These highlights do not include all the information needed to use ADVATE safely and effectively. See full prescribing information for ADVATE.

Transcription

1 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), Plsm/Albumin-Free Method] For Intrvenous Use, Lyophilized Powder for Reconstitution Initil U.S. Approvl: 2003 RECENT MAJOR CHANGES Indictions nd Usge (1.3) 12/2011 Dosge nd Administrtion (2.3) 12/2011 INDICATIONS AND USAGE ADVATE is n Antihemophilic Fctor (Recombinnt) indicted for: Control nd prevention of bleeding episodes in dults nd children (0-16 yers) with Hemophili A. (1.1) Periopertive mngement in dults nd children (0-16 yers) with Hemophili A. (1.2) Routine prophylxis to prevent or reduce the frequency of bleeding episodes in dults nd children (0-16 yers) with Hemophili A. (1.3) ADVATE is not indicted for the tretment of von Willebrnd disese. (1) DOSAGE AND ADMINISTRATION For intrvenous use 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 intrvenous injection of the reconstituted product 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 with 5 ml of Sterile Wter for Injection, USP is vilble s lyophilized powder in single-use vils contining nominlly 250, 500, 1000, 1500, 2000 nd 3000 IU. ADVATE with 2 ml of Sterile Wter for Injection, USP is vilble s lyophilized powder in single-use glss vils contining nominlly 250, 500, 1000 or 1500 IU. (3) CONTRAINDICATIONS Known nphylxis to mouse or hmster protein or other constituents of the product. (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 hs been detected in ptients receiving Fctor VIII-contining products, including ADVATE. 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) ADVERSE REACTIONS The serious dverse drug rections 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: 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. (8.4) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling. FULL PRESCRIBING INFORMATION: CONTENTS 1 INDICATIONS AND USAGE 3 DOSAGE FORMS AND STRENGTHS 1.1 Control nd Prevention of Bleeding Episodes 4 CONTRAINDICATIONS 1.2 Periopertive Mngement 1.3 Routine Prophylxis 2 DOSAGE AND ADMINISTRATION 2.1 Control nd Prevention of Bleeding Episodes 2.2 Periopertive Mngement 2.3 Routine Prophylxis 2.4 Instruction for Use 2.5 Preprtion nd Reconstitution 2.6 Administrtion 5 WARNINGS AND PRECAUTIONS 5.1 Anphylxis nd Hypersensitivity Rections 5.2 Neutrlizing Antibodies 5.3 Monitoring Lbortory Tests 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 6.2 Post Mrketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lbor nd Delivery 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 10 OVERDOSAGE 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 14 CLINICAL STUDIES 14.1 Originl Sfety nd Efficcy Study 14.2 Continution Study 14.3 Periopertive Mngement Study 14.4 Routine Prophylxis Study 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling * Sections or subsections omitted from the full prescribing informtion re not listed Revised: December 2011

2 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] 1. INDICATIONS AND USAGE 1.1 Control nd Prevention of Bleeding Episodes ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] is n Antihemophilic Fctor (Recombinnt) indicted for control nd prevention of bleeding episodes in dults nd children (0-16 yers) with Hemophili A. 1.2 Periopertive Mngement ADVATE is indicted in the periopertive mngement in dults nd children (0-16 yers) with Hemophili A. 1.3 Routine Prophylxis ADVATE is indicted for routine prophylxis to prevent or reduce the frequency of bleeding episodes in dults nd children (0-16 yers) with Hemophili A. ADVATE is not indicted for the tretment of von Willebrnd disese. 