7Disconnect the syringe from the. 9Reconnect the syringe to the ADVATE

Transcription

1 TROUBLESHOOTING GUIDE The following instructions will guide you through recovering ADVATE if the initil reconstitution procedure does not work. Some steps my need to be repeted from this initil reconstitution procedure. RECOVERY PROCEDURE 1Position the ADVATE with BAXJECT III system with the diluent vil on top. The diluent vil hs the blue stripe. Resons why there might be diluent trnsfer difficulty: If you ctivted the ADVATE with BAXJECT III system upside down (blue stripe t bottom) If the system is tilted while diluent is trnsferring If the blue cp locted on the side of the system is removed before ctivting the system If you hve injected ir into the system in error If you did not press down hrd enough to ctivte 4Press the plunger on the syringe ll the wy down to expel ny ir from the syringe. 7Disconnect the syringe from the system. Agin, press the plunger ll the wy down to expel ny ir from the syringe ADVATE Turn the system over 10 so tht the vil with the ADVATE solution is on top (blue stripe t bottom). 2Mke sure the product nd diluent vils re fully ctivted nd pressed into the plstic housing. 5Connect syringe to the system. Do not inject ir. Swirl ADVATE with BAXJECT III 8 gently nd continuously until the ADVATE is completely dissolved. Slowly pull the plunger 11 bck to withdrw the mixed ADVATE into the syringe. 3Remove the blue cp locted on the side of the reconstitution system. 6Pull the plunger bck slowly to withdrw ir from the vils; this will drw diluent into the ADVATE vil. If these steps fil to ddress the problems you re hving, plese contct your helthcre provider or locl hemophili tretment center. 9Reconnect the syringe to the ADVATE with BAXJECT III system. 12 Disconnect the syringe from the system. It is cceptble for smll mount of liquid to remin in the vil. You re now redy to infuse (no fster thn 10 ml per minute over period of 5 minutes). ADVATE [Antihemophilic Fctor (Recombinnt)] Importnt Informtion Indictions ADVATE is medicine used to replce clotting fctor (fctor VIII or ntihemophilic fctor) tht is missing in people with hemophili A (lso clled clssic hemophili). ADVATE is used to prevent nd control bleeding in dults nd children (0-16 yers) with hemophili A. Your helthcre provider my give you ADVATE when you hve surgery. ADVATE cn reduce the number of bleeding episodes in dults nd children (0-16 yers) when used regulrly (prophylxis). ADVATE is not used to tret von Willebrnd disese. DETAILED IMPORTANT RISK INFORMATION You should not use ADVATE if you: Are llergic to mice or hmsters. Are llergic to ny ingredients in ADVATE. Tell your helthcre provider if you re pregnnt or brestfeeding becuse ADVATE my not be right for you. You should tell your helthcre provider if you: Hve or hve hd ny medicl problems. Tke ny medicines, including prescription nd non-prescription medicines, such s over-the-counter medicines, supplements or herbl remedies. Hve ny llergies, including llergies to mice or hmsters. Hve been told tht you hve inhibitors to fctor VIII (becuse ADVATE my not work for you). DETAILED IMPORTANT RISK INFORMATION continued Your body my form inhibitors to fctor VIII. An inhibitor is prt of the body s norml defense system. If you form inhibitors, it my stop ADVATE from working properly. Consult with your helthcre provider to mke sure you re crefully monitored with blood tests for the development of inhibitors to fctor VIII. You cn hve n llergic rection to ADVATE. Cll your helthcre provider right wy nd stop tretment if you get rsh or hives, itching, tightness of the throt, chest pin or tightness, difficulty brething, lighthededness, dizziness, nuse or finting. Side effects tht hve been reported with ADVATE include: cough, hedche, joint swelling/ching, sore throt, fever, itching, unusul tste, dizziness, hemtom, bdominl pin, hot flshes, swelling of legs, dirrhe, chills, runny nose/congestion, nuse/vomiting, sweting, nd rsh. Tell your helthcre provider bout ny side effects tht bother you or do not go wy or if your bleeding does not stop fter tking ADVATE. You re encourged to report negtive side effects of prescription drugs to the FDA. Visit or cll FDA Plese see ccompnying ADVATE full Prescribing Informtion. Bxter, Advte nd Bxject III re trdemrks of Bxter Interntionl Inc. Copyright 2014, Bxter Helthcre Corportion. All rights reserved. USBS/34/ (1) Bxter, Advte nd Bxject III re trdemrks of Bxter Interntionl Inc. Copyright 2014, Bxter Helthcre Corportion. All rights reserved. USBS/34/

2 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ADVATE sfely nd effectively. See full prescribing informtion for ADVATE. ADVATE (Antihemophilic Fctor [Recombinnt]) Lyophilized Powder for Reconstitution for Intrvenous Injection Initil U.S. Approvl: 2003 RECENT MAJOR CHANGES Dosge nd Administrtion (2) 04/2014 INDICATIONS AND USAGE ADVATE is recombinnt ntihemophilic fctor indicted for use in children nd dults with hemophili A for: Control nd prevention of bleeding episodes. Periopertive mngement. Routine prophylxis to prevent or reduce the frequency of bleeding episodes. ADVATE is not indicted for the tretment of von Willebrnd disese. (1) DOSAGE AND ADMINISTRATION For intrvenous injection fter reconstitution only (2) Ech vil of ADVATE contins the lbeled mount of recombinnt fctor VIII in Interntionl Units (IU). (2) The required dosge is determined using the following formuls: Desired increment in fctor VIII concentrtion (IU/dL or % of norml)=[totl dose (IU)/body weight (kg)] x 2 [IU/dL]/[IU/kg]; OR Required dose (IU) = body weight (kg) x desired fctor VIII rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL). (2) Frequency of ADVATE dministrtion is determined by the type of bleeding episode nd the recommendtion of the treting physicin. (2.1, 2.2) For prophylxis regimen to prevent or reduce frequency of bleeding episodes, dose between 20 to 40 IU per kg every other dy (3 to 4 times weekly). Alterntively, n every third dy dosing regimen trgeted to mintin FVIII trough levels 1% my be employed. (2.3) DOSAGE FORMS AND STRENGTHS ADVATE is vilble s lyophilized powder in single-use vils contining nominlly 250, 500, 1000, 1500, 2000, 3000 or 4000 IU. (3) CONTRAINDICATIONS Do not use in ptients who hve life-thretening hypersensitivity rections, including nphylxis, to mouse or hmster protein or other constituents of the product (mnnitol, trehlose, sodium chloride, histidine, Tris, clcium chloride, polysorbte 80, nd/or glutthione). (4) WARNINGS nd PRECAUTIONS Anphylxis nd severe hypersensitivity rections my occur. Ptients my develop hypersensitivity to mouse or hmster protein, which is present in trce mounts in the product. Should symptoms occur, discontinue tretment with ADVATE nd dminister pproprite tretment. (5.1) Development of ctivity-neutrlizing ntibodies my occur. If expected plsm fctor VIII ctivity levels re not ttined, or if bleeding is not controlled with n pproprite dose, perform n ssy tht mesures fctor VIII inhibitor concentrtion. (5.2, 5.3) ADVERSE REACTIONS Serious dverse drug rections reported re hypersensitivity nd fctor VIII inhibitors. (6.1) The most common dverse drug rections observed in 10% of ptients re pyrexi, hedche, cough, nsophryngitis, vomiting, rthrlgi, nd limb injury. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Bxter Helthcre Corportion t or FDA t FDA-1088 or USE IN SPECIFIC POPULATIONS Pregnncy: No humn or niml dt. Use only if clerly needed. (8.1) Peditric Use: Clernce (bsed on per kg body weight) is higher in the peditric popultion. Higher or more frequent dosing my be needed. (8.4) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling. FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Guidelines 2.2 Preprtion nd Reconstitution 2.3 Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Rections 5.2 Neutrlizing Antibodies 5.3 Monitoring Lbortory Tests 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 6.2 Post Mrketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES Revised: 04/ REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION nd FDA- Approved Ptient Lbeling * Sections or subsections omitted from the full prescribing informtion re not listed

