HERCEPTIN (trastuzumab) Intravenous Infusion Initial U.S. Approval: 1998

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. HERCEPTIN (trstuzum) Intrvenous Infusion Initil U.S. Approvl: 1998 WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, nd PULMONARY TOXICITY See full prescriing informtion for complete oxed wrning Crdiomyopthy: cn result in su-clinicl nd clinicl crdic filure mnifesting s CHF, nd decresed LVEF, with gretest risk when dministered concurrently with nthrcyclines. Evlute crdic function prior to nd during tretment. Discontinue for crdiomyopthy. (5.1, 2.2) Infusion rections, Pulmonry toxicity: Discontinue for nphylxis, ngioedem, interstitil pneumonitis, or cute respirtory distress syndrome. (5.2, 5.4) RECENT MAJOR CHANGES Indictions nd Usge, Adjuvnt Tretment of Brest Cncer (1.1) 05/2008 Dosge nd Administrtion, Recommended Doses nd Schedules (2.1) 03/2009 Wrnings nd Precutions, Crdiomyopthy (5.1) 05/ INDICATIONS AND USAGE is HER2/neu receptor ntgonist indicted for the tretment of HER2 overexpressing rest cncer (1.1, 1.2) DOSAGE AND ADMINISTRATION For intrvenous (IV) infusion only. Do not dminister s n IV push or olus (5.2). Adjuvnt Tretment of HER2-Overexpressing Brest Cncer (2.1) Administer t either: Initil dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks, or Initil dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over minutes IV infusion every three weeks for 52 weeks. Metsttic HER2-Overexpressing Brest Cncer (2.1) Initil dose of 4 mg/kg s 90 minute IV infusion followed y susequent weekly doses of 2 mg/kg s 30 minute IV infusions. FULL PRESCRIBING INFORMATION: CONTENTS* WARNING CARDIOMYOPATHY, INFUSION REACTIONS, PULMONARY TOXICITY 1 INDICATIONS AND USAGE 1.1 Adjuvnt Brest Cncer 1.2 Metsttic Brest Cncer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Doses nd Schedules 2.2 Dose Modifictions 2.3 Preprtion for Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Crdiomyopthy 5.2 Infusion Rections 5.3 Excertion of Chemotherpy-Induced Neutropeni 5.4 Pulmonry Toxicity 5.5 HER2 Testing 5.6 Emryo-Fetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 6.3 Post-Mrketing Experience 7 DRUG INTERACTIONS DOSAGE FORMS AND STRENGTHS Multidose vil nominlly contining 440 mg s lyophilized, sterile powder. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Crdiomyopthy (5.1, 6.1) Infusion Rections (5.2, 6.1) Pulmonry Toxicity (5.4, 6.1) Excertion of Chemotherpy-Induced Neutropeni (5.3, 6.1) HER2 testing should e performed y lortories with demonstrted proficiency. (5.5) My cuse oligohydrmnios nd fetl hrm when dministered to pregnnt womn. Pregnncy registry ville ( ). (5.6, 8.1) ADVERSE REACTIONS Adjuvnt Brest Cncer Adverse rections ( 2% higher incidence with -contining tretment compred with control tretment) re ftigue, infection, neutropeni, nemi, mylgi, dyspne, rsh/desqumtion, hedche, dirrhe, nd nuse. (6.1) Metsttic Brest Cncer Adverse rections ( 15% incidence with monotherpy or 5% with / pclitxel) re nuse, fever, infection, rsh, incresed cough, vomiting, dirrhe, hedche, nd nemi. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Genentech t or FDA t FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION. Revised: 03/ USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 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 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Adjuvnt Brest Cncer 14.2 Metsttic Brest Cncer 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Stility nd Storge 17 PATIENT COUNSELING INFORMATION * Sections or susections omitted from the Full Prescriing Informtion re not listed.