2. DOSAGE AND ADMINISTRATION For Intrvenous Use After Reconstitution Only Initite tretment with ADVATE under the supervision of physicin experienced in the tretment of Hemophili A. Ech vil of ADVATE hs the recombinnt Fctor VIII potency in Interntionl Units stted on the lbel. The expected in vivo pek increse in Fctor VIII level expressed s IU/dL of plsm or percent norml cn be estimted by multiplying the dose dministered per kg body weight (IU/kg) by 2. The 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. [See Dosge nd Administrtion (2.1) nd (2.2)] The expected in vivo pek increse in Fctor VIII level expressed s IU/dL (or % 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 Dose (IU) = 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)] 2.1 Control nd Prevention of Bleeding Episodes A guide for dosing in the tretment of bleeding episodes is provided in Tble 1. The creful control of tretment dose is especilly importnt in cses of life-thretening bleeding episodes. Tble 1 ADVATE Dosing for Tretment of Bleeding Episodes in Adults nd Children Type of Bleeding Episodes Minor Erly hemrthrosis, mild muscle bleeding, or mild orl bleeding episode. Moderte Moderte bleeding into muscles, 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. Required Pek Post-infusion Fctor VIII Activity in the Blood (s % of Norml or IU/dL) Dose (IU/kg) = Desired Fctor VIII Rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL) Dosge nd Frequency Necessry to Mintin the Therpeutic Plsm Level Interntionl Units per kg Repet infusions every 12 to 24 hours (8 to 24 hours for ptients under the ge of 6) for one to three dys until the bleeding episode is resolved (s indicted by relief of pin) or heling is chieved Interntionl Units per kg Repet infusions every 12 to 24 hours (8 to 24 hours for ptients under the ge of 6) for three dys or more until the bleeding episode is resolved (s indicted by relief of pin) or heling is chieved. Initil dose Interntionl Units per kg Repet dose Interntionl Units per kg every 8 to 24 hours (6 to 12 hours for ptients under the ge of 6) until resolution of the bleeding episode hs occurred. 2.2 Periopertive Mngement A guide for dosing in periopertive mngement is provided in Tble 2. The creful control of dose nd durtion of tretment is especilly importnt in cses of mjor surgery. Type of Surgery Minor Including tooth extrction Mjor Exmples include intrcrnil, intr-bdominl, or intrthorcic surgery, joint replcement surgery Tble 2 ADVATE Dosing for Periopertive Mngement in Adults nd Children Required Pek Post-infusion Fctor VIII Activity in the Blood Frequency of Infusion (% of Norml or IU/dL) A single bolus infusion (30-50 Interntionl Units/kg ) beginning within one hour of the opertion. Optionl dditionl dosing every 12 to 24 hours s needed to control bleeding. For dentl procedures, djunctive therpy my be considered (pre- nd post-opertive) Dose (IU/kg) = Desired Fctor VIII Rise (IU/dL or % of norml) x 0.5 (IU/kg per IU/dL) Preopertive bolus infusion: Interntionl Units/ kg. Verify 100% ctivity hs been chieved prior to surgery. Mintennce bolus infusion (40-60 Interntionl Units/kg ) repet infusions every 8 to 24 hours (6 to 24 hours for ptients under the ge of 6), depending on the desired level of Fctor VIII nd stte of wound heling. 2.3 Routine Prophylxis For prevention of bleeding episodes, doses between 20 to 40 Interntionl Units of Fctor VIII per kg body weight every other dy (3 to 4 times weekly) my be utilized. Alterntively, n every third dy dosing regimen trgeted to mintin FVIII trough levels 1% my be employed. Adjust dose bsed on the ptient s clinicl response. 1,2 2.4 Instruction for Use Administer ADVATE by intrvenous (IV) injection fter reconstitution. Ask ptients to follow the specific preprtion nd dministrtion procedures provided by their physicins. For instructions, sk ptients to follow the recommendtions in the FDA-pproved ptient lbeling. [See FDA-Approved Ptient Lbeling (17)] Perform reconstitution, product dministrtion, nd hndling of the dministrtion set nd needles with cution. Percutneous puncture with needle contminted with blood cn trnsmit infectious viruses including HIV (AIDS) nd heptitis. Obtin immedite medicl ttention if injury occurs. Plce needles in shrps continer fter single use. Discrd ll equipment, including ny reconstituted ADVATE, in n pproprite continer. 