3 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt)] 1. INDICATIONS AND USAGE ADVATE (Antihemophilic Fctor [Recombinnt]) is recombinnt ntihemophilic fctor indicted for use in children nd dults with hemophili A (congenitl fctor VIII deficiency or clssic hemophili) for: Control nd prevention of bleeding episodes. Periopertive mngement. Routine prophylxis to prevent or reduce the frequency of bleeding episodes. ADVATE is not indicted for the tretment of von Willebrnd disese. 2. DOSAGE AND ADMINISTRATION For intrvenous injection fter reconstitution only. 2.1 Dosing Guidelines Dosge nd durtion of tretment depend on the severity of fctor VIII deficiency, the loction nd extent of the bleeding, nd the ptient s clinicl condition. Creful control of replcement therpy is especilly importnt in cses of mjor surgery or life-thretening bleeding episodes. Ech vil of ADVATE hs the recombinnt fctor VIII potency in Interntionl Units (IU) stted on the lbel on the externl housing. The expected in vivo pek increse in fctor VIII level expressed s IU/dL of plsm or percent of norml cn be estimted using the following formuls: IU/dL (or % of norml) = [totl dose (IU)/body weight (kg)] x 2 [IU/dL]/[IU/kg] OR Required dose (Interntionl Units) = body weight (kg) x desired fctor VIII rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL) Exmples (ssuming ptient s bseline fctor VIII level is < 1% of norml): 1. A dose of 1750 IU ADVATE dministered to 70 kg ptient should be expected to result in pek post-infusion fctor VIII increse of 1750 IU x {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of norml). 2. A pek level of 70% is required in 40 kg child. In this sitution, the pproprite dose would be 40 kg x 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU. Bse the dose nd frequency on the individul clinicl response. Ptients my vry in their phrmcokinetic (e.g., hlf-life, in vivo recovery) nd clinicl responses to ADVATE. Although you cn estimte the dose by the clcultions bove, whenever possible, perform pproprite lbortory tests including seril fctor VIII ctivity ssys. [see Wrnings nd Precutions (5.4) nd Clinicl Phrmcology (12.3)] Control nd Prevention of Bleeding Episodes A guide for dosing ADVATE for the control nd prevention of bleeding episodes is provided in Tble 1. The gol of tretment is to mintin plsm fctor VIII ctivity level t or bove the plsm levels (in % of norml or in IU/dL) outlined in Tble 1. Tble 1 Dosing for Control nd Prevention of Bleeding Episodes Type of Bleeding Episodes Minor Erly hemrthrosis, mild muscle bleeding, or mild orl bleeding episode. Moderte Muscle bleeding, bleeding into the orl cvity, definite hemrthroses, nd known trum. Mjor Significnt gstrointestinl bleeding, intrcrnil, intr-bdominl or intrthorcic bleeding, centrl nervous system bleeding, bleeding in the retrophryngel or retroperitonel spces or iliopsos sheth, frctures, hed trum. Fctor VIII Level Required (% of norml or IU/dL) Dose (IU/kg) Frequency of Doses (hours) Every hours (Every 8 to 24 hours for ptients under the ge of 6) Every hours (Every 8 to 24 hours for ptients under the ge of 6) Every 8-24 hours (Every 6 to 12 hours for ptients under the ge of 6) Dose (IU/kg) = Desired fctor VIII rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL) Durtion of Therpy (dys) Until the bleeding episode is resolved (s indicted by relief of pin) or heling is chieved (pproximtely 1 to 3 dys). Until the bleeding episode is resolved (s indicted by relief of pin) or heling is chieved (pproximtely 3 dys or more). Until resolution of the bleeding episode hs occurred. Periopertive Mngement A guide for dosing ADVATE during surgery (periopertive mngement) is provided in Tble 2. The gol of tretment is to mintin plsm fctor VIII ctivity level t or bove the plsm level (in % of norml or in IU/dL) outlined in Tble 2. Type of Surgery Minor Including tooth extrction Mjor Intrcrnil, intr-bdominl, or intrthorcic surgery, joint replcement surgery Tble 2 Dosing for Periopertive Mngement Fctor VIII Level Required (% of norml or IU/dL) Dose (IU/kg) (pre- nd postopertive) Frequency of Doses (hours) Single dose within one hour of the opertion. Repet fter hours for optionl dditionl dosing s needed to control bleeding One dose preopertive to chieve 100% ctivity. Every 8-24 hours (Every 6 to 24 hours for ptients under the ge of 6) Dose (IU/kg) = Desired fctor VIII rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL) Durtion of Therpy (dys) Single dose or repet s needed to control bleeding. For dentl procedures, djunctive therpy my be considered. Depend on the desired level of fctor VIII nd stte of wound heling. Routine Prophylxis Use dose of 20 to 40 Interntionl Units of fctor VIII per kg body weight every other dy (3 to 4 times weekly). Alterntively, use every third dy dosing regimen trgeted to mintin FVIII trough levels 1%. Adjust dose bsed on the ptient s clinicl response. 1,2 2.2 Preprtion nd Reconstitution Preprtion Do not remove ADVATE or diluent vils from the externl housing. Alwys work on clen surfce nd wsh your hnds before performing the procedures. Exmine the pckging contining ADVATE to ensure no dmge or peeling of the lid is evident. Do not use if the lid is not completely seled on the blister. Do not remove ADVATE or diluent vils from the externl housing. Reconstitution 1. Allow the ADVATE pckge to rech room temperture. 2. Open the pckge by peeling wy the lid. Remove ADVATE from the pckge nd verify tht the expirtion dte on the lbel hs not pssed nd the potency unit number is sme s expected. Inspect prenterl drug products for discolortion nd prticulte mtter. The ADVATE powder should be white to off-white in color nd the diluent free from foreign prticles. Do not use if the criteri re not met. 3. Plce the ADVATE on flt surfce with the diluent vil on top (Figure A). The diluent vil hs blue stripe. Do not remove the blue cp until instructed in lter step. 4. With one hnd holding the ADVATE housing, press down firmly on the diluent vil with the other hnd until the system is fully collpsed nd the diluent flows down into the ADVATE vil (Figure B). Do not tilt the system until the trnsfer is complete. 5. Verify tht diluent trnsfer is complete. Swirl gently until the powder is completely dissolved (Figure C). Do not shke. Do not refrigerte fter reconstitution. 2.3 Administrtion For intrvenous injection only. Inspect prenterl drug products for prticulte mtter nd discolortion prior to dministrtion. The solution should be cler nd colorless in ppernce. If not, do not use the solution nd notify Bxter immeditely. Administer ADVATE t room temperture within 3 hours of reconstitution. Use plstic syringes with this product becuse proteins in the product tend to stick to the surfce of glss syringes. Administrtion Procedures 1. Use septic technique. 2. Remove the blue cp from the housing. Connect the syringe to the system (Figure D). Do not inject ir into the ADVATE. 3. Turn the system upside down (fctor concentrte vil now on top). Drw the fctor concentrte into the syringe by pulling the plunger bck slowly (Figure E). 4. Disconnect the syringe, ttch suitble needle, nd inject intrvenously s instructed. If ptient is to receive more thn one ADVATE-BAXJECT III system or combintion of n ADVATE-BAXJECT II nd n ADVATE-BAXJECT III system, the contents my be drwn into the sme syringe. 5. Administer ADVATE over period of 5 minutes (mximum infusion rte 10 ml/min). Determine the pulse rte before nd during dministrtion of ADVATE. Should significnt increse in pulse rte occur, reducing the rte of dministrtion or temporrily hlting the injection usully llows the symptoms to dispper promptly.