2 FULL PRESCRIBING INFORMATION WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, nd PULMONARY TOXICITY Crdiomyopthy cn result in su-clinicl nd clinicl crdic filure mnifesting s CHF nd decresed LVEF. The incidence nd severity of left ventriculr crdic dysfunction ws highest in ptients who received concurrently with nthrcycline-contining chemotherpy regimens. Evlute left ventriculr function in ll ptients prior to nd during tretment with. Discontinue tretment in ptients receiving djuvnt therpy nd strongly consider discontinution of tretment in ptients with metsttic rest cncer for cliniclly significnt decrese in left ventriculr function. [see Wrnings nd Precutions (5.1) nd Dosge nd Administrtion (2.2)] Infusion Rections; Pulmonry Toxicity dministrtion cn result in serious infusion rections nd pulmonry toxicity. Ftl infusion rections hve een reported. In most cses, symptoms occurred during or within 24 hours of dministrtion of. infusion should e interrupted for ptients experiencing dyspne or cliniclly significnt hypotension. Ptients should e monitored until signs nd symptoms completely resolve. Discontinue for infusion rections mnifesting s nphylxis, ngioedem, interstitil pneumonitis, or cute respirtory distress syndrome. [see Wrnings nd Precutions (5.2, 5.4)] 1 INDICATIONS AND USAGE 1.1 Adjuvnt Brest Cncer is indicted for djuvnt tretment of HER2 overexpressing node positive or node negtive (ER/PR negtive or with one high risk feture [see Clinicl Studies (14.1)]) rest cncer s prt of tretment regimen consisting of doxoruicin, cyclophosphmide, nd either pclitxel or docetxel with docetxel nd cropltin s single gent following multi-modlity nthrcycline sed therpy. 1.2 Metsttic Brest Cncer is indicted: In comintion with pclitxel for first-line tretment of HER2-overexpressing metsttic rest cncer As single gent for tretment of HER2-overexpressing rest cncer in ptients who hve received one or more chemotherpy regimens for metsttic disese. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Doses nd Schedules Do not dminister s n intrvenous push or olus. Do not mix with other drugs. Adjuvnt Tretment, Brest Cncer: Administer ccording to one of the following doses nd schedules for totl of 52 weeks of therpy: During nd following pclitxel, docetxel, or docetxel/cropltin: Initil dose of 4mg/kg s n intrvenous infusion over 90 minutes then t 2 mg/kg s n intrvenous infusion over 30 minutes weekly during chemotherpy for the first 12 weeks (pclitxel or docetxel) or 18 weeks (docetxel/cropltin). One week following the lst weekly dose of, dminister t 6 mg/kg s n intrvenous infusion over minutes every three weeks. As single gent within three weeks following completion of multimodlity, nthrcycline-sed chemotherpy regimens. Initil dose t 8 mg/kg s n intrvenous infusion over 90 minutes Susequent doses t 6 mg/kg s n intrvenous infusion over minutes every three weeks. [see Dose Modifiction (2.2)] Metsttic Tretment, Brest Cncer: Administer, lone or in comintion with pclitxel, t n initil dose of 4 mg/kg s 90 minute intrvenous infusion followed y susequent once weekly doses of 2 mg/kg s 30 minute intrvenous infusions until disese progression. 2.2 Dose Modifictions Infusion Rections [see Boxed Wrning, Wrnings nd Precutions (5.2)] Decrese the rte of infusion for mild or moderte infusion rections Interrupt the infusion in ptients with dyspne or cliniclly significnt hypotension Discontinue for severe or life-thretening infusion rections. Crdiomyopthy [see Boxed Wrning, Wrnings nd Precutions (5.1)] Assess left ventriculr ejection frction (LVEF) prior to initition of nd t regulr intervls during tretment. Withhold dosing for t lest 4 weeks for either of the following: 16% solute decrese in LVEF from pre-tretment vlues LVEF elow institutionl limits of norml nd 10% solute decrese in LVEF from pretretment vlues. my e resumed if, within 4 8 weeks, the LVEF returns to norml limits nd the solute decrese from seline is 15%. Permnently discontinue for persistent ( > 8 weeks) LVEF decline or for suspension of dosing on more thn 3 occsions for crdiomyopthy. 