll individuls. 6 ADVERSE REACTIONS In hildren 5 through 17 yers of ge, the most ommon injetionsite retions oserved in linil studies with dministered y needle nd syringe were pin ( 60%), redness ( 20%) nd swelling ( 10%). The most ommon systemi dverse events were hedhe, mylgi ( 20%), irritility, mlise nd fever ( 10%). In dults 18 through 64 yers of ge, the most ommon injetionsite dverse retions oserved in linil studies with dministered y needle nd syringe were tenderness ( 60%), pin ( 40%), swelling ( 20%), redness nd ithing ( 10%). The most ommon systemi dverse events oserved were musle hes ( 30%), hedhe nd mlise ( 20%). In dults 18 through 64 yers of ge, using the PhrmJet Strtis NeedleFree Injetion System, the most ommon injetionsite dverse retions oserved in linil study with up to 7 dys postvintion were tenderness ( 80%), swelling, pin, redness ( 60%), ithing ( 20%) nd ruising ( 10%). The most ommon systemi dverse events within this period were mylgi, mlise ( 30%) nd hedhe ( 20%). In dults 65 yers of ge nd older, the most ommon injetionsite dverse retions oserved in linil studies with dministered y needle nd syringe were tenderness ( 30%) nd pin ( 10%). No systemi dverse retions ourred in 10% of sujets in this ge group. 6.1 CLINICAL TRIALS EXPERIENCE Beuse linil studies re onduted under widely vrying onditions, dverse retion rtes oserved in the linil studies of vine nnot e diretly ompred to rtes in the linil studies of nother vine nd my not reflet the rtes oserved in linil prtie. Children In linil studies, hs een dministered to, nd sfety informtion olleted for, 3,009 hildren ges 6 months through 17 yers. Clinil sfety dt for in hildren re presented from three linil studies (Studies 1, 2 nd 3). Dt from omprtorontrolled tril (Study 1) re presented, followed y pooled dt from two open lel studies (Studies 2 nd 3). Sujets 6 months through 8 yers of ge reeived one or two vintions, dministered y needle nd syringe, s determined y previous vintion history (for further detils on linil study design, dosing nd demogrphis see Clinil Studies [14]). Study 1 inluded 1,468 sujets for sfety nlysis, ges 6 months through 17 yers, rndomized to reeive (735 sujets) or nother U.S.liensed trivlent intivted influenz vine (mnuftured y Snofi Psteur, In.) (733 sujets). Study 2 inluded 1,976 sujets for sfety nlysis, ges 6 months through 17 yers. All sujets reeived. Study 3 inluded 298 sujets for sfety nlysis, ges 6 months through 8 yers. All sujets reeived. The sfety ssessment ws similr for the three peditri studies. Lol (injetion site) dverse retions nd systemi dverse events were soliited for 7 dys postvintion (Tles 2 nd 3). Unsoliited dverse events were olleted for 30 dys postvintion. All dverse events re presented regrdless of ny tretment uslity ssigned y study investigtors. Among the peditri studies, there were no vinerelted deths or vinerelted serious dverse events reported in hildren 5 yers of ge nd older. In this setion, sfety dt from the peditri studies re limited to hildren 5 yers of ge nd older. is not pproved for use in hildren less thn 5 yers of ge. See Wrnings nd Preutions [5.1] nd Use in Speifi Popultions [8.4] for risks of in hildren less thn 5 yers of ge. In the omprtorontrolled tril (Study 1), the rte of fever fter the first dose of in sujets ged 5 through 8 yers ws 16% s ompred to 8% in sujets who reeived the omprtor. The rte of fever in sujets ged 9 through 17 yers following single dose of ws 6% s ompred to 4% in sujets who reeived the omprtor. In ll three peditri studies, the rtes of fever in sujets ged 5 through 8 yers who reeived were lower fter dose 2 thn dose 1. Dt in Tles 2 nd 3 re presented for hildren 5 yers nd older.