2.5 Preprtion nd Reconstitution The procedures below re provided s generl guidelines for the preprtion nd reconstitution of ADVATE. Alwys work on clen surfce nd wsh your hnds before performing the following procedures: 1. Bring the ADVATE (dry fctor concentrte) nd Sterile Wter for Injection, USP (diluent) to room temperture. 2. Remove cps from the fctor concentrte nd diluent vils. 3. Clense stoppers with germicidl solution nd llow to dry prior to use. Plce the vils on flt surfce. 4. Open the BAXJECT II device pckge by peeling wy the lid, without touching the inside (Figure A). Do not remove the device from the pckge. 5. Turn the pckge over. Press stright down to fully insert the cler plstic spike through the diluent vil stopper (Figure B). 6. Grip the BAXJECT II pckge t its edge nd pull the pckge off the device (Figure C). Do not remove the blue cp from the BAXJECT II device. Do not touch the exposed white plstic spike. 7. Turn the system over so tht the diluent vil is on top. Quickly insert the white plstic spike fully into the ADVATE vil stopper by pushing stright down (Figure D). The vcuum will drw the diluent into the ADVATE vil. 8. Swirl gently until ADVATE is completely dissolved. Do not refrigerte fter reconstitution. 2.6 Administrtion ADVATE is for intrvenous use fter reconstitution only. Inspect prenterl drug products for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. 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. 1. Use septic technique. 2. Remove the blue cp from the BAXJECT II device. Connect the syringe to the BAXJECT II device (Figure E). Do not inject ir. 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 F). 4. Disconnect the syringe; ttch suitble needle nd inject intrvenously s instructed under Administrtion by Bolus Infusion. If ptient is to receive more thn one vil of ADVATE, the contents of multiple vils my be drwn into the sme syringe. Plese note tht the BAXJECT II device is intended for use with single vil of ADVATE nd Sterile Wter for Injection, USP only; therefore, reconstituting nd withdrwing second vil into the syringe requires second BAXJECT II device. 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. 3. DOSAGE FORMS AND STRENGTHS ADVATE with 5 ml of Sterile Wter for Injection, USP is vilble s lyophilized powder in single-use glss vils contining nominlly 250, 500, 1000, 1500, 2000 or 3000 Interntionl Units (IU). ADVATE with 2 ml of Sterile Wter for Injection, USP is vilble s lyophilized powder in single-use glss vils contining nominlly 250, 500, 1000 or 1500 IU. Reconstitute using Sterile Wter for Injection, USP (swfi) provided in the kit. Ech vil of ADVATE is lbeled with the recombinnt ntihemophilic fctor (rahf) ctivity expressed in Interntionl Units per vil. 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 Known nphylxis to mouse or hmster protein or other constituents of the product.

3 5. WARNINGS AND PRECAUTIONS 5.1 Anphylxis nd Hypersensitivity Rections Allergic-type hypersensitivity rections, including nphylxis, re possible nd hve been reported with ADVATE. Symptoms hve mnifested s dizziness, presthesis, rsh, flushing, fce swelling, urticri, dyspne, nd pruritus. [See Ptient Counseling Informtion (17)] ADVATE contins trce mounts of mouse immunoglobulin G (MuIgG): mximum of 0.1 ng/iu ADVATE nd hmster proteins: mximum of 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 Crefully monitor ptients treted with AHF products for the development of Fctor VIII inhibitors by pproprite clinicl observtions nd lbortory tests. Inhibitors hve been reported following dministrtion of ADVATE predominntly in previously untreted ptients (PUPs) nd previously minimlly treted ptients (MTPs). 