4 3. DOSAGE FORMS AND STRENGTHS ADVATE is vilble s lyophilized powder in single-use vils contining nominlly 250, 500, 1000, 1500, 2000, 3000, or 4000 IU. The IU strengths come with 2 ml Sterile Wter for Injection (swfi); the IU strengths come with 5 ml of swfi. Ech ADVATE is lbeled on the housing with the recombinnt ntihemophilic fctor (rahf) ctivity expressed in Interntionl Units per system. This potency ssignment employs fctor VIII concentrte stndrd tht is referenced to WHO (World Helth Orgniztion) interntionl stndrd for fctor VIII concentrtes nd is evluted by pproprite methodology to ensure ccurcy of the results. 4. CONTRAINDICATIONS ADVATE is contrindicted in ptients who hve life-thretening hypersensitivity rections, including nphylxis, to mouse or hmster protein or other constituents of the product (mnnitol, trehlose, sodium chloride, histidine, Tris, clcium chloride, polysorbte 80, nd/or glutthione). 5. WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Rections Allergic-type hypersensitivity rections, including nphylxis, hve been reported with ADVATE. Symptoms include dizziness, presthesi, rsh, flushing, fcil swelling, urticri, dyspne, nd pruritus. ADVATE contins trce mounts of mouse immunoglobulin G (MuIgG) 0.1 ng/iu ADVATE, nd hmster proteins 1.5 ng/iu ADVATE. Ptients treted with this product my develop hypersensitivity to these non-humn mmmlin proteins. Discontinue ADVATE if hypersensitivity symptoms occur nd dminister pproprite emergency tretment. 5.2 Neutrlizing Antibodies Neutrlizing ntibodies (inhibitors) hve been reported following dministrtion of ADVATE predominntly in previously untreted ptients (PUPs) nd previously minimlly treted ptients (MTPs). Monitor ll ptients for the development of fctor VIII inhibitors by pproprite clinicl observtion nd lbortory testing. If expected plsm fctor VIII ctivity levels re not ttined, or if bleeding is not controlled with n expected dose, perform n ssy tht mesures fctor VIII inhibitor concentrtion. [see Wrnings nd Precutions (5.3)] 5.3 Monitoring Lbortory Tests Monitor plsm fctor VIII ctivity levels by the one-stge clotting ssy to confirm the dequte fctor VIII levels hve been chieved nd mintined when cliniclly indicted. [see Dosge nd Administrtion (2.1)] Perform the Bethesd ssy to determine if fctor VIII inhibitor is present. If expected fctor VIII ctivity plsm levels re not ttined, or if bleeding is not controlled with the expected dose of ADVATE, use Bethesd Units (BU) to titer inhibitors. If the inhibitor titer is less thn 10 BU per ml, the dministrtion of dditionl ntihemophilic fctor concentrte my neutrlize the inhibitor nd my permit n pproprite hemosttic response. If the inhibitor titer is bove 10 BU per ml, dequte hemostsis my not be chieved. The inhibitor titer my rise following ADVATE infusion s result of n nmnestic response to fctor VIII. The tretment or prevention of bleeding in such ptients requires the use of lterntive therpeutic pproches nd gents. 6. ADVERSE REACTIONS The serious dverse rections seen with ADVATE re hypersensitivity rections nd the development of high-titer inhibitors necessitting lterntive tretments to fctor VIII. The most common dverse rections observed in clinicl trils (frequency 10% of subjects) were pyrexi, hedche, cough, nsophryngitis, vomiting, rthrlgi, nd limb injury. 6.1 Clinicl Tril Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in clinicl trils of nother drug nd my not reflect the rtes observed in clinicl prctice. ADVATE hs been evluted in five completed clinicl trils in previously treted ptients (PTPs) nd one ongoing tril in previously untreted ptients (PUPs) with severe to modertely severe hemophili A (fctor VIII 2% of norml). A totl of 234 subjects hve been treted with ADVATE s of Mrch Totl exposure to ADVATE ws 44,926 infusions. The medin durtion of prticiption per subject ws (rnge: 1 to 1,256) dys nd the medin number of exposure dys to ADVATE per subject ws 128 (rnge: 1 to 598). 3 The summry of dverse rections with frequency 5% (defined s dverse events occurring within 24 hours of infusion or ny dverse event cuslly relted occurring within the tril period) is shown in Tble 3. No subject ws withdrwn from clinicl tril due to n dverse rection. There were no deths in ny of the clinicl trils. Tble 3 Summry of Adverse Rections with Frequency 5% (N = 234 Treted Subjects b ) MedDRA c MedDRA Number Number of Percent of System Orgn Clss Preferred Term of ADRs Subjects Subjects Generl disorders nd Pyrexi dministrtion site conditions Nervous system disorders Hedche Respirtory, thorcic, nd medistinl disorders Cough Infections nd infesttions Nsophryngitis Gstrointestinl disorders Vomiting Musculoskeletl nd connective tissue disorders Arthrlgi Injury, poisoning, nd procedurl complictions Limb injury Upper respirtory Infections nd infesttions trct infection Phryngolryngel Respirtory, thorcic, nd medistinl disorders pin Respirtory, thorcic, nd medistinl disorders Nsl congestion Gstrointestinl disorders Dirrhe Gstrointestinl disorders Nuse Generl disorders nd dministrtion site Pin conditions Skin nd subcutneous tissue disorders Rsh Infections nd infesttions Er infection Injury, poisoning, nd procedurl complictions Procedurl pin Respirtory, thorcic, nd medistinl disorders Rhinorrhe Adverse rections re defined s ll dverse events tht occurred () within 24 hours fter being infused with investigtionl product, or (b) ll dverse events ssessed relted or possibly relted to investigtionl product, or (c) dverse events for which the investigtor s or sponsor s opinion of cuslity ws missing or indeterminte. b The ADVATE clinicl progrm included 234 treted subjects from 5 completed studies in PTPs nd 1 ongoing tril in PUPs s of 27 Mrch c MedDRA version 8.1 ws used. Immunogenicity The development of fctor VIII inhibitors with the use of ADVATE ws evluted in clinicl trils with peditric PTPs (<6 yers of ge with >50 fctor VIII exposures) nd PTPs ( 10 yers of ge with >150 fctor VIII exposures). Of 198 subjects who were treted for t lest 10 exposure dys or on study for minimum of 120 dys, 1 dult developed lowtiter inhibitor (2 BU in the Bethesd ssy) fter 26 exposure dys. Eight weeks lter, the inhibitor ws no longer detectble, nd in vivo recovery ws norml t 1 nd 3 hours fter infusion of nother mrketed recombinnt fctor VIII concentrte. This single event results in fctor VIII inhibitor frequency in PTPs of 0.51% (95% CI of 0.03 nd 2.91% for the risk of ny fctor VIII inhibitor development). 3,4 No fctor VIII inhibitors were detected in the 53 treted peditric PTPs. In clinicl trils tht enrolled previously untreted subjects (defined s hving hd up to 3 exposures to fctor VIII product t the time of enrollment), 5 (20%) of 25 subjects who received ADVATE developed inhibitors to fctor VIII. 3 Four subjects developed high titer (>5 BU) nd one ptient developed low-titer inhibitors. Inhibitors were detected t medin of 11 exposure dys (rnge 7 to 13 exposure dys) to investigtionl product. Immunogenicity lso ws evluted by mesuring the development of ntibodies to heterologous proteins. 182 treted subjects were ssessed for nti-chinese hmster ovry (CHO) cell protein ntibodies. Of these subjects, 3 showed n upwrd trend in ntibody titer over time nd 4 showed repeted but trnsient elevtions of ntibodies. 182 treted subjects were ssessed for muigg protein ntibodies. Of these, 10 showed n upwrd trend in nti-muigg ntibody titer over time nd 2 showed repeted but trnsient elevtions of ntibodies. Four subjects who demonstrted ntibody elevtions reported isolted events of urticri, pruritus, rsh, nd slightly elevted eosinophil counts. All of these subjects hd numerous repet exposures to the study product without recurrence of the events nd cusl reltionship between the ntibody findings nd these clinicl events hs not been estblished. Of the 181 subjects who were treted nd ssessed for the presence of nti-humn von Willebrnd Fctor (VWF) ntibodies, none displyed lbortory evidence indictive of positive serologic response. The detection of ntibody formtion is highly dependent on the sensitivity nd specificity of the ssy. Additionlly, the observed incidence of ntibody (including neutrlizing ntibody) positivity in n ssy my be influenced by severl fctors including ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, comprison of the incidence of ntibodies to ADVATE with the incidence of ntibodies to other products my be misleding. 6.2 Post-Mrketing Experience The following dverse rections hve been identified during post-pprovl use of ADVATE. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. Among ptients treted with ADVATE, cses of serious llergic/hypersensitivity rections including nphylxis hve been reported nd fctor VIII inhibitor formtion (observed predominntly in PUPs). Tble 4 represents the most frequently reported post-mrketing dverse rections s MedDRA Preferred Terms.