2.3 Preprtion for Administrtion Reconstitution Reconstitute ech 440 mg vil of with 20 ml of Bcteriosttic Wter for Injection (BWFI), USP, contining 1.1% enzyl lcohol s preservtive to yield multi-dose solution contining 21 mg/ml trstuzum. In ptients with known hypersensitivity to enzyl lcohol, reconstitute with 20 ml of Sterile Wter for Injection (SWFI) without preservtive to yield single use solution. Use pproprite septic technique when performing the following reconstitution steps: Using sterile syringe, slowly inject the 20 ml of diluent into the vil contining the lyophilized cke of. The strem of diluent should e directed into the lyophilized cke. Swirl the vil gently to id reconstitution. DO NOT SHAKE. Slight foming of the product my e present upon reconstitution. Allow the vil to stnd undistured for pproximtely 5 minutes. Prenterl drug products should e inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. Inspect visully for prticultes nd discolortion. The solution should e free of visile prticultes, cler to slightly oplescent nd colorless to ple yellow. Store reconstituted t 2-8 C; discrd unused fter 28 dys. If is reconstituted with SWFI without preservtive, use immeditely nd discrd ny unused portion. Dilution Determine the dose (mg) of [see Dosge nd Administrtion (2.1)]. Clculte the volume of the 21 mg/ml reconstituted solution needed, withdrw this mount from the vil nd dd it to n infusion g contining 250 ml of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. Gently invert the g to mix the solution. 3 DOSAGE FORMS AND STRENGTHS 440 mg lyophilized powder per multi-use vil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Crdiomyopthy cn cuse left ventriculr crdic dysfunction, rrhythmis, hypertension, disling crdic filure, crdiomyopthy, nd crdic deth

3 [see Boxed Wrning: Crdiomyopthy]. cn lso cuse symptomtic decline in left ventriculr ejection frction (LVEF). There is 4 6 fold increse in the incidence of symptomtic myocrdil dysfunction mong ptients receiving s single gent or in comintion therpy compred with those not receiving. The highest solute incidence occurs when is dministered with n nthrcycline. Withhold for 16% solute decrese in LVEF from pre-tretment vlues or n LVEF vlue elow institutionl limits of norml nd 10% solute decrese in LVEF from pretretment vlues. [see Dosge nd Administrtion (2.2)] The sfety of continution or resumption of in ptients with -induced left ventriculr crdic dysfunction hs not een studied. Crdic Monitoring Conduct thorough crdic ssessment, including history, physicl exmintion, nd determintion of LVEF y echocrdiogrm or MUGA scn. The following schedule is recommended: Bseline LVEF mesurement immeditely prior to initition of LVEF mesurements every 3 months during nd upon completion of Repet LVEF mesurement t 4 week intervls if is withheld for significnt left ventriculr crdic dysfunction [see Dosge nd Administrtion (2.2)] LVEF mesurements every 6 months for t lest 2 yers following completion of s component of djuvnt therpy. In Study 1, 16% (136/844) of ptients discontinued due to clinicl evidence of myocrdil dysfunction or significnt decline in LVEF. In Study 3, the numer of ptients who discontinued due to crdic toxicity ws 2.6% (44/1678). In Study 4, totl of 2.9% (31/1056) ptients in the TCH rm (1.5% during the chemotherpy phse nd 1.4% during the monotherpy phse) nd 5.7% (61/1068) ptients in the AC-TH rm (1.5% during the chemotherpy phse nd 4.2% during the monotherpy phse) discontinued due to crdic toxicity. Among 32 ptients receiving djuvnt chemotherpy (Studies 1 nd 2) who developed congestive hert filure, one ptient died of crdiomyopthy nd ll other ptients were receiving crdic mediction t lst