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 The clinicl response to ADVATE my vry. If bleeding is not controlled with the recommended dose, determine the plsm level of Fctor VIII nd dminister sufficient dose of ADVATE to chieve stisfctory clinicl response. If the ptient s plsm Fctor VIII level fils to increse s expected or if bleeding is not controlled fter the expected dose, suspect the presence of n inhibitor (neutrlizing ntibodies) nd perform pproprite tests s follows: 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)] 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 Antihemophilic 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 drug rections (ADRs) seen with ADVATE re hypersensitivity rections nd the development of high-titer inhibitors necessitting lterntive tretments to Fctor VIII. The most common ADRs 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 studies in previously treted ptients (PTPs) nd one ongoing study 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 (rnge: 1 to 598). 3 The summry of dverse rections (ADRs) with frequency 5% (defined s dverse events occurring within 24 hours of infusion or ny event cuslly relted occurring within study period) is shown in Tble 3. No subject ws withdrwn from study due to n ADR. There were no deths in ny of the clinicl studies. Tble 3 Summry of Adverse Rections (ADRs) with Frequency 5% in 234 Treted Subjects b MedDRA c System Orgn Clss MedDRA Preferred Term Number of ADRs Number of Subjects Percent of Subjects Generl disorders nd dministrtion site conditions Pyrexi 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 Infections nd infesttions Upper respirtory trct infection Respirtory, thorcic nd medistinl disorders Phryngolryngel pin Respirtory, thorcic nd medistinl disorders Nsl congestion Gstrointestinl disorders Dirrhe Gstrointestinl disorders Nuse Generl disorders nd dministrtion site conditions Pin Skin nd subcutneous tissue disorders Rsh Infections nd infesttions Er infection Injury, poisoning nd procedurl complictions Procedurl pin Respirtory, thorcic nd medistinl disorders Rhinorrhe ADRs re defined s ny Adverse Event tht occurred within 24 hours fter being infused with investigtionl product OR ll Adverse Events ssessed relted or possibly relted to investigtionl product OR Adverse 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 study in PUPs s of 27 Mrch IMMUNOGENICITY The development of Fctor VIII inhibitors with the use of ADVATE ws evluted in clinicl studies 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 low-titer inhibitor (2.0 [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 studies 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 ptients 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 ptients, 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. 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. 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. 7. DRUG INTERACTIONS There re no known drug interctions reported with ADVATE. Drug interction studies hve not been performed. 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. Prescribe ADVATE only if cliniclly needed. 8.2 Lbor nd Delivery There re no dequte nd well-controlled humn studies tht hve investigted the effects of ADVATE during lbor nd delivery. Prescribe ADVATE only if cliniclly 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. Prescribe ADVATE only if cliniclly needed. 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. 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 Study, 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 (14.4)] 8.5 Geritric Use Clinicl studies 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. c MedDRA version 8.1 ws used.

4 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] 10. OVERDOSAGE No symptoms of overdose with ADVATE hve been reported. 