3 Tle 2: Proportion of Sujets 5 through 17 Yers of Age with Soliited Lol Adverse Retions or Systemi Adverse Events within 7 Dys fter Administrtion of First or Seond Dose of, Irrespetive of Cuslity (Study 1) Perentge of Sujets in eh Age Group Reporting Event Sujets 5 through 8 yers Sujets 9 through 17 yers N=161 Comprtor N=165 N=254 Comprtor N=250 After the First Dose Lol Adverse Retions Pin Redness Indurtion Systemi Adverse Events Mylgi Mlise Hedhe Any Fever Fever F Nuse/ Vomiting Dirrhe N=39 Comprtor N=53 After the Seond Dose Lol Adverse Retions Pin Redness Indurtion 8 17 Systemi Adverse Events Dirrhe 13 6 Hedhe Mylgi Mlise 5 8 Nuse/ Vomiting 3 8 Any Fever Fever F Proportion of sujets reporting eh soliited lol dverse retion or systemi dverse event y tretment group sed on the numer of sujets ontriuting t lest one dt vlue for n individul sign/symptom (individul event denomintors). N = numer of sujets in the Sfety Popultion for eh tretment group. Tle 3: Proportion of Sujets 5 through 17 Yers of Age with Soliited Lol Adverse Retions or Systemi Adverse Events Within 7 Dys fter Administrtion of, Irrespetive of Cuslity (Studies 2 nd 3) Perentge of Sujets in eh Age Group Reporting Event Studies 2 nd 3 Study 2 Sujets 5 through 8 yers Sujets 9 through 17 yers Dose 1 Dose 2 Dose 1 N=82595 N=82426 N=397 Lol Adverse Retions Pin Erythem Swelling Systemi Adverse Events Irritility d Hedhe Mlise or feeling generlly unwell Any Fever Fever F Generl Musle Ahe (Mylgi) Nuse/Vomiting Vomiting/Dirrhe d 5 6 Loss of ppetite d 5 4 Dirrhe Proportion of sujets reporting eh soliited lol dverse retion or systemi dverse event y tretment group sed on the numer of sujets ontriuting t lest one dt vlue for n individul sign/symptom (individul event denomintors). N = numer of sujets in the Sfety Popultion for eh tretment group. Denomintors for Dose 1 were: N=82 for Vomiting/Dirrhe, Irritility, Loss of ppetite, N=513 for Mlise, Dirrhe, Nuse/ Vomiting nd N= for ll other prmeters. Denomintors for Dose 2 were: N=82 for Vomiting/ Dirrhe, Irritility, Loss of ppetite, N=344 for Mlise, Dirrhe nd Nuse/Vomiting nd N= for ll other prmeters. These preferred terms were used to desrie Soliited Adverse Events in Study 2. d These preferred terms were used to desrie Soliited Adverse Events in Study 3. In Study 1, unsoliited dverse events tht ourred in 5% of sujets who reeived in ges 5 yers through 8 yers following the first or seond dose inluded ough (15%) nd pyrexi (9%). Unsoliited dverse events tht ourred in 5% of sujets who reeived in ges 9 yers through 17 yers following the first dose inluded ough (7%), orophryngel pin (7%), hedhe (7%) nd nsl ongestion (6%). In Studies 2 nd 3, unsoliited dverse events tht ourred in 5% of sujets ges 5 yers through 8 yers fter the first or seond dose inluded the following: upper respirtory trt infetion (13%), ough (10%), rhinorrhe (7%), hedhe (5%), nsophryngitis (5%) nd pyrexi (5%). Unsoliited dverse events tht ourred in 5% of sujets who reeived in ges 9 yers through 17 yers following the first dose inluded upper respirtory trt infetion (9%) nd hedhe (8%). Adults In linil studies ompring to pleo or nother U.S.liensed trivlent intivted influenz vine, single dose of ws dministered to, nd sfety informtion olleted for, 11,104 sujets ges 18 through 64 yers nd 836 sujets ges 65 yers nd older. Clinil sfety dt for in dults re presented from three linil studies (Studies 4 through 6). In these studies, Afluri nd omprtor vine or pleo were dministered y needle nd syringe. Study 4 inluded 1,357 sujets for sfety nlysis, ges 18 through 64 yers, rndomized to reeive (1,089 sujets) or pleo (268 sujets) (see Clinil Studies [14]). Study 5 inluded 15,020 sujets for sfety nlysis, ges 18 through 64 yers, rndomized to reeive (10,015 sujets) or pleo (5,005 sujets) (see Clinil Studies [14]). Study 6 inluded 1,266 sujets for sfety nlysis, ges 65 yers nd older, rndomized to reeive (630 sujets) or nother U.S.liensed trivlent intivted influenz vine (mnuftured y Snofi Psteur In.) s n tive omprtor (636 sujets) (see Clinil Studies [14]). The sfety ssessment ws identil for the three dult studies. Lol (injetionsite) dverse retions nd systemi dverse events were soliited for 5 dys postvintion (Tle 4). Unsoliited dverse events were olleted for 21 dys postvintion. All dverse events re presented regrdless of ny tretment uslity ssigned y study investigtors. Among dult studies 4 through 6, there were no vinerelted deths or vinerelted serious dverse events reported. Tle 4: Proportion of Sujets 18 Yers of Age nd Older with Soliited Lol Adverse Retions or Systemi Adverse Events within 5 Dys fter Administrtion of or Pleo, Irrespetive of Cuslity (Studies 4, 5 nd 6) Perentge of Sujets in eh Age Group Reporting Event Study 4 Sujets 18 through 64 yers Study 5 Sujets 18 through 64 yers N=1087 Pleo 1088 N=266 N=10,015 Study 6 Sujets 65 yers Pleo Comprtor N=5005 N=630 N=636 Lol Adverse Retions Tenderness (Pin on touhing) Pin (without touhing) Redness <1 3 1 Swelling <1 7 8 Bruising <1 1 Systemi Adverse Events Hedhe Mlise Musle hes Nuse Chills/ Shivering Fever <1 1 Proportion of sujets reporting eh soliited lol dverse retion or systemi dverse event y tretment group sed on the numer of sujets ontriuting t lest one dt vlue for n individul sign/symptom (individul event denomintors). N = numer of sujets in the Sfety Popultion for eh tretment group.