follow-up. Approximtely hlf of the surviving ptients hd recovery to norml LVEF (defined s 50%) on continuing medicl mngement t the time of lst follow-up. Incidence of congestive hert filure is presented in Tle 1. The sfety of continution or resumption of in ptients with -induced left ventriculr crdic dysfunction hs not een studied. Tle 1 Incidence of Congestive Hert Filure in Adjuvnt Brest Cncer Studies Incidence of CHF Study Regimen Control 1 & 2 AC Pclitxel+ 2% (32/1677) 0.4% (7/1600) 3 Chemo 2% (30/1678) 0.3% (5/1708) 4 AC Docetxel+ 2% (20/1068) 0.3% (3/1050) 4 Docetxel+Cro+ 0.4% (4/1056) 0.3% (3/1050) Includes 1 ptient with ftl crdiomyopthy. Anthrcycline (doxoruicin) nd cyclophosphmide Tle 2 Incidence of Crdic Dysfunction in Metsttic Brest Cncer Studies NYHA I-IV Incidence NYHA III-IV Study Event Control Control 5 (AC) Crdic Dysfunction 5 Crdic (pclitxel) Dysfunction 28% 7% 19% 3% 11% 1% 4% 1% Crdic 6 7% N/A 5% N/A Dysfunction c Congestive hert filure or significnt symptomtic decrese in LVEF. Anthrcycline (doxoruicin or epiruicin) nd cyclophosphmide c Includes 1 ptient with ftl crdiomyopthy. In Study 4, the incidence of NCI-CTC Grde 3/4 crdic ischemi/infrction ws higher in the contining regimens: (AC- TH: 0.3% (3/1068) nd TCH 0.2% (: 2/1056)) s compred to none in AC-T. 5.2 Infusion Rections Infusion rections consist of symptom complex chrcterized y fever nd chills, nd on occsion included nuse, vomiting, pin (in some cses t tumor sites), hedche, dizziness, dyspne, hypotension, rsh, nd stheni. [see Adverse Rections (6.1)]. In postmrketing reports, serious nd ftl infusion rections hve een reported. Severe rections which include ronchospsm, nphylxis, ngioedem, hypoxi, nd severe hypotension, were usully reported during or immeditely following the initil infusion. However, the onset nd clinicl course were vrile including progressive worsening, initil improvement followed y clinicl deteriortion, or delyed post-infusion events with rpid clinicl deteriortion. For ftl events, deth occurred within hours to dys following serious infusion rection. Interrupt infusion in ll ptients experiencing dyspne, cliniclly significnt hypotension, nd intervention of medicl therpy dministered, which my include: epinephrine, corticosteroids, diphenhydrmine, ronchodiltors, nd oxygen. Ptients should e evluted nd crefully monitored until complete resolution of signs nd symptoms. Permnent discontinution should e strongly considered in ll ptients with severe infusion rections. There re no dt regrding the most pproprite method of identifiction of ptients who my sfely e retreted with fter experiencing severe infusion rection. Prior to resumption of infusion, the mjority of ptients who experienced severe infusion rection were pre-medicted with ntihistmines nd/or corticosteroids. While some ptients tolerted infusions, others hd recurrent severe infusion rections despite pre-medictions. 5.3 Excertion of Chemotherpy-Induced Neutropeni In rndomized, controlled clinicl trils in women with metsttic rest cncer, the per-ptient incidences of NCI CTC Grde 3-4 neutropeni nd of ferile neutropeni were higher in ptients receiving in comintion with myelosuppressive chemotherpy s compred to those who received chemotherpy lone. The incidence of septic deth ws not significntly incresed. [see Adverse Rections (6.1)]. 5.4 Pulmonry Toxicity use cn result in serious nd ftl pulmonry toxicity. Pulmonry toxicity includes dyspne, interstitil pneumonitis, pulmonry infiltrtes, pleurl effusions, non-crdiogenic pulmonry edem, pulmonry insufficiency nd hypoxi, cute respirtory distress syndrome, nd pulmonry firosis. Such events cn occur s sequele of infusion rections [see Wrnings nd Precutions (5.2)]. Ptients with symptomtic intrinsic lung disese or with extensive tumor involvement of the lungs, resulting in dyspne t rest, pper to hve more severe toxicity. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessry for selection of ptients pproprite for therpy ecuse these re the only ptients studied nd for whom enefit hs een shown. Assessment for HER2 overexpression nd of HER2 gene mplifiction should e performed y