11. DESCRIPTION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] is purified glycoprotein consisting of 2,332 mino cids tht is synthesized by geneticlly engineered CHO cell line. In culture, the CHO cell line expresses 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 Antihemophilic 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. When reconstituted with the provided Sterile Wter for Injection, USP, the product contins the following stbilizers nd excipients in trgeted mounts: Tble 5 Approximte Concentrtion of Stbilizer nd Excipient fter Reconstitution Stbilizer nd Excipient 5 ml Reconstitution (for 250, 500, 1000, 1500, 2000, 3000 IU) Trget 2 ml Reconstitution (for 250, 500, 1000, 1500 IU) Trget Tris (hydroxymethyl) minomethne 10 mm 25 mm Clcium Chloride 1.7 mm 4.2 mm Mnnitol 3.2% (w/v) 8% (w/v) Sodium Chloride 90 mm 225 mm α, α-trehlose 0.8% (w/v) 2% (w/v) Histidine 10 mm 25 mm Glutthione (Reduced) 0.08 mg/ml 0.2 mg/ml Polysorbte % (w/v) 0.025% (w/v) ADVATE is vilble in single-dose vils tht contin nominlly 250, 500, 1000, 1500, 2000 nd 3000 Interntionl Units (IU) per vil. The product contins the following stbilizers nd excipients: mnnitol, trehlose, sodium chloride, histidine, Tris, clcium chloride, polysorbte 80, nd glutthione. VWF is coexpressed 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. Ech vil of ADVATE is lbeled with the rahf ctivity expressed in Interntionl Units per vil. 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 study of ADVATE produced t Orth, Austri (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 Phrmcokinetic prmeters for dults for ech study preprtion in the per-protocol nlysis re presented in Tble 6. Tble 6 Phrmcokinetic Prmeters for ADVATE nd RECOMBINATE (Per-Protocol Anlysis, Adult Subjects Age > 16 yers) Prmeter RECOMBINATE (n = 20) Men ± SD ADVATE (n = 20) Men ± SD AUC 0-48h (IU hrs/dl) b 1638 ± ± 338 In vivo recovery (IU/dL/IU/kg) c 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/hr/kg) 0.03 ± ± subjects were enrolled in the clinicl study. The per-protocol nlysis included 30 ptients (20 dults nd 10 children). The PK prmeters in the tble re clculted for dult subjects only. b Are under the plsm Fctor VIII concentrtion x time curve from 0 to 48 hours post-infusion. 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 the description of the clinicl study results for discussion of the effect of long-term exposure on the phrmcokinetic properties of ADVATE. [See Clinicl Studies (14.2)] In n nlysis of dt from 58 unique subjects with 65 surgicl procedures in the periopertive mngement study, 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 (per-protocol 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. Tble 7 Phrmcokinetic Prmeters (Men ± SD) of ADVATE by Age Group (N = 51; 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 study 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 Single doses, severlfold higher thn the recommended clinicl dose (relted to body weight), did not demonstrte ny cute or toxic effect for ADVATE in lbortory nimls (mouse, rt, rbbit, nd dog). Multiple dose studies were not performed with ADVATE but were performed with the relted product, RECOMBINATE, nd with formultion buffers of ADVATE Crcinogenesis, Mutgenesis, Impirment of Fertility No studies hve been conducted with the ctive ingredient in ADVATE to ssess its mutgenic or crcinogenic potentil. 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. 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. 14. CLINICAL STUDIES 14.1 Originl Sfety nd Efficcy Study The originl sfety nd efficcy study evluted the phrmcokinetics (double-blinded, rndomized, cross-over), sfety, immunogenicity, nd hemosttic efficcy (open-lbel) of ADVATE in 111 subjects. The study ws conducted with 103 Cucsin; 7 Blck nd 1 Asin US nd Europen 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, portl vein hypertension (INR >1.4), presence of splenomegly, spider ngiomt, history of esophgel hemorrhge or documented esophgel vrices, hypersensitivity to RECOMBINATE rahf, or scheduled to receive immunomodulting drug 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 n ordinl scle of excellent, good, fir, or none, bsed on the qulity of hemostsis chieved with ADVATE produced in the Orth fcility 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 protocol-mndted 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 new bleeding episodes). 4 These rtes re presented in Tble 8. c 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.