4 In Study 4, hedhe ws the only unsoliited dverse event tht ourred in 5% of sujets who reeived or pleo (8% versus 6%, respetively). In Study 5, hedhe ws the only unsoliited dverse event tht ourred in 5% of sujets who reeived or pleo (12% versus 11%, respetively). In Study 6, unsoliited dverse events tht ourred in 5% of sujets who reeived inluded hedhe (8%), nsl ongestion (7%), ough (5%), rhinorrhe (5%), nd phryngolryngel pin (5%). Studies 1 to 6 were ll onduted when ws dministered y needle nd syringe. Additionlly, sfety informtion hs een olleted in linil study of dministered using the PhrmJet Strtis NeedleFree Injetion System (Study 7). Study 7 inluded 1,247 sujets for sfety nlysis, ges 18 through 64 yers, rndomized to reeive y either the PhrmJet Strtis NeedleFree Injetion System (624 sujets) or needle nd syringe (623 sujets). No deths or vinerelted serious dverse events were reported in Study 7. Lol (injetionsite) dverse retions nd systemi dverse events were soliited for 7 dys postvintion (Tle 5). Tle 5: Proportion of Sujets 18 through 64 Yers of Age with Soliited Lol Adverse Retions or Systemi Adverse Events within 7 Dys fter Administrtion of y PhrmJet Strtis NeedleFree Injetion System or Needle nd Irrespetive of Cuslity (Study 7). Perentge of Sujets Reporting Event Study 7 Sujets 18 through 64 yers PhrmJet Strtis Needle Needle nd Free Injetion System N= N= Lol Adverse Retions Tenderness Swelling Pin Redness Ithing Bruising 18 5 Systemi Adverse Events Mylgi Mlise Hedhe Chills 7 7 Nuse 7 7 Vomiting 1 2 Fever 0 0 Proportion of sujets reporting eh lol dverse retion or systemi dverse event y tretment group sed on the numer of sujets ontriuting t lest one dt vlue for n individul sign/ symptom (individul event denomintors). N = numer of sujets in the Sfety Popultion for eh tretment group. Denomintors for the PhrmJet Strtis NeedleFree Injetion System group were: N=540 for ithing nd N= for ll other prmeters. Denomintors for the needle nd syringe group were: N=527 for ithing nd N= for ll other prmeters. A totl of 155 sujets (pproximtely rndomly distriuted etween PhrmJet Strtis NeedleFree Injetion System nd needle nd syringe groups) reeived Diry Crds without ithing listed s soliited symptom. In Study 7, no unsoliited dverse events ourred in 5% of sujets who reeived dministered vi PhrmJet Strtis NeedleFree Injetion System up to 28 dys postvintion. 6.2 POSTMARKETING EXPERIENCE Beuse postmrketing reporting of dverse retions is voluntry nd from popultion of unertin size, it is not lwys possile to relily estimte their frequeny or estlish usl reltionship to vine exposure. The dverse retions desried hve een inluded in this setion euse they: 1) represent retions tht re known to our following immuniztions generlly or influenz immuniztions speifilly; 2) re potentilly serious; or 3) hve een reported frequently. These dverse retions reflet experiene in oth hildren nd dults nd inlude those identified during postpprovl use of outside the US sine Blood nd lymphti system disorders Trnsient thromoytopeni Immune system disorders Allergi retions inluding nphylti shok nd serum sikness Nervous system disorders Neurlgi, presthesi, onvulsions (inluding ferile seizures), enephlopthy, neuritis or neuropthy, trnsverse myelitis, nd GBS Vsulr disorders Vsulitis with trnsient renl involvement Skin nd suutneous tissue disorders Pruritus, urtiri, nd rsh Generl disorders nd dministrtion site onditions Cellulitis nd lrge injetion site swelling 6.3 ADVERSE REACTIONS ASSOCIATED WITH INFLUENZA VACCINATION Anphylxis hs een reported fter dministrtion of. Egg protein n indue immedite hypersensitivity retions mong persons who hve severe egg llergy. Allergi retions inlude hives, ngioedem, sthm, nd systemi nphylxis (see Contrinditions [4]). Neurologil disorders temporlly ssoited with influenz vintion, suh s enephlopthy, opti neuritis/neuropthy, prtil fil prlysis, nd rhil plexus neuropthy, hve een reported. Mirosopi polyngiitis (vsulitis) hs een reported temporlly ssoited with influenz vintion. 