4 lortories with demonstrted proficiency in the specific technology eing utilized. Improper ssy performnce, including use of suoptimlly fixed tissue, filure to utilize specified regents, devition from specific ssy instructions, nd filure to include pproprite controls for ssy vlidtion, cn led to unrelile results. Severl FDA-pproved commercil ssys re ville to id in the selection of ptients for therpy. These include HercepTest nd Pthwy HER-2/neu (IHC ssys) nd PthVysion nd HER2 FISH phrmdx (FISH ssys). Users should refer to the pckge inserts of specific ssy kits for informtion on the vlidtion nd performnce of ech ssy. Limittions in ssy precision (prticulrly for the IHC method) nd in the direct linkge etween ssy result nd overexpression of the trget (for the FISH method) mke it indvisle to rely on single method to rule out potentil enefit. A negtive FISH result does not rule out HER2 overexpression nd potentil enefit from. Tretment outcomes for metsttic rest cncer (Study 5) s function of IHC nd FISH testing re provided in Tle 9. Tretment outcomes for djuvnt rest cncer (Studies 2 nd 3) s function of IHC nd FISH testing re provided in Tle 7. HER2 Protein Overexpression Detection Methods HER2 protein overexpression cn e estlished y mesuring HER2 protein using n IHC method. HercepTest, one test pproved for this use, ws ssessed for concordnce with the Clinicl Tril Assy (CTA), using tumor specimens collected nd stored independently from those otined in clinicl studies in women with metsttic rest cncer. Dt re provided in the pckge insert for HercepTest. HER2 Gene Amplifiction Detection Method The presence of HER2 protein overexpression nd gene mplifiction re highly correlted, therefore the use of FISH to detect gene mplifiction my e employed for selection of ptients pproprite for therpy. PthVysion, one test pproved for this use, ws evluted in n explortory, retrospective ssessment of ville CTA 2+ or 3+ tumor specimens collected s prt of ptient screening for clinicl studies in metsttic rest cncer (Studies 5 nd 6). Dt re provided in the pckge insert for PthVysion. 5.6 Emryo-Fetl Toxicity (Pregnncy Ctegory D) cn cuse fetl hrm when dministered to pregnnt womn. Post-mrketing cse reports suggest tht use during pregnncy increses the risk of oligohydrmnios during the second nd third trimesters. If is used during pregnncy or if womn ecomes pregnnt while tking, she should e pprised of the potentil hzrd to fetus. [see Use in Specific Popultions (8.1)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lel: Crdiomyopthy [see Wrnings nd Precutions (5.1)] Infusion rections [see Wrnings nd Precutions (5.2)] Excertion of chemotherpy-induced neutropeni [see Wrnings nd Precutions (5.3)] Pulmonry toxicity [see Wrnings nd Precutions (5.4)] The most common dverse rections in ptients receiving re fever, nuse, vomiting, infusion rections, dirrhe, infections, incresed cough, hedche, ftigue, dyspne, rsh, neutropeni, nemi, nd mylgi. Adverse rections requiring interruption or discontinution of tretment include CHF, significnt decline in left ventriculr crdic function, severe infusion rections, nd pulmonry toxicity [see Dosge nd Administrtion (2.2)]. 