5 Tble 8 Rte of New Bleeding Episodes During Prophylxis Bleeding Episode Etiology Men (± SD) New Bleeding Episodes/Subject/Month Spontneous 0.34 ± 0.49 Post-trumtic 0.39 ± 0.46 Unknown 0.33 ± 0.34 Overll 0.52 ± 0.71 Etiology ws indeterminte The phrmcokinetic properties of ADVATE were investigted t the beginning of tretment in multicenter study 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 study. The phrmcokinetics of ADVATE ws investigted in n interim nlysis of study of peditric previously treted subjects < 6 yers of ge. [See Peditric Use (8.4) nd Clinicl Phrmcology (12)] 14.2 Continution Study Additionl (open-lbel) sfety nd efficcy dt were bsed on 82 subjects who continued with tretment following prticiption in the pivotl study. An interim nlysis of efficcy from the continution study ws conducted for 27 subjects who self-dministered ADVATE produced in Neuchâtel on routine prophylctic regimen during minimum period of 50 exposure dys to ADVATE. New 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 new 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 the mjority (63%) of ll new bleeding episodes ws rted s excellent or good. 86% of the bleeding episodes 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 study design, key inclusion nd exclusion criteri, tretment, number of subjects nd ge rnge for the originl periopertive mngement study cn be found in Tble 9. Tble 9 Study Design, Key Inclusion nd Exclusion Criteri, Tretment, Number of Subjects nd Age Rnge for ADVATE Periopertive Mngement Study 6 Tretment(s) Number of Subjects Age Rnge, Rce Periopertive Mngement Interim: Interim: 1. Preopertive 10 Procedures: yers Mjor: 6 Dentl loding dose: FVIII level 60- Minor: 4 Cucsin: 9 100% of norml; Orthopedic: 5 Blck: 1 Mjor/Minor loding dose: FVIII level Dentl: % of norml Finl: 2. Intr- nd Post-Opertive Finl: yers *BI: s cliniclly indicted; Procedures: 65 *CI: initil rte for subjects >12y: 4 IU kg -1 h Mjor: 22 Cucsin: 55-1 ; initil rte subjects 5-12y: 5 IU kg -1 h Minor: 35 Blck: 3-1 for; then Orthopedic: 40 Asin: 1 investigtor-determined Dentl: 8 3. Home Replcement Therpy 7 to <13 yers (n=3 subjects) 13 to <16 yers (n=8 subjects) Prescribed by investigtor for up 16 or older (n=48 subjects) to 6 weeks for mjor orthopedic procedures nd up to 2 weeks for ll other procedures * BI is intermittent bolus infusion nd CI is continuous infusion An interim nlysis of the hemosttic efficcy of ADVATE during the periopertive mngement of subjects undergoing surgicl procedures ws conducted for 10 of 25 plnned subjects. Ten subjects underwent 10 surgicl procedures while receiving ADVATE. 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 study. 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 study durtion nd study mediction exposure, is presented in Tble 10. Tble 10 Surgicl Procedures, Study Durtion, nd Study Mediction Exposure Surgery Type Dys of Study ADVATE Cumultive ADVATE Exposure 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 ,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 study 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 study of the reltive efficcy of ADVATE use in 2 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 perprotocol 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 hemorrhges per yer upon entering the study. Ech subject in the per-protocol group ws dherent to > 90% of the prescribed number of prophylctic infusions; no subject in the study 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). 22 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 study 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: 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 Clinicl Prmeters Medin (IQR) 1 Annul Bleed Rte (ABR) Medin (IQR) 1 Joint ABR Medin (IQR) 1 Non-Joint ABR Medin (IQR) 1 Spontneous ABR Medin (IQR) 1 Trumtic ABR Tble 11 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 PKdriven Prophylxis (n = 53) 44.0 (20.8) 1.0 (2.1) 1.0 (4.1) 1.0 (4.1) 38.7 (24.8) 0.5 (2.0) 1.0 (4.1) 1.0 (2.1) 4.0 (11.9) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 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) 1 Inter-qurtile-rnge (IQR) is defined s the difference between the 75th percentile (3rd qurtile) nd the 25th 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 12. Tble 12 Annulized Bleed Rte by Age Ctegory nd Any Prophylxis vs On-Demnd (Per Protocol) Age Ctegory Children ( 7 to <12 yers old) Adolescents ( 12 to <16 yers old) Adults ( 16 yers old nd older) Any Prophylxis Percentge of N Min Med Mx Subjects With Zero Bleeds On-Demnd N Min Med Mx % % % All Subjects % Percentge of Subjects With Zero Bleeds All subjects bleed during On-Demnd As secondry endpoint, the study 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 domin nd 2 summry scores (Tble 13). Tble 13 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) 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) Physicl Component Score 3.56 (1.56, 5.56) Mentl Component Score (-3.66, 1.23) Positive chnge vlues re in the fvorble direction.