7 DRUG INTERACTIONS 7.1 CONCURRENT USE WITH OTHER VACCINES There re no dt to ssess the onomitnt dministrtion of with other vines. If is given t the sme time s nother injetle vine(s), the vine(s) should e dministered in seprte syringes nd seprte rm should e used. should not e mixed with ny other vine in the sme syringe or vil. 7.2 CONCURRENT USE WITH IMMUNOSUPPRESSIVE THERAPIES The immunologil response to my e diminished in individuls reeiving ortiosteroid or immunosuppressive therpies. 8 USE IN SPECIFIC POPULATIONS 8.1 PREGNANCY Pregnny Ctegory B: A reprodutive nd developmentl toxiity study hs een performed in femle rts t dose pproximtely 265 times the humn dose (on mg/kg sis) nd reveled no evidene of impired femle fertility or hrm to the fetus due to. There re, however, no dequte nd wellontrolled studies in pregnnt women. Beuse niml reprodution studies re not lwys preditive of humn response, should e given to pregnnt womn only if lerly needed. In the reprodutive nd developmentl toxiity study, the effet of on emryofetl nd prewening development ws evluted in pregnnt rts. Animls were dministered y intrmusulr injetion twie prior to gesttion, one during the period of orgnogenesis (gesttion dy 6), nd one lter in pregnny (gesttion dy 20), 0.5 ml/rt/osion (pproximtely 265fold exess reltive to the projeted humn dose on ody weight sis). No dverse effets on mting, femle fertility, pregnny, prturition, lttion prmeters, nd emryofetl or prewening development were oserved. There were no vinerelted fetl mlformtions or other evidene of tertogenesis. 8.3 NURSING MOTHERS hs not een evluted in nursing mothers. It is not known whether is exreted in humn milk. Beuse mny drugs re exreted in humn milk, ution should e exerised when is dministered to nursing womn. 8.4 PEDIATRIC USE is not pproved for use in hildren less thn 5 yers of ge. In linil study in whih hildren reeived or USliensed omprtor vine (Study 1, see Clinil Trils Experiene, [6.1]), the inidene of fever in hildren 6 months through 35 months of ge following the first nd seond doses of were 37% nd 15%, respetively, s ompred to 14% following eh dose in the omprtor group. Among hildren 3 yers through 4 yers of ge, the inidene of fever following the first nd seond doses of were 32% nd 14%, respetively, s ompred to 11% nd 16% in the omprtor. In n openlel study (Study 2), fever, irritility, loss of ppetite, nd vomiting/ dirrhe ourred more frequently in hildren 6 months through 35 months of ge s ompred to older hildren. Aross three peditri studies of (Studies 1, 2, nd 3), 1.2% of eligile hildren (n=1,764) were disontinued from the seond vintion euse of severe fever ( 104ºF) within 48 hours of the first vintion. Aross the three peditri studies, two hildren, 7month old nd 3yer old, experiened vinerelted ferile seizures (rte of 0.07% ross studies), one of whih ws serious. Administrtion of CSL s 2010 Southern Hemisphere influenz vine ws ssoited with inresed rtes of fever nd ferile seizures, predominntly in hildren elow the ge of 5 yers s ompred to previous yers, in postmrketing reports onfirmed y postmrketing studies (see Wrnings nd Preutions [5.1]).

5 The PhrmJet Strtis NeedleFree Injetion System is not pproved s method of dministering to hildren nd dolesents less thn 18 yers of ge due to lk of dequte dt supporting sfety nd effetiveness in this popultion. 8.5 GERIATRIC USE In linil studies, hs een dministered to, nd sfety informtion olleted for, 836 sujets ges 65 yers nd older (see Clinil Trils Experiene [6.1]). After dministrtion of, hemgglutintioninhiiting ntiody responses in persons 65 yers of ge nd older were lower s ompred to younger dult sujets (see Clinil Studies [14]). The PhrmJet Strtis NeedleFree Injetion System is not pproved s method of dministering to dults 65 yers of ge nd older due to lk of dequte dt supporting sfety nd effetiveness in this popultion. 