5 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] Orgn System [MedDRA Primry SOC] Immune system disorders Blood nd lymphtic system disorders Generl disorders nd dministrtion site conditions Tble 4 Post-Mrketing Experience Preferred Term Anphylctic rection Hypersensitivity Fctor VIII inhibition Injection site rection Chills Ftigue/Mlise Chest discomfort/pin Less-thn-expected therpeutic effect These rections hve been mnifested by dizziness, presthesis, rsh, flushing, fce swelling, urticri, nd/or pruritus. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory C. Animl reproduction studies hve not been conducted with ADVATE. It is not known whether ADVATE cn cuse fetl hrm when dministered to pregnnt womn or whether it cn ffect reproductive cpcity. ADVATE should be given to pregnnt womn only if clerly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should be exercised when ADVATE is dministered to nursing womn. 8.4 Peditric Use In comprison to dults, children present with higher fctor VIII clernce (bsed on per kg body weight) vlues nd thus lower hlf-life nd recovery of fctor VIII. [see Clinicl Phrmcology (12.3)] This my be explined by differences in body composition nd should be tken into ccount when dosing or following fctor VIII levels in the peditric popultion. 5 Becuse clernce (bsed on per kg body weight) hs been demonstrted to be higher in the peditric popultion, lrger or more frequent dosing bsed on per kg body weight my be needed in this popultion. [see Clinicl Phrmcology (12.3)] In the ADVATE routine prophylxis clinicl tril, 3 children ged 7 to <12 nd 4 dolescents ged 12 to < 16 were included in the per-protocol nlysis. The reductions in nnulized bleeding rte per subject per yer during ny prophylxis regimen s compred to during on-demnd therpy were similr mong children, dolescents, nd dults. [see Clinicl Studies (14)] 8.5 Geritric Use Clinicl trils of ADVATE did not include sufficient numbers of subjects ged 65 nd over to determine whether they respond differently compred to younger subjects. Individulize dose selection for geritric ptients. 11. DESCRIPTION ADVATE [Antihemophilic Fctor (Recombinnt)] is purified glycoprotein consisting of 2,332 mino cids tht is synthesized by geneticlly engineered Chinese hmster ovry (CHO) cell line nd the product does not contin plsm or lbumin. The CHO cell line employed in the production of ADVATE is derived from tht used in the biosynthesis of RECOMBINATE [Antihemophilic Fctor (Recombinnt)]. ADVATE hs been shown to be comprble to RECOMBINATE with respect to its biochemicl nd physicochemicl properties, s well s its non-clinicl in vivo phrmcology. In culture, the CHO cell line expresses the recombinnt ntihemophilic fctor (rahf into the cell culture medium. The rahf is purified from the culture medium using series of chromtogrphy columns. The purifiction process includes n immunoffinity chromtogrphy step in which monoclonl ntibody directed ginst fctor VIII is employed to selectively isolte the rahf from the medium. The cell culture nd purifiction processes used in the mnufcture of ADVATE employ no dditives of humn or niml origin. The production process includes dedicted, virl inctivtion solvent-detergent tretment step. The rahf synthesized by the CHO cells hs the sme biologicl effects on clotting s humn ntihemophilic fctor (hahf). Structurlly the recombinnt protein hs similr combintion of heterogeneous hevy nd light chins s found in AHF (Humn). ADVATE is formulted s sterile, non-pyrogenic, white to off-white powder for intrvenous injection. ADVATE in single-use vil contins nominlly 250, 500, 1000, 1500, 2000, 3000, or 4000 Interntionl Units (IU). The product contins the following stbilizers nd excipients: mnnitol, trehlose, sodium chloride, histidine, Tris, clcium chloride, polysorbte 80, nd glutthione. Von Willebrnd fctor (VWF) is co-expressed with fctor VIII nd helps to stbilize it in culture. The finl product contins no more thn 2 ng VWF/IU rahf, which will not hve ny cliniclly relevnt effect in ptients with von Willebrnd disese. The product contins no preservtive. When reconstituted with the provided Sterile Wter for Injection, USP, the finl solution contins the following stbilizers nd excipients in trgeted mounts: Tble 5 Approximte Concentrtion of Stbilizer nd Excipient fter Reconstitution Stbilizer nd Excipient 2 ml Reconstitution (for 250, 500, 1000, 1500 IU) Trget 5 ml Reconstitution (for 2000, 3000, 4000 IU) Trget Tris (hydroxymethyl) minomethne 25 mm 10 mm Clcium Chloride 4.2 mm 1.7 mm Mnnitol 8% (w/v) 3.2% (w/v) Sodium Chloride 225 mm 90 mm α, α-trehlose 2% (w/v) 0.8% (w/v) Histidine 25 mm 10 mm Glutthione (Reduced) 0.2 mg/ml 0.08 mg/ml Polysorbte % (w/v) 0.01% (w/v) Ech ADVATE housing is lbeled with the rahf ctivity expressed in interntionl units. Biologicl potency is determined by n in vitro ssy, which employs fctor VIII concentrte stndrd tht is referenced to WHO interntionl stndrd for fctor VIII concentrtes. One interntionl unit, s defined by the WHO stndrd for blood cogultion fctor VIII, humn, is pproximtely equl to the level of fctor VIII ctivity found in 1 ml of fresh pooled humn plsm. The specific ctivity of ADVATE is 4000 to Interntionl Units per milligrm of protein. 12. CLINICAL PHARMACOLOGY 12.1 Mechnism of Action ADVATE temporrily replces the missing cogultion fctor VIII tht is needed for effective hemostsis Phrmcodynmics The ctivted prtil thromboplstin time (PTT) is prolonged in ptients with hemophili. Determintion of PTT is conventionl in vitro ssy for biologicl ctivity of fctor VIII. Tretment with ADVATE normlizes the PTT over the effective dosing period Phrmcokinetics A rndomized, crossover phrmcokinetic tril of ADVATE (test) nd RECOMBINATE [Antihemophilic Fctor (Recombinnt)] (reference) ws conducted in 56 non-bleeding subjects. The subjects received either of the products s n IV infusion (50 ± 5 IU/kg body weight) nd there ws wshout period of 72 hours to 4 weeks between the two infusions. The phrmcokinetic prmeters were clculted from fctor VIII ctivity mesurements in blood smples obtined up to 48 hours following ech infusion. 4 The per-protocol nlysis included 30 ptients (20 dults nd 10 children). Phrmcokinetic prmeters for the 20 dults for ech tril preprtion re presented in Tble 6. Tble 6 Phrmcokinetic Prmeters (Men ± SD) for ADVATE nd RECOMBINATE (N=20 Adult Subjects Age >16 yers) Prmeter RECOMBINATE ADVATE (n=20) (n=20) AUC 0-48h (IU hrs/dl) 1638 ± ± 338 In vivo recovery (IU/dL/IU/kg) b 2.74 ± ± 0.53 Hlf-life (hrs) ± ± 4.15 C mx (IU/dL) 136 ± ± 28 MRT (hrs) ± ± 5.91 V ss (dl/kg) 0.43 ± ± 0.10 CL (dl/hrs/kg) 0.03 ± ± 0.01 Are under the plsm fctor VIII concentrtion x time curve from 0 to 48 hours post-infusion. b Clculted s (C mx bseline fctor VIII) divided by the dose in IU/kg, where C mx is the mximl post-infusion fctor VIII mesurement. The 90% confidence intervls for the rtios of the men AUC (0-48h) nd in vivo recovery vlues for the test nd control products were within the pre-estblished limits of 0.80 nd In ddition, in vivo recoveries t the onset of tretment nd fter 75 exposure dys were compred for 62 subjects. Results of this nlysis indicted no significnt chnge in the in vivo recovery t the onset of tretment nd fter 75 exposure dys. [see Clinicl Studies (14.2)] In n nlysis of dt from 58 subjects with 65 surgicl procedures in the periopertive mngement tril, the trget fctor VIII level ws met or exceeded in ll cses following single loding dose rnging from 29 to 104 IU/kg. Phrmcokinetic prmeters clculted from interim phrmcokinetic dt for 51 subjects 16 yers of ge (intent-to-tret nlysis) re vilble for 0 neontes, 3 infnts, 21 children, nd 27 dolescents s shown in Tble 7. The clernce of ADVATE in infnts, children, older children, nd dolescents ws 26%, 23%, 42%, nd 23% higher thn dults (0.031 dl/hr/kg). The hlf-life of ADVATE in infnts, children, older children, nd dolescents ws 27%, 15%, 10%, nd 3% lower thn dults (12.08 hours). The extent to which these differences my be cliniclly significnt is not known.