6 FULL PRESCRIBING INFORMATION ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] 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 plsm- nd 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 onestge clotting nd chromogenic fctor VIII ssy. Thromb Hemost : PATIENT COUNSELING INFORMATION See FDA-pproved ptient lbeling (Ptient Informtion 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. 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ADVATE is vilble in single-dose vils tht contin the following nominl product strengths: Nominl Strength Fctor VIII Potency Rnge NDC (Includes 5 ml swfi Diluent) NDC (Includes 2 ml swfi Diluent) 250 IU IU per vil NDC NDC IU IU per vil NDC NDC IU IU per vil NDC NDC IU IU per vil NDC NDC IU IU per vil NDC IU IU per vil NDC Actul Fctor VIII ctivity in Interntionl Units is stted on the lbel of ech ADVATE crton nd vil Storge nd Hndling ADVATE is pckged with 5 ml or 2 ml of Sterile Wter for Injection, USP, BAXJECT II Needleless Trnsfer Device, one Terumo Microbore Infusion set (2 ml only), one full prescribing physicin insert, nd one ptient insert. ADVATE should be refrigerted (2-8 C [36-46 F]) in powder form. 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. The dte tht ADVATE is removed from refrigertion should be noted on the crton. Do not use beyond the expirtion dte printed on the vil or six months fter dte noted on the crton, whichever is erlier. After storge t room temperture, the product must not be returned to the refrigertor. Avoid freezing to prevent dmge to the diluent vil. 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 under U.S. Ptent Numbers: 5,733,873; 5,854,021; 5,919,766; 5,955,448; 6,313,102; 6,586,573; 6,649,386; 7,087,723; nd 7,247,707. Mde ccording to the method of U.S. Ptent Numbers: 5,470,954; 6,100,061; 6,475,725; 6,555,391; 6,936,441; 7,094,574; 7,253,262; nd 7,381,796. Bxter Helthcre Corportion, Westlke Villge, CA USA U.S. License No. 140 Printed in USA Issued December 2011

7 FDA-Approved Lbeling ADVATE (d-vte) [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] 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. ADVATE with 5 ml Diluent ADVATE with 2 ml Diluent 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). Hemophili A is n inherited bleeding disorder tht prevents blood from clotting normlly. ADVATE is used to prevent nd control bleeding in people with Hemophili A. Your helthcre provider my give you ADVATE when you hve surgery. ADVATE is not used to tret von Willebrnd Disese. Who should not use ADVATE? You should not use ADVATE if you re llergic to mice or hmsters. re 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. re brestfeeding. It is not known if ADVATE psses into your milk nd if it cn hrm your bby. re 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 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 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 comes in six different dosge strengths: 250 Interntionl Units (IU), 500 IU, 1000 IU, 1500 IU, 2000 IU* nd 3000 IU*. The ctul strength will be imprinted on the lbel nd on the box. The six different strengths re color coded, s follows: Light-blue Pink Green Purple Ornge Silver Dosge strength of pproximtely 250 Interntionl Units per vil ( IU/vil) Dosge strength of pproximtely 500 Interntionl Units per vil ( IU/vil) Dosge strength of pproximtely 1000 Interntionl Units per vil ( IU/vil) Dosge strength of pproximtely 1500 Interntionl Units per vil ( IU/vil) Dosge strength of pproximtely 2000 Interntionl Units per vil ( IU/vil) (*vilble only with 5 ml swfi) Dosge strength of pproximtely 3000 Interntionl Units per vil ( IU/vil) (*vilble only 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 vils contining powdered product (without sterile diluent dded) 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 6 months from this dte or the expirtion dte listed on the vil, whichever is erlier. do not return the product bck to the refrigertor. Store vils in their originl box nd protect them 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 ADVATE left in the vil 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 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: December 2011