11 DESCRIPTION, Influenz Vine for intrmusulr injetion, is sterile, ler, olorless to slightly oplesent suspension with some sediment tht resuspends upon shking to form homogeneous suspension. is prepred from influenz virus propgted in the llntoi fluid of emryonted hiken eggs. Following hrvest, the virus is purified in surose density grdient using ontinuous flow zonl entrifugtion. The purified virus is intivted with etpropioltone, nd the virus prtiles re disrupted using sodium turodeoxyholte to produe split virion. The disrupted virus is further purified nd suspended in phosphte uffered isotoni solution. is stndrdized ording to USPHS requirements for the influenz seson nd is formulted to ontin 45 mg hemgglutinin (HA) per 0.5 ml dose in the reommended rtio of 15 mg HA for eh of the three influenz strins reommended for the Northern Hemisphere influenz seson: A/Cliforni/7/2009 (H1N1), NYMC X181, A/Texs/50/2012 (H3N2), NYMC X223 nd B/Msshusetts/2/2012, NYMC BX51B. Thimerosl, merury derivtive, is not used in the mnufturing proess for the single dose presenttions; therefore these produts ontin no preservtive. The multidose presenttion ontins thimerosl, dded s preservtive; eh 0.5 ml dose ontins 24.5 mg of merury. A single 0.5 ml dose of ontins sodium hloride (4.1 mg), monosi sodium phosphte (80 mg), disi sodium phosphte (300 mg), monosi potssium phosphte (20 mg), potssium hloride (20 mg), nd lium hloride (1.5 mg). From the mnufturing proess, eh 0.5 ml dose my lso ontin residul mounts of sodium turodeoxyholte ( 10 ppm), ovlumin (<1 mg), neomyin sulfte ( 3 nnogrms [ng]), polymyxin B ( 0.5 ng), nd etpropioltone ( 2 ng). The ruer tip p nd plunger used for the preservtivefree, singledose syringes nd the ruer stoppers used for the multidose vil were not mde with nturl ruer ltex. 12 CLINICAL PHARMACOLOGY 12.1 MECHANISM OF ACTION Influenz illness nd its omplitions follow infetion with influenz viruses. Glol surveillne of influenz identifies yerly ntigeni vrints. For exmple, sine 1977 ntigeni vrints of influenz A (H1N1 nd H3N2) nd influenz B viruses hve een in glol irultion. Speifi levels of hemgglutintion inhiition (HI) ntiody titers postvintion with intivted influenz vine hve not een orrelted with protetion from influenz virus. In some humn studies, ntiody titers of 1:40 or greter hve een ssoited with protetion from influenz illness in up to 50% of sujets. 2,3 Antiody ginst one influenz virus type or sutype onfers limited or no protetion ginst nother. Furthermore, ntiody to one ntigeni vrint of influenz virus might not protet ginst new ntigeni vrint of the sme type or sutype. Frequent development of ntigeni vrints through ntigeni drift is the virologi sis for sesonl epidemis nd the reson for the usul hnge to one or more new strins in eh yer s influenz vine. Therefore, intivted influenz vines re stndrdized to ontin the HA of three strins (i.e., typilly two type A nd one type B) representing the influenz viruses likely to e irulting in the US during the upoming winter. Annul revintion with the urrent vine is reommended euse immunity delines during the yer fter vintion nd irulting strins of influenz virus hnge from yer to yer NONCLINICAL TOXICOLOGY 13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY hs not een evluted for rinogeni or mutgeni potentil, or mle infertility in nimls. A reprodutive study of femle rts vinted with reveled no impirment of fertility (see Pregnny, 8.1). 14 CLINICAL STUDIES 14.1 EFFICACY AGAINST LABORATORYCONFIRMED INFLUENZA In Study 5, the effiy of ws demonstrted in rndomized, oserverlind, pleoontrolled study onduted in 15,044 sujets. Helthy sujets 18 through 64 yers of ge were rndomized in 2:1 rtio to reeive single dose of (enrolled sujets: 10,033; evlule sujets: 9,889) or pleo (enrolled sujets: 5,011; evlule sujets: 4,960). The men ge of ll rndomized sujets ws 35.5 yers. 54.4% were femle nd 90.2% were White. Lortoryonfirmed influenz ws ssessed y tive nd pssive surveillne of influenzlike illness (ILI) eginning 2 weeks postvintion until the end of the influenz seson, pproximtely 6 months postvintion. ILI ws defined s t lest one respirtory symptom (e.g., ough, sore throt, nsl ongestion) nd t lest one systemi symptom (e.g., orl temperture of F or higher, feverishness, hills, ody hes). Nsl nd throt sws were olleted from sujets who presented with n ILI for lortory onfirmtion y virl ulture nd reltime reverse trnsription polymerse hin retion. Influenz virus strin ws further hrterized using gene sequening nd pyrosequening. Attk rtes nd vine effiy, defined s the reltive redution in the influenz infetion rte for ompred to pleo, were lulted using the per protool popultion. Vine effiy ginst lortoryonfirmed influenz infetion due to influenz A or B virus strins ontined in the vine ws 60% with lower limit of the 95% CI of 41% (Tle 6). Tle 6: LortoryConfirmed Influenz