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. Adjuvnt Brest Cncer Studies The dt elow reflect exposure to cross three rndomized, open-lel studies, Studies 1, 2, nd 3, with (n= 3355) or without (n= 3308) trstuzum in the djuvnt tretment of rest cncer. The dt summrized in Tle 3 elow, from Study 3, reflect exposure to in 1678 ptients; the medin tretment durtion ws 51 weeks nd medin numer of infusions ws 18. Among the 3386 ptients enrolled in Study 3, the medin ge ws 49 yers (rnge: 21 to 80 yers), 83% of ptients were Cucsin, nd 13% were Asin. Tle 3 Adverse Rections for Study 3, All Grdes : MedDRA (v. 7.1) Adverse Event Preferred Term 1 Yer (n= 1678) Oservtion (n=1708) Crdic Hypertension 64 (4%) 35 (2%) Dizziness 60 (4%) 29 (2%) Ejection Frction Decresed 58 (3.5%) 11 (0.6%) Plpittions 48 (3%) 12 (0.7%) Crdic Arrhythmis 40 (3%) 17 (1%) Crdic Filure Congestive 30 (2%) 5 (0.3%) Crdic Filure 9 (0.5%) 4 (0.2%) Crdic Disorder 5 (0.3%) 0 (0%) Ventriculr Dysfunction 4 (0.2%) 0 (0%) Respirtory Thorcic Medistinl Disorders Nsophryngitis 135 (8%) 43 (3%) Cough 81 (5%) 34 (2%) Influenz 70 (4%) 9 (0.5%) Dyspne 57 (3%) 26 (2%) URI 46 (3%) 20 (1%) Rhinitis 36 (2%) 6 (0.4%) Phryngolryngel Pin 32 (2%) 8 (0.5%) Sinusitis 26 (2%) 5 (0.3%) Epistxis 25 (2%) 1 (0.06%) Pulmonry Hypertension 4 (0.2%) 0 (0%) Interstitil Pneumonitis 4 (0.2%) 0 (0%) Gstrointestinl Disorders Dirrhe 123 (7%) 16 (1%) Nuse 108 (6%) 19 (1%) Vomiting 58 (3.5%) 10 (0.6%) Constiption 33 (2%) 17 (1%) Dyspepsi 30 (2%) 9 (0.5%) Upper Adominl Pin 29 (2%) 15 (1%) Musculoskeletl & Connective Tissue Disorders Arthrlgi 137 (8%) 98 (6%) Bck Pin 91 (5%) 58 (3%) Mylgi 63 (4%) 17 (1%) Bone Pin 49 (3%) 26 (2%) Muscle Spsm 46 (3%) 3 (0.2%) Nervous System Disorders Hedche 162 (10%) 49 (3%) Presthesi 29 (2%) 11 (0.6%) Skin & Sucutneous Tissue Disorders Rsh 70 (4%) 10 (.6%) Nil Disorders 43 (2%) 0 (0%) Pruritis 40 (2%) 10 (0.6%) Generl Disorders Pyrexi 100 (6%) 6 (0.4%)

5 Tle 3 (cont d) Adverse Rections for Study 3, All Grdes : MedDRA (v. 7.1) Adverse Event Preferred Term 1 Yer (n= 1678) Oservtion (n=1708) Edem Peripherl 79 (5%) 37 (2%) Chills 85 (5%) 0 (0%) Aestheni 75 (4.5%) 30 (2%) Influenz-like Illness 40 (2%) 3 (0.2%) Sudden Deth 1 (.06%) 0 (0%) Infections Nsophryngitis 135 (8%) 43 (3%) UTI 39 (3%) 13 (0.8%) Immune System Disorders Hypersensitivity 10 (0.6%) 1 (0.06%) Autoimmune Thyroiditis 4 (0.3%) 0 (0%) The incidence of Grde 3/4 dverse rections ws <1% in oth rms for ech listed term. Higher level grouping term. The dt from Studies 1 nd 2 were otined from 3206 ptients enrolled, of which 1635 ptients received ; the medin tretment durtion ws 50 weeks. The medin ge ws 49.0 yers (rnge: 24-80); 84% of ptients were White, nd 7% were Blck, 4% were Hispnic, nd 4% were Asin. In Study 1, only Grde 3-5 dverse events, tretment-relted Grde 2 events, nd Grde 2-5 dyspne were collected during nd for up to 3 months following protocol-specified tretment. The following non-crdic dverse rections of Grde 2-5 occurred t n incidence of t lest 2% greter mong ptients rndomized to plus chemotherpy s compred to chemotherpy lone: rthrlgi (31% vs. 28%), ftigue (28% vs. 22%), infection (22% vs. 14%), hot flshes (17% vs. 15%), nemi (13% vs. 7%), dyspne (12% vs. 4%), rsh/desqumtion (11% vs. 7%), neutropeni (7% vs. 5%), hedche (6% vs. 4%), nd insomni (3.7% vs. 1.5%). The mjority of these events were Grde 2 in severity. In Study 2, dt collection ws limited to the following investigtor-ttriuted tretment-relted dverse rections NCI-CTC Grde 4 nd 5 hemtologic toxicities, Grde 3 5 non-hemtologic toxicities, selected Grde 2 5 toxicities ssocited with txnes (mylgi, rthrlgis, nil chnges, motor neuropthy, sensory neuropthy) nd Grde 1 5 crdic toxicities occurring during chemotherpy nd/or tretment. The following non-crdic dverse rections of Grde 2 5 occurred t n incidence of t lest 2% greter mong ptients rndomized to plus chemotherpy s compred to chemotherpy lone: rthrlgi (11% vs. 8.4%), mylgi (10% vs. 8%), nil chnges (9% vs. 7%), nd dyspne (2.5% vs. 0.1%). The mjority of these events were Grde 2 in severity. Sfety dt from Study 4 reflect exposure to s prt of n djuvnt tretment regimen from 2124 ptients receiving t lest one dose of study tretment [AC-TH: n = 1068; TCH: n = 1056]. The overll medin tretment durtion ws 54 weeks in oth the AC-TH nd TCH rms. The medin numer of infusions ws 26 in the AC-TH rm nd 30 in the TCH rm, including