6 Tble 7 Phrmcokinetic Prmeters (Men ± SD) of ADVATE by Age Group (N=51 Peditric Subjects Age 16 yers; Intent-to-Tret Anlysis) Prmeters Infnts (N = 3) (1 month to < 2 yrs) Children (N = 8) (2 to < 5 yrs) Older Children (N = 13) (5 to < 12 yrs) Adolescents (N = 27) (12 to < 16 yrs) AUC (IU hr/dl) 1385 ± ± ± ± 528 C mx (IU/dL) 98.0 ± ± ± ± 21.7 MRT (hrs) 11.6 ± ± ± ± 5.6 CL (dl/hr/kg) ± ± ± ± Hlf-life (hrs) 8.86 ± ± ± ± 3.72 V ss (dl/kg) 0.43 ± ± ± ± 0.08 Recovery b IU/dL/IU/kg 1.96 ± ± ± ± 0.42 Volume of distribution t stedy stte b Incrementl recovery t C mx clculted s (C mx bseline Fctor VIII) divided by the dose in IU/kg, where C mx is the mximl post-infusion Fctor VIII mesurement In crossover phrmcokinetic tril of rahf-pfm reconstituted in 2 ml versus 5 ml Sterile Wter for Injection, USP (swfi) in previously treted severe hemophili A dult nd dolescent ptients, the AUCs of the two formultions were comprble nd the 90% confidence intervl rnged from 90.4 to 102.6, indicting tht the two formultions re phrmcokineticlly equivlent. 13. NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility No studies hve been conducted with the ctive ingredient in ADVATE to ssess its mutgenic or crcinogenic potentil. RECOMBINATE ws tested for mutgenicity t doses considerbly exceeding plsm concentrtions in vitro, nd t doses up to ten times the expected mximl clinicl dose in vivo. At tht concentrtion, it did not cuse reverse muttions, chromosoml berrtions, or n increse in micronuclei formtion in bone mrrow polychromtic erythrocytes. Studies in nimls hve not been performed to evlute crcinogenic potentil Animl Toxicology nd/or Phrmcology Single doses up to 4,750 IU/kg did not demonstrte ny cute or toxic effect for ADVATE in lbortory nimls (rt nd rbbit). 14. CLINICAL STUDIES Originl Sfety nd Efficcy Study A sfety nd efficcy tril evluted the phrmcokinetics (double-blinded, rndomized, cross-over), sfety, immunogenicity, nd hemosttic efficcy (open-lbel) of ADVATE in 111 subjects. The tril ws conducted in the US nd Europe with 103 Cucsin, 7 Blck, nd 1 Asin previously treted subjects (PTPs with 150 exposure dys) dignosed with moderte to severe hemophili A (FVIII level 2% of norml) who were 10 yers of ge (20 were 10 to <13, 22 were 13 to <16, nd 69 were 16 yers nd older). Subjects with history of, or detectble FVIII inhibitor were excluded. Subjects self-dministered ADVATE for routine prophylxis nd for the tretment of bleeding episodes. A globl ssessment of efficcy ws rendered by the subject (for home tretment) or study site investigtor (for tretment under medicl supervision) using scle of excellent, good, fir, or none, bsed on the qulity of hemostsis chieved with ADVATE for the tretment of ech new bleeding episode. A totl of 510 bleeding episodes were reported, with men (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of these 510 episodes, 439 (86%) were rted excellent or good in their response to tretment with ADVATE, 61 (12%) were rted fir, 1 (0.2%) ws rted s hving no response, nd for 9 (2%), the response to tretment ws unknown. A totl of 411 (81%) bleeding episodes were mnged with single infusion, 62 (12%) required 2 infusions, 15 (3%) required 3 infusions, nd 22 (4%) required 4 or more infusions of ADVATE for stisfctory resolution. A totl of 162 (32%) bleeding episodes occurred spontneously, 228 (45%) were the result of ntecedent trum, nd for 120 (24%) bleeding episodes, the etiology ws unknown. 4 The rte of new bleeding episodes during the 75-exposure-dy prophylctic regimen ( 25 IU/kg body weight 3-4 times per week) ws clculted s function of the etiology of bleeding episodes for 107 evluble subjects (n = 274 bleeding episodes). 4 These rtes re presented in Tble 8. Tble 8 Rte of New Bleeding Episodes During Prophylxis Types of Bleeding Episode Men (± SD) New Bleeding Episodes/Subject/Month Spontneous 0.34 ± 0.49 Post-trumtic 0.39 ± 0.46 Unknown/Indeterminte 0.33 ± 0.34 Overll 0.52 ± 0.71 The phrmcokinetic properties of ADVATE were investigted t the beginning of tretment in multicenter tril of previously treted subjects nd t the end of tretment in subset of subjects (N=13) who hd completed t lest 75 exposure dys of tretment with ADVATE. Post-infusion levels nd clernce of fctor VIII during the periopertive period were exmined in n interim nlysis of subjects enrolled in surgery tril. The phrmcokinetics of ADVATE ws investigted in n interim nlysis of tril of peditric previously treted subjects < 6 yers of ge. [see Use in Specific Popultion (8.4) nd Clinicl Phrmcology (12.3)] Continution Study Additionl (open-lbel) sfety nd efficcy dt were collected on 82 subjects who continued with tretment following prticiption in the pivotl clinicl tril. An interim nlysis of efficcy from the continution tril ws conducted for 27 subjects who self-dministered ADVATE on routine prophylctic regimen during minimum period of 50 exposure dys to ADVATE. Bleeding episodes were treted with ADVATE nd the outcome of tretment ws rted s excellent, good, fir, or none, bsed on the qulity of hemostsis chieved. A totl of 51 bleeding episodes occurred in 13 of the 27 subjects being treted with ADVATE. By etiology, 53% of these bleeding events resulted from trum nd 27% occurred spontneously; the other 20% hd n undetermined etiology. The response to tretment with ADVATE for 63% of ll bleeding episodes ws rted s excellent or good. In 86% of episodes, bleeding resolved with only 1 infusion nd n dditionl 6% were resolved by second infusion. In vivo recoveries t the onset of tretment nd fter 75 exposure dys were compred for 62 subjects. There were no significnt differences between the in vivo recoveries t the onset of tretment nd the in vivo recoveries fter 75 exposure dys. Periopertive Mngement Study The sfety nd efficcy of ADVATE for periopertive mngement ws investigted in 59 subjects with severe or modertely severe hemophili A (fctor VIII 2%) who were 7 yers of ge: 3 were 7 to <13, 8 were 13 to < 16, nd 48 were 16; 55 were Cucsin, 3 were Blck, nd 1 ws Asin. Fifty-eight subjects underwent 65 surgicl procedures (1 subject elected not to undergo the plnned procedure). Of the 65 procedures, 22 were clssified s mjor, 35 were clssified s minor, nd 8 were dentl. Prior to surgery, subjects received pre-opertive loding dose imed t incresing the plsm fctor VIII level to 60% to 100% of norml for dentl procedures or 80% to 120% of norml for ll other surgicl procedures. During the surgery, study subjects received replcement therpy by either bolus or continuous infusion, s prescribed by the investigtor. For continuous infusion, the initil rte ws 4 IU/kg/hr for subjects >12 yers of ge nd 5 IU/kg/hr for subjects 5 to 12 yers of ge. After dischrge, subjects continued to receive ADVATE for control of hemostsis s prescribed by the investigtor for up to 6 weeks for mjor orthopedic procedures nd up to 2 weeks for ll other procedures. An interim nlysis of the hemosttic efficcy for 10 subjects from 14 to 64 yers of ge (9 Cucsin nd 1 Blck) who underwent 10 surgicl procedures (comprising 6 mjor, 4 minor, nd 5 orthopedic). Eight subjects