Infetion Rte nd Vine Effiy in Adults 18 through 64 Yers of Age (Study 5) Sujets Lortory Confirmed Influenz Cses Influenz Infetion Rte N N n/n % % Vine Effiy Lower Limit of the 95% CI Vinemthed Strins Pleo Any Influenz Virus Strin Pleo Arevitions: CI, onfidene intervl The Per Protool Popultion ws identil to the Evlule Popultion in this study. Vine effiy = 1 minus the rtio of /pleo infetion rtes. The ojetive of the study ws to demonstrte tht the lower limit of the CI for vine effiy ws greter thn 40% IMMUNOGENICITY IN CHILDREN ADMINISTRATION VIA NEEDLE AND SYRINGE Study 1 ws rndomized, oserverlind, omprtorontrolled study to evlute the immunologil noninferiority of to U.S.liensed trivlent intivted influenz vine (mnuftured y Snofi Psteur, In.) in sujets 6 months through 17 yers of ge. Study vines were dministered y needle nd syringe. Results re presented for hildren 5 through 17 yers of ge (Tle 7). A totl of 832 sujets (ged 5 through 17 yers) were enrolled. Sujets were rndomized in 1:1 rtio to reeive (enrolled sujets: 417; evlule sujets: 383) or the omprtor vine (enrolled sujets: 415; evlule sujets: 383). Children 6 months through 8 yers of ge with no history of influenz vintion reeived 2 doses pproximtely 28 dys prt. Children 6 months through 8 yers of ge with history of influenz vintion nd hildren 9 yers of ge nd older reeived 1 dose. Children 6 months through 35 months of ge reeived 0.25 ml of or omprtor influenz vine, nd hildren 3 yers of ge nd older reeived 0.5 ml of or omprtor influenz vine. Nerly equl proportions of sujets were mle (49.9%) nd femle (50.1%), nd the mjority were White (85.0%) or Blk (10.3%). Immunogeniity ssessments were performed prior to vintion nd t 21 dys fter vintion. The oprimry endpoints were HI Geometri Men Titer () rtios (djusted for seline HI titers) nd the differene in seroonversion rtes for eh vine strin 21 dys fter the finl vintion. Prespeified noninferiority riteri required tht the upper ound of the 2sided 95% CI of the rtio (Comprtor/) did not exeed 1.5 nd the upper ound of the 2sided 95% CI of the seroonversion rte differene (Comprtor minus ) did not exeed 10.0% for eh strin. As shown in Tle 6, noninferiority of to the omprtor vine ws demonstrted in the per protool popultion for influenz A sutypes A(H1N1)

6 nd A(H3N2), ut not for influenz type B. For influenz type B, noninferiority ws demonstrted for HI s, ut not for seroonversion rtes. Note tht the study ws powered to ssess the prespeified noninferiority riteri sed on 1400 evlule sujets. Anlysis of the 761 sujets ged 5 through 17 yers redued the power of the study nd widened the onfidene intervls. In the prespeified nlysis, ws not inferior to the omprtor vine for ll three virus strins. Postho nlyses of immunogeniity y gender did not demonstrte signifint differenes etween mles nd femles. The study ws not suffiiently diverse to ssess differenes etween res or ethniities. Tle 7: PostVintion HI Antiody s, Seroonversion Rtes, nd Anlyses of NonInferiority of to U.S.Liensed Comprtor, Sujets 5 through 17 Yers of Age (Study 1) Strin A (H1N1) A (H3N2) Postvintion Comprtor N=380 N= B Differene Seroonversion % Rtio Comprtor over 1.03 (0.88, 1.21) 1.07 (0.94, 1.23) 1.10 (0.94, 1.29) Comprtor N=381 N= Arevitions: CI, onfidene intervl;, geometri men titer. rtios re djusted for seline HI titers. Comprtor minus 0.1 (6.8, 7.0) 2.4 (4.0, 8.9) 5.1 (1.3, 11.4) Met oth predefined noninferiority riteri? Seroonversion rte is defined s 4fold inrese in postvintion HI ntiody titer from previntion titer 1:10 or n inrese in titer from < 1:10 to 1:40. Note tht the study ws powered to ssess the prespeified noninferiority riteri sed on 1400 evlule sujets IMMUNOGENICITY IN ADULTS AND OLDER ADULTS ADMINISTRATION VIA NEEDLE AND SYRINGE Two rndomized, ontrolled linil studies of evluted the immune responses y mesuring HI ntiody titers to eh virus strin in the vine in dults s ompred to pleo (dults 18 through 64 yers) or nother U.S. liensed trivlent influenz vine (dults 65 yers). In these studies, postvintion immunogeniity ws evluted on ser otined 21 dys fter dministrtion of single dose of. Study 4 ws rndomized, doulelinded, pleoontrolled, multienter study in helthy sujets ges 18 through 64 yers. A totl of 1,357 sujets were