8 Instructions For Use ADVATE [Antihemophilic Fctor (Recombinnt), Plsm/Albumin-Free Method] (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 t the end of this leflet. 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. 7. Swirl the connected vils gently nd continuously until the ADVATE is completely dissolved. Do not shke. The ADVATE solution should look cler nd colorless. If not, do not use it nd notify Bxter immeditely. 8. Tke off the blue cp from the BAXJECT II device nd connect the syringe. Be creful to not inject ir. ADVATE 5 ml ADVATE 2 ml 1. Prepre clen flt surfce nd gther ll the mterils you will need for the infusion. Check the expirtion dte, nd let the vil with the ADVATE concentrte nd the Sterile Wter for Injection, USP (diluent) 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. If you re using more thn one vil of ADVATE, mke sure you mix ech vil of ADVATE with the Sterile Wter for Injection, USP tht is provided in the box.. When ADVATE is provided with 5 ml of Sterile Wter for Injection, USP, the drug product nd its diluent re provided in n ornge box; the 5 ml diluent vil hs grey cp. b. When ADVATE is provided with 2 ml of Sterile Wter for Injection, USP, the drug product nd its diluent re provided in purple box; the 2 ml diluent vil hs trnsprent cp. 2. Remove cps from the ADVATE concentrte nd diluent vils to expose the centers of the rubber stoppers. 9. Turn over the connected vils so tht the ADVATE vil is on top. Drw the ADVATE solution into the syringe by pulling bck the plunger slowly. Disconnect the syringe from the vils. 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. 10. If you re using more thn one vil of ADVATE, the contents of more thn one vil my be drwn into the sme syringe. Mke sure you mix ech vil of ADVATE with the Sterile Wter for Injection, USP tht is provided in the box (Following Steps 1-9). You will need seprte BAXJECT II device to mix ech dditionl vil of ADVATE. 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). 11. Insert the needle into the vein nd remove the tourniquet. Slowly infuse the ADVATE. Do not infuse ny fster thn 10 ml per minute. 3. Disinfect the stoppers with n lcohol swb (or other suitble solution suggested by your helthcre provider or hemophili center) by rubbing the stoppers firmly for severl seconds nd llow them to dry prior to use. Plce the vils on flt surfce. 4. Open the BAXJECT II device pckge by peeling wy the lid, without touching the inside of the pckge. Do not remove the BAXJECT II device from the pckge. 12. Tke the needle out of the vein nd use sterile guze to put pressure on the infusion site for severl minutes. Do not recp the needle. Plce it with the used syringe in hrd-wlled Shrps continer for proper disposl. Remove the peel-off lbel from the ADVATE vil 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. 5. Turn the pckge with the BAXJECT II device upside down nd plce it over the top of the diluent vil. Fully insert the cler plstic spike of the device into the center of the diluent vil s stopper by pushing stright down. Grip the pckge t its edge nd lift it off the device. Be creful not to touch the white plstic spike. Do not remove the blue cp from the BAXJECT II device. The diluent vil now hs the BAXJECT II device connected to it nd is redy to be connected to the ADVATE vil. 13. Dispose of the used vils nd BAXJECT II system in your hrdwlled Shrps continer without tking them prt. Do not dispose of these supplies in ordinry household trsh. Importnt: Contct your helthcre provider or locl hemophili tretment center if you experience ny problems. 6. To connect the diluent vil to the ADVATE vil, turn the diluent vil over nd plce it on top of the vil contining ADVATE concentrte. Fully insert the white plstic spike into the ADVATE vil s stopper by pushing stright down. Diluent will flow into the ADVATE vil. This should be done right wy to keep the liquid free of germs. Bxter, Advte, Bxject nd Cre re trdemrks of Bxter Interntionl Inc. registered in the U.S. Ptent nd Trdemrk Office. Ptented under U.S. Ptent Numbers: 5,733,873; 5,854,021; 5,919,766; 5,955,448; 6,313,102; 6,586,573; 6,649,386; 7,087,723; nd 7,247,707. Mde ccording to the method of U.S. Ptent Numbers: 5,470,954; 6,100,061; 6,475,725; 6,555,391; 6,936,441; 7,094,574; 7,253,262; nd 7,381,796. Bxter Helthcre Corportion Westlke Villge, CA USA U.S. License No. 140 Printed in USA Issued December 2011