received ADVATE by intermittent bolus infusion nd 2 subjects received combintion of continuous nd intermittent bolus infusion. Nine of the 10 subjects completed the tril. Six of the surgicl procedures were clssified s mjor, nd 4 were minor. Of the 6 mjor surgeries, 5 were for orthopedic complictions of hemophili. A brief description of ech surgicl procedure, long with tril durtion nd tril mediction exposure, is presented in Tble 9. Tble 9 Surgicl Procedures, Tril Durtion, nd Tril Mediction Exposure ADVATE Cumultive ADVATE Exposure Surgery Type Dys of Study Exposure Dys (Interntionl Units) Totl hip replcement ,600 Knee joint replcement ,060 Knee rthrodesis ,080 Trnsposition of the left ulnr nerve ,560 Insertion of Mediport ,893 Dentl extrction ,599 Left elbow synovectomy ,180 Teeth extrction ,350 Right knee rthroscopy, chondroplsty nd synovectomy 32,334 Wisdom teeth extrction ,357 ADVATE ws dministered by continuous infusion for the first 48 hours post-opertively, followed by bolus infusions for the reminder of tril tretment. For ech of the 10 subjects, intr- nd post-opertive qulity of hemostsis chieved with ADVATE ws ssessed by the operting surgeon nd study site investigtor, respectively, using n ordinl scle of excellent, good, fir, or none. The sme rting scle ws used to evlute control of hemorrhge from surgicl drin plced t the incision site in one subject. The qulity of hemostsis chieved with ADVATE ws rted s excellent or good for ll ssessments. Routine Prophylxis Study In multicenter, open-lbel, prospective, rndomized, controlled postmrketing clinicl tril of ADVATE use in two prophylctic tretment regimens compred to tht of on-demnd tretment, 53 PTPs with severe to modertely severe hemophili A (FVIII level < 2 IU/dL) were nlyzed in the per-protocol group. Subjects were initilly treted for 6 months of on-demnd therpy nd then rndomized to 12 months of either stndrd prophylxis regimen (20-40 IU/kg every 48 hours) or PK-driven prophylxis regimen (20-80 IU/kg every 72 hours). All subjects hd history of t lest 8 joint bleeding episodes per yer upon entering the tril. Ech subject in the per-protocol group ws dherent to > 90% of the prescribed number of prophylctic infusions; no subject in the tril surpssed the upper boundry of 110% of the prescribed number of prophylctic infusions. The medin nnul bleed rte during the on-demnd therpy period ws 44 bleeds per subject per yer compred to 1 bleed per subject per yer while on either prophylxis regimen, which ws sttisticlly significnt difference (p<0.0001). Twenty-two of 53 (42%) subjects experienced no bleeding episodes while on prophylxis for one yer. While there ws no sttisticlly significnt difference in bleeding frequency observed between the two prophylxis regimens studied, the tril ws not powered to demonstrte equivlence in bleeding rte between the two prophylxis rms. The eqution used to determine the weight-djusted dose of the product used in the PK-driven prophylxis rm, s clculted from the individul subject s incrementl recovery nd hlf-life vlues to chieve trough level of 1 IU/dL t the inter-dosing intervl of 72 hours is defined s follows:

7 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] D i = (2) 72/t / r. (i is the subject) i i D = trget FVIII dose (IU/kg) tht ensures tht trough level of 1 IU/dL is chieved fter 72 hours r = FVIII incrementl recovery (IU/dL / IU/kg) s determined by the subject s PK nlysis t = FVIII hlf-life (hrs) s determined by the subject s PK nlysis Tble 10 Annul Bleed Rte of Prophylxis Compred to On-Demnd Tretment On-Demnd (n = 53) Stndrd Prophylxis (n=30) PK-Driven Prophylxis (n=23) Either Stndrd or PK- Driven Prophylxis (n=53) Clinicl Prmeters Medin (IQR) Annul Bleed Rte(ABR) 44.0 (20.8) 1.0 (2.1) 1.0 (4.1) 1.0 (4.1) Medin (IQR) Joint ABR 38.7 (24.8) 0.5 (2.0) 1.0 (4.1) 1.0 (2.1) Medin (IQR) Non-Joint ABR (11.9) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) Medin (IQR) Spontneous ABR Medin (IQR) Trumtic ABR 32.0 (26.8) 0.0 (1.9) 0.0 (2.0) 0.0 (1.9) 11.5 (17.2) 0.0 (1.0) 1.0 (1.0) 0.0 (1.0) Inter-qurtile-rnge (IQR) is defined s the difference between the 75 th percentile (3rd qurtile) nd the 25 th percentile (first qurtile). The nnulized bleed rtes by ge ctegory during on-demnd nd either stndrd or PK-driven prophylxis regimens re shown in Tble 11. Tble 11 Annulized Bleed Rte by Age Ctegory nd Any Prophylxis vs On-Demnd (Per Protocol) Any Prophylxis On-Demnd Age Ctegory Percentge of Percentge of N Min Medin Mx Subjects With Zero Bleeds N Min Medin Mx Subjects With Zero Bleeds Children ( 7 to <12 yers old) % Adolescents ( 12 to <16 yers old) % Adults ( 16 yers old nd older) % All Subjects % All subjects bleed during On-Demnd As secondry endpoint, the tril ssessed ll Short Form Helth Survey (SF-36v1) domins. The SF-36v1 is vlid nd relible mesure of helth-relted qulity of life tht is comprised of 8 domins ctegorized into 2 summry scores (Tble 12). Tble 12 Men Chnge in SF-36v1 Helth Domin Scores Between End of On-Demnd nd End of Prophylxis Tretment Regimens SF-36v1 Helth Domin Men Chnge 95% Confidence Intervl Physicl Functioning (PF) 0.89 (-1.02, 2.81) Role Physicl (RP) 3.56 (0.32, 6.79) Bodily Pin (BP) 4.13 (1.63, 6.62) Generl Helth (GH) 1.36 (-0.72, 3.45) Physicl Component Score 3.56 (1.56, 5.56) Vitlity (VT) 0.21 (-2.22, 2.63) Socil Functioning (SF) 1.72 (-0.57, 4.00) Role Emotionl (RE) (-3.78, 1.19) Mentl Helth (MH) (-2.89, 2.49) Mentl Component Score (-3.66, 1.23) Positive chnge vlues re in the fvorble direction. Humn Fctors Usbility Study A humn fctors study ws performed with 44 prticipnts to evlute the usbility of the ADVATE in the BAXJECT III reconstitution system. Prticipnts in the study included 15 ptients, 16 cregivers, nd 13 helthcre providers. During the study, prticipnts viewed n instructionl video then performed the reconstitution steps utilizing the instructions for use (IFU). Objective performnce dt were collected nd evluted. Prticipnts comments from post-evlution interview were reviewed for their ppropriteness nd pplicbility. As result, the content of the pckge insert ws revised to clrify the instructions for use. 15. REFERENCES 1. Fischer K, Collins P, Björkmn S, Blnchette V, Oh M, Fritsch S, Schroth P, Spotts G, Ewenstein B. Trends in bleeding ptterns during prophylxis for severe hemophili: observtions from series of prospective clinicl trils. Hemophili (3): Collins PW, Blnchette VS, Fischer K, Björkmn S, Oh M, Fritsch S, Schroth P, Astermrk J, Spotts G, Ewenstein B, The rahf-pfm Study Group. Brek-through bleeding in reltion to predicted fctor VIII levels in ptients receiving prophylctic tretment for severe hemophili A. J Thromb Hemost (3): Shpiro A, Gruppo R, Pbinger I et l. Integrted nlysis of sfety nd efficcy of plsmnd lbumin-free recombinnt fctor VIII (rahf-pfm) from six clinicl studies in ptients with hemophili A. Expert Opin Biol Ther : Trntino MD, Collins PW, Hy PW et l. Clinicl evlution of n dvnced ctegory ntihemophilic fctor prepred using plsm/lbumin-free method: phrmcokinetics, efficcy, nd sfety in previously treted ptients with hemophili A. Hemophili : Björkmn S, Blnchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Ptrone L, Ewenstein BM, Collins PW, ADVATE Clinicl Progrm Group. Comprtive phrmcokinetics of plsm- nd lbumin-free recombinnt fctor VIII in children nd dults: the influence of blood smpling schedule on observed ge-relted differences nd implictions for dose tiloring. J Thromb Hemost (4): Negrier C, Shpiro A, Berntorp E et l. Surgicl evlution of recombinnt fctor VIII prepred using plsm/lbumin-free method: efficcy nd sfety of ADVATE in previously treted ptients. Thromb.Hemost : White II GC, Courter S, Bry GL, et l: A multicenter study of recombinnt fctor VIII (Recombinte) in previously treted ptients with hemophili A. Thromb Hemost : Lee CA, Owens D, Bry G, et l: Phrmcokinetics of recombinnt fctor VIII (Recombinte) using one-stge clotting nd chromogenic fctor VIII ssy. Thromb Hemost : HOW SUPPLIED/STORAGE AND HANDLING How Supplied ADVATE in BAXJECT III system is pckged with 2 ml or 5 ml of Sterile Wter for Injection, one Terumo Microbore Infusion set (2 ml only), one full prescribing physicin insert, nd one ptient insert. ADVATE is vilble in single-dose vils tht contin the following nominl product strengths: Nominl Strength Fctor VIII Potency Rnge Crton NDC (Includes 2 ml swfi Diluent) Crton NDC (Includes 5 ml swfi Diluent) 250 IU IU per vil IU IU per vil IU IU per vil IU IU per vil IU IU per vil IU IU per vil IU IU per vil Actul fctor VIII ctivity in Interntionl Units is stted on the lbel of ech ADVATE housing or crton. The product is not mde with nturl rubber ltex. Storge nd Hndling Refrigerte ADVATE in powder form t 2-8 C (36-46 F). ADVATE my be stored t room temperture up to 30 C (86 F) for period of up to 6 months not to exceed the expirtion dte. Record on the crton the dte ADVATE is removed from refrigertion. The product must not be returned to refrigerted temperture. Do not use beyond the expirtion dte printed on the ADVATE lbel or crton. Do not freeze. 17. PATIENT COUNSELING INFORMATION Advise the ptient to red the FDA-Approved Ptient Lbeling nd Instructions for Use. Advise ptients to report ny dverse rections or problems following ADVATE dministrtion to their physicin or helthcre provider. Allergic-type hypersensitivity rections hve been reported with ADVATE. Wrn ptients of the erly signs of hypersensitivity rections, including hives, pruritus, generlized urticri, ngioedem, hypotension, shock, nphylxis nd cute respirtory distress. Advise ptients to discontinue use of the product if these symptoms occur nd seek immedite emergency tretment with resuscittive mesures such s the dministrtion of epinephrine nd oxygen. Inhibitor formtion my occur with the tretment of ptient with hemophili A. Advise ptients to contct their physicin or tretment center for further tretment nd/ or ssessment if they experience lck of clinicl response to fctor VIII replcement therpy, s this my be mnifesttion of n inhibitor. Advise ptients to consult with their physicins or helthcre provider prior to trvel. While trveling, dvise ptients to bring n dequte supply of ADVATE bsed on their current regimen of tretment. To enroll in the confidentil, industry-wide Ptient Notifiction System, cll Bxter, Advte, Bxject nd Recombinte re trdemrks of Bxter Interntionl Inc. Bxter, Advte nd Bxject re registered in the U.S. Ptent nd Trdemrk Office. Ptented: see Bxter Helthcre Corportion Westlke Villge, CA USA U.S. License No. 140 Printed in USA USBS/34/ Issued: 04/2014

8 FDA-Approved Ptient Lbeling ADVATE (d-vte) [Antihemophilic Fctor (Recombinnt)] This leflet summrizes importnt informtion bout ADVATE. Plese red it crefully before using this medicine. This informtion does not tke the plce of tlking with your helthcre provider, nd it does not include ll of the importnt informtion bout ADVATE. If you hve ny questions fter reding this, sk your helthcre provider. Wht is the most importnt informtion I need to know bout ADVATE? Do not ttempt to do n infusion to yourself unless you hve been tught how by your helthcre provider or hemophili center. You must crefully follow your helthcre provider s instructions regrding the dose nd schedule for infusing ADVATE so tht your tretment will work best for you. Wht is ADVATE? ADVATE is medicine used to replce clotting fctor (fctor VIII or ntihemophilic fctor) tht is missing in people with hemophili A (lso clled clssic hemophili). The product does not contin plsm or lbumin. Hemophili A is n inherited bleeding disorder tht prevents blood from clotting normlly. ADVATE is used to prevent nd control bleeding in dults nd children (0-16 yers) with hemophili A. Your helthcre provider my give you ADVATE when you hve surgery. ADVATE cn reduce the number of bleeding episodes in dults nd children (0-16 yers) when used regulrly (prophylxis). ADVATE is not used to tret von Willebrnd disese. Who should not use ADVATE? You should not use ADVATE if you: Are llergic to mice or hmsters. Are llergic to ny ingredients in ADVATE. Tell your helthcre provider if you re pregnnt or brestfeeding becuse ADVATE my not be right for you. How should I use ADVATE? ADVATE is given directly into the bloodstrem. You my infuse ADVATE t hemophili tretment center, t your helthcre provider s office or in your home. You should be trined on how to do infusions by your helthcre provider or hemophili tretment center. Mny people with hemophili A lern to infuse their ADVATE by themselves or with the help of fmily member. Your helthcre provider will tell you how much ADVATE to use bsed on your weight, the severity of your hemophili A, nd where you re bleeding. You my hve to hve blood tests done fter getting ADVATE to be sure tht your blood level of fctor VIII is high enough to clot your blood. Cll your helthcre provider right wy if your bleeding does not stop fter tking ADVATE. Wht should I tell my helthcre provider before I use ADVATE? You should tell your helthcre provider if you: Hve or hve hd ny medicl problems. Tke ny medicines, including prescription nd non-prescription medicines, such s over-the-counter medicines, supplements or herbl remedies. Hve ny llergies, including llergies to mice or hmsters. Are brestfeeding. It is not known if ADVATE psses into your milk nd if it cn hrm your bby. Are pregnnt or plnning to become pregnnt. It is not known if ADVATE my hrm your unborn bby. Hve been told tht you hve inhibitors to fctor VIII (becuse ADVATE my not work for you). Wht re the possible side effects of ADVATE? You cn hve n llergic rection to ADVATE. Cll your helthcre provider right wy nd stop tretment if you get rsh or hives, itching, tightness of the throt, chest pin or tightness, difficulty brething, lighthededness, dizziness, nuse or finting. Side effects tht hve been reported with ADVATE include: cough sore throt unusul tste bdominl pin dirrhe nuse/ vomiting hedche fever dizziness hot flshes chills sweting joint swelling/ ching itching hemtom swelling of legs runny nose/ congestion rsh Tell your helthcre provider bout ny side effects tht bother you or do not go wy. These re not ll the possible side effects with ADVATE. You cn sk