vinted (1,089 sujets with nd 268 with pleo). Sujets who reeived were vinted using either the preservtivefree or thimeroslontining presenttion. The evlule popultion onsisted of 1,341 sujets (1,077 in the group nd 264 in the pleo group). The men ge of the entire evlule popultion reeiving ws 38 yers. 62.5% of sujets were femle, 81.3% were White, 12.1% were Blk, nd 6.2% were Asin. Serum HI ntiody responses to met the prespeified oprimry endpoint riteri for ll three virus strins (Tle 8). Similr responses were oserved etween genders. The study ws not suffiiently diverse to ssess immunogeniity y re or ethniity. Tle 8: Serum Antiody Responses in Sujets 18 through 64 Yers of Age Reeiving (Study 4) Strin Vrile N=1077 vlue Pleo N=264 vlue A(H1N1) HI Titer 1: % (96.7, 98.6) 74.6% (68.9, 79.8) Seroonversion Rte (%) 48.7% (45.6, 51.7) 2.3% (0.8, 4.9) A(H3N2) HI Titer 1: % (99.5, 100.0) 72.0% (66.1, 77.3) Seroonversion Rte (%) 71.5% (68.7, 74.2) 0.0% (N/A) B HI Titer 1: % (92.7, 95.6) 47.0% (40.8, 53.2) Seroonversion Rte (%) 69.7% (66.9, 72.5) 0.4% (< 0.1, 2.1) HI titer 1:40 is defined s the proportion of sujets with minimum postvintion HI ntiody titer of 1:40. Lower ound of 95% CI for HI ntiody titer 1:40 should e > 70% for the study popultion. Seroonversion rte is defined s 4fold inrese in postvintion HI ntiody titer from previntion titer 1:10 or n inrese in titer from < 1:10 to 1:40. Lower ound of 95% CI for seroonversion should e > 40% for the study popultion. No Study 6 ws rndomized, oserverlind, omprtorontrolled study tht enrolled 1,268 sujets 65 yers of ge nd older (Tle 8). This study ompred the immune response following dministrtion of to tht following USliensed trivlent intivted influenz vine (mnuftured y Snofi Psteur In.). Sujets were rndomized in 1:1 rtio to reeive single vintion of (enrolled sujets: 631; evlule sujets: 605) or the omprtor vine (enrolled sujets: 637; evlule sujets: 610). Immunogeniity ssessments were performed prior to vintion nd t 21 dys fter vintion. Most of the sujets in the perprotool immunogeniity popultion were femle (56.7%) nd White (97.4%). 2.0% were Blk nd less thn 1.0% were of other res or ethniities. The oprimry endpoints were HI rtios (djusted for seline HI titers) nd the differene in seroonversion rtes for eh vine strin 21 dys fter vintion. Prespeified noninferiority riteri required tht the upper ound of the 2sided 95% CI of the rtio (Comprtor/) did not exeed 1.5 nd the upper ound of the 2sided 95% CI of the seroonversion rte differene (Comprtor minus ) did not exeed 10.0% for eh strin. As shown in Tle 9, noninferiority of to the omprtor vine ws demonstrted in the per protool popultion for influenz A sutypes A(H1N1) nd A(H3N2), ut not for influenz type B. For the B strin, noninferiority ws demonstrted for HI s, ut not for seroonversion rtes. Postho nlyses of immunogeniity y gender did not demonstrte signifint differenes etween mles nd femles. The study ws not suffiiently diverse to ssess differenes etween res or ethniities. Tle 9: PostVintion HI Antiody s, Seroonversion Rtes, nd Anlyses of NonInferiority of to U.S. Liensed Comprtor, Adults 65 Yers of Age nd Older (Study 6) Strin Postvintion Comprtor N=605 N=610 A(H1N1) A(H3N2) B Rtio Comprtor over 1.04 (0.92, 1.18) 0.95 (0.83, 1.08) 1.12 (1.01, 1.25) Seroonversion % Differene Comprtor N=605 N= Comprtor minus 4.1 (1.4, 9.6) 0.7 (5.9, 4.5) 5.2 (0.1, 10.4) Met oth predefined noninferiority riteri? Arevitions: CI, onfidene intervl;, geometri men titer. Postvintion s were djusted for seline HI titers. Seroonversion rte is defined s 4fold inrese in postvintion HI ntiody titer from previntion titer 1:10 or n inrese in titer from < 1:10 to 1: IMMUNOGENICITY IN ADULTS ADMINISTRATION VIA PHARMAJET STRATIS NEEDLEFREE INJECTION SYSTEM Study 7 ws rndomized, omprtorontrolled noninferiority study tht enrolled 1,250 sujets 18 through 64 yers of ge. This study ompred the immune response following dministrtion of when delivered IM using either the PhrmJet Strtis NeedleFree Injetion System or needle nd syringe. Immunogeniity ssessments were performed prior to vintion nd t 28 dys fter vintion in the immunogeniity popultion (1130 sujets, 562 PhrmJet Strtis NeedleFree Injetion System group, 568 needle nd syringe group). The oprimry endpoints were HI rtios for eh vine strin nd the solute differene in seroonversion rtes for eh vine strin 28 dys fter vintion. As shown in Tle 10, noninferiority of dministrtion of y the PhrmJet Strtis NeedleFree Injetion System ompred to dministrtion of y needle nd syringe ws demonstrted in the immunogeniity popultion for ll strins. Postho nlyses of immunogeniity y ge showed tht younger sujets (18 through 49 yers) eliited higher immunologil responses thn older sujets (50 through 64 yers). Postho nlyses of immunogeniity ording to gender nd ody mss index did not revel signifint influenes of these vriles on immune responses. The study popultion ws not suffiiently diverse to ssess immunogeniity y re or ethniity. No

7 Tle 10: Bseline nd PostVintion HI Antiody s, Seroonversion Rtes, nd Anlyses of NonInferiority of Administered y PhrmJet Strtis NeedleFree Injetion System or Needle nd, Adults 18 through 64 Yers of Age (Study 7) Strin Needle nd N=568 Bseline Postvintion Rtio Seroonversion % Differene PhrmJet Strtis NeedleFree Injetion System N=562 Needle nd N=568 PhrmJet Strtis NeedleFree Injetion System N=562 A(H1N1) A(H3N2) B Needle nd over PhrmJet Strtis NeedleFree Injetion System 0.99 (0.88, 1.12) 1.08 (0.96, 1.21) 0.94 (0.83, 1.06) Needle nd N=568 PhrmJet Strtis NeedleFree Injetion System N= Needle nd minus PhrmJet Strtis NeedleFree Injetion System 0.8 (4.8, 6.5) 1.3 (4.5, 7.1) 0.3 (5.2, 5.9) Met oth predefined noninferiority riteri? Arevitions: CI, onfidene intervl;, geometri men titer rtio is defined s postvintion for Needle nd /PhrmJet Strtis NeedleFree Injetion System Seroonversion rte is defined s 4fold inrese in postvintion HI ntiody titer from previntion titer 1:10 or n inrese in titer from < 1:10 to 1:40. Noninferiority (NI) riteri for the rtio: upper ound of 2sided 95% CI on the rtio of Needle nd /PhrmJet Strtis NeedleFree Injetion System. should not exeed 1.5. NI riteri for the seroonversion rte (SCR) differene: upper ound of 2sided 95% CI on the differene etween SCR Needle nd SCR PhrmJet Strtis NeedleFree Injetion System should not exeed 10%. 15 REFERENCES 1. Centers for Disese Control nd Prevention. Prevention nd Control of Influenz: Reommendtions of the Advisory Committee on Immuniztion Prties (ACIP). MMWR Reomm Rep 2010;59 (RR8): Hnnoun C, Megs F, Piery J. Immunogeniity nd Protetive Effiy of Influenz Vintion. Virus Res 2004;103: Hoson D, Curry RL, Bere AS, et l. The Role of Serum HemgglutintionInhiiting Antiody in Protetion ginst Chllenge Infetion with Influenz A2 nd B Viruses. J Hyg Cm 1972;70: HOW SUPPLIED/STORAGE AND HANDLING 16.1 HOW SUPPLIED Eh produt presenttion inludes pkge insert nd the following omponents: Crton Presenttion Components NDC Numer PreFilled MultiDose Vil Ten 0.5 ml singledose syringes without needles [NDC ] One 5 ml vil, whih ontins ten 0.5 ml doses [NDC ] 16.2 STORAGE AND HANDLING Store refrigerted t 28 C (3646 F). Do not freeze. Disrd if produt hs een frozen. Protet from light. Do not use eyond the expirtion dte printed on the lel. One the stopper of the multidose vil hs een piered the vil must e disrded within 28 dys. 17 PATIENT COUNSELING INFORMATION Inform the vine reipient or gurdin of the potentil enefits nd risks of immuniztion with. Inform the vine reipient or gurdin tht is n intivted vine tht nnot use influenz ut stimultes the immune system to produe ntiodies tht protet ginst influenz, nd tht the full effet of the vine is generlly hieved pproximtely 3 weeks fter vintion. Instrut the vine reipient or gurdin to report ny severe or unusul dverse retions to their helthre provider. Provide the vine reipient or gurdin with Vine Informtion Sttements whih re required y the Ntionl Childhood Vine Injury At of 1986 to e given prior to immuniztion. These mterils re ville free of hrge t the Centers for Disese Control nd Prevention (CDC) wesite ( Instrut the vine reipient or gurdin tht nnul revintion is reommended. Mnuftured y: iocsl Pty Ltd. Prkville, Vitori, 3052, Austrli US Liense No Distriuted y: iocsl In.1020 First Avenue, King of Prussi, PA 19406, USA is registered trdemrk of CSL Limited used under liense. iocsl Pty Ltd. nd iocsl In. re susidiries of CSL Limited. PhrmJet nd STRATIS re registered trdemrks of PhrmJet.