your helthcre provider for informtion tht is written for helthcre professionls. Wht re the ADVATE dosge strengths? ADVATE with 2 ml or 5 ml Sterile Wter for Injection in BAXJECT III system comes in six different dosge strengths: 250 Interntionl Units (IU), 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU nd 4000 IU. The ctul strength will be imprinted on the lbel on the housing nd on the box. The six different strengths re color coded, s follows: Light-blue Pink Green Purple Ornge Silver Drk Green Dosge strength of pproximtely 250 Interntionl Units ( IU) (with 2 ml swfi) Dosge strength of pproximtely 500 Interntionl Units ( IU) (with 2 ml swfi) Dosge strength of pproximtely 1000 Interntionl Units ( IU) (with 2 ml swfi) Dosge strength of pproximtely 1500 Interntionl Units ( IU) (with 2 ml swfi) Dosge strength of pproximtely 2000 Interntionl Units ( IU) (with 5 ml swfi) Dosge strength of pproximtely 3000 Interntionl Units ( IU) (with 5 ml swfi) Dosge strength of pproximtely 4000 Interntionl Units ( IU) (with 5 ml swfi) Alwys check the ctul dosge strength printed on the lbel to mke sure you re using the strength prescribed by your helthcre provider. Alwys check the expirtion dte printed on the box. Do not use the product fter the expirtion dte printed on the box. How do I store ADVATE? Do not freeze ADVATE. Store ADVATE in refrigertor (2 to 8 C [36 to 46 F]) or t room temperture (up to 30 C [86 F]) for up to 6 months. If you choose to store ADVATE t room temperture: Note the dte tht the product is removed from refrigertion on the box. Do not use fter six months from this dte or fter the expirtion dte. Do not return the product bck to the refrigertor. Store ADVATE in the originl box nd protect from extreme exposure to light. Reconstituted product (fter mixing dry product with wet diluent) must be used within 3 hours nd cnnot be stored or refrigerted. Discrd ny unused ADVATE t the end of your infusion. Wht else should I know bout ADVATE nd Hemophili A? Your body my form inhibitors to fctor VIII. An inhibitor is prt of the body s norml defense system. If you form inhibitors, it my stop ADVATE from working properly. Consult with your helthcre provider to mke sure you re

9 crefully monitored with blood tests for the development of inhibitors to fctor VIII. Medicines re sometimes prescribed for purposes other thn those listed here. Do not use ADVATE for condition for which it is not prescribed. Do not shre ADVATE with other people, even if they hve the sme symptoms tht you hve. Resources t Bxter vilble to the ptients: For more product informtion on ADVATE, plese visit or cll For informtion on ptient ssistnce progrms tht re vilble to you, including the Bxter CARE Progrm, plese contct the Bxter Insurnce Assistnce Helpline t For informtion on dditionl Bxter ptient resources, plese visit Issued: 04/2014 Instructions For Use ADVATE [Antihemophilic Fctor (Recombinnt)] (For intrvenous use only) Do not ttempt to do n infusion to yourself unless you hve been tught how by your helthcre provider or hemophili center. See below for step-by-step instructions for reconstituting ADVATE in BAXJECT III system. Alwys follow the specific instructions given by your helthcre provider. The steps listed below re generl guidelines for using ADVATE. If you re unsure of the procedures, plese cll your helthcre provider before using. Cll your helthcre provider right wy if bleeding is not controlled fter using ADVATE. Your helthcre provider will prescribe the dose tht you should tke. Your helthcre provider my need to tke blood tests from time to time. Tlk to your helthcre provider before trveling. Pln to bring enough ADVATE for your tretment during this time. Dispose of ll mterils, including ny leftover reconstituted ADVATE product, in n pproprite continer. 1. Prepre clen flt surfce nd gther ll the mterils you will need for the infusion. Check the expirtion dte, nd let the ADVATE wrm up to room temperture. Wsh your hnds nd put on clen exm gloves. If infusing yourself t home, the use of gloves is optionl. 2. Open the ADVATE pckge by peeling wy the lid. Remove the ADVATE from the pckge nd visully inspect the contents of the product nd diluent vil. The ADVATE powder should be white to off-white in color nd the diluent should not contin prticles. Do not use if discolortion or prticles re seen. 3. Plce on flt surfce with the diluent vil on top. The diluent vil hs blue stripe. 4. With one hnd holding the ADVATE housing, press down firmly on the diluent vil with the other hnd until the system is fully collpsed nd the diluent flows down into the ADVATE vil. Both vils will move into the housing when pressed. If you don t see the diluent trnsfer to the product vil, press the vils gin to ssure they re completely inserted. Do not remove the blue cp until instructed in lter step. 5. Swirl the ADVATE gently nd continuously until the ADVATE is completely dissolved. Do not shke. Do not refrigerte fter reconstitution. Inspect the ADVATE solution for prticulte mtter nd discolortion prior to dministrtion. The solution should be cler nd colorless in ppernce. If not, do not use the solution nd notify your helthcre provider immeditely. 6. Tke off the blue cp from the housing nd connect the syringe. Be creful to not inject ir into the ADVATE. 7. Turn over the ADVATE so tht the vil contining the ADVATE solution is on top. Drw the ADVATE solution into the syringe by pulling bck the plunger slowly. If the solution does not drw into the syringe, be sure tht both vils re pressed firmly together. The contents of more thn one vil my be drwn into single, ppropritely sized syringe if you re using more thn one vil of ADVATE. 8. Disconnect the syringe from the system. Attch the infusion needle to the syringe using winged (butterfly) infusion set, if vilble. Point the needle up nd remove ny ir bubbles by gently tpping the syringe with your finger nd slowly nd crefully pushing ir out of the syringe nd needle. Apply tourniquet nd get the injection site redy by wiping the skin well with n lcohol swb (or other suitble solution suggested by your helthcre provider or hemophili center). 9. Insert the needle into the vein nd remove the tourniquet. Slowly infuse the ADVATE. Do not infuse ny fster thn 10 ml per minute. 10. Tke the needle out of the vein nd use sterile guze to put pressure on the infusion site for severl minutes. 11. Do not recp the needle. Plce the needle, syringe, nd ADVATE in hrd-wlled shrps continer for proper disposl. Do not dispose of these supplies in ordinry household trsh. Remove the peel-off lbel from the housing nd plce it in your logbook. Clen ny spilled blood with freshly prepred mixture of 1 prt blech nd 9 prts wter, sop nd wter, or ny household disinfecting solution. Importnt: Contct your helthcre provider or locl hemophili tretment center if you experience ny problems. Bxter, Advte, Bxject, nd Cre re trdemrks of Bxter Interntionl Inc. registered in the U.S. Ptent nd Trdemrk Office. Ptented: see Bxter Helthcre Corportion Westlke Villge, CA USA U.S. License No. 140 Printed in USA Issued 04/2014 USBS/34/