weekly infusions during the chemotherpy phse nd every three week dosing in the monotherpy period. Among these ptients, the medin ge ws 49 yers (rnge 22 to 74 yers). In Study 4, the toxicity profile ws similr to tht reported in Studies 1, 2, nd 3 with the exception of low incidence of CHF in the TCH rm. Metsttic Brest Cncer Studies The dt elow reflect exposure to in one rndomized, openlel study, Study 5, of chemotherpy with (n=235) or without (n=234) trstuzum in ptients with metsttic rest cncer, nd one single-rm study (Study 6; n=222) in ptients with metsttic rest cncer. Dt in Tle 5 re sed on Studies 5 nd 6. Among the 464 ptients treted in Study 5, the medin ge ws 52 yers (rnge: yers). Eighty-nine percent were White, 5% Blck, 1% Asin nd 5% other rcil/ethnic groups. All ptients received 4 mg/kg initil dose of followed y 2 mg/kg weekly. The percentges of ptients who received tretment for 6 months nd 12 months were 58% nd 9%, respectively. Among the 352 ptients treted in single gent studies (213 ptients from Study 6), the medin ge ws 50 yers (rnge yers), 100% hd rest cncer, 86% were White, 3% were Blck, 3% were Asin, nd 8% in other rcil/ethnic groups. Most of the ptients received 4 mg/kg initil dose of followed y 2 mg/kg weekly. The percentges of ptients who received tretment for 6 months nd 12 months were 31% nd 16%, respectively. Tle 4 Per-Ptient Incidence of Adverse Rections Occurring in 5% of Ptients in Uncontrolled Studies or t Incresed Incidence in the Arm (Studies 5 nd 6) (Percent of Ptients) Single Agent n = Pclitxel n = 91 Pclitxel Alone n = 95 + AC n = 143 AC Alone n = 135 Body s Whole Pin Astheni Fever Chills Hedche Adominl pin Bck pin Infection Flu syndrome Accidentl injury Allergic rection Crdiovsculr Tchycrdi Congestive hert filure Digestive Nuse Dirrhe Vomiting Nuse nd vomiting Anorexi Heme & Lymphtic Anemi Leukopeni Metolic Peripherl edem Edem Musculoskeletl Bone pin Arthrlgi Nervous Insomni Dizziness

6 Tle 4 (cont d) Per-Ptient Incidence of Adverse Rections Occurring in 5% of Ptients in Uncontrolled Studies or t Incresed Incidence in the Arm (Studies 5 nd 6) (Percent of Ptients) Single Agent n = Pclitxel n = 91 Pclitxel Alone n = 95 + AC n = 143 AC Alone n = 135 Presthesi Depression Peripherl neuritis Neuropthy Respirtory Cough incresed Dyspne Rhinitis Phryngitis Sinusitis Skin Rsh Herpes simplex Acne < 1 Urogenitl Urinry trct infection Dt for single gent were from 4 studies, including 213 ptients from Study 6. Anthrcycline (doxoruicin or epiruicin) nd cyclophosphmide The following susections provide dditionl detil regrding dverse rections oserved in clinicl trils of djuvnt rest, metsttic rest cncer, or post-mrketing experience. Crdiomyopthy Seril mesurement of crdic function (LVEF) ws otined in clinicl trils in the djuvnt tretment of rest cncer. In Study 3, the medin durtion of follow-up ws 12.6 months (12.4 months in the oservtion rm; 12.6 months in the 1-yer rm); nd in Studies 1 nd 2, 23 months in the AC-T rm, 24 months in the AC-TH rm. In Studies 1 nd 2, 6% of ptients were not permitted to initite following completion of AC chemotherpy due to crdic dysfunction (LVEF < 50% or 15 point decline in LVEF from seline to end of AC). Following initition of therpy, the incidence of new-onset dose-limiting myocrdil dysfunction ws higher mong ptients receiving nd pclitxel s compred to those receiving pclitxel lone in Studies 1 nd 2, nd in ptients receiving monotherpy compred to oservtion in Study 3 (see Tle 5, Figures 1 nd 2). Studies 1 & 2 AC TH (n=1606) AC T (n=1488) Study 3 (n=1678) Oservtion (n=1708) Study 4 c TCH (n=1056) AC TH (n=1068) Tle 5 Per-ptient Incidence of New Onset Myocrdil Dysfunction (y LVEF) Studies 1, 2, 3 nd 4 LVEF <50% nd Asolute Decrese from Bseline LVEF <50% 22.8% (366) 9.1% (136) 8.6% (144) 2.7% (46) 8.5% (90) 17% (182) 10% decrese 18.3% (294) 5.4% (81) 7.0% (118) 2.0% (35) 5.9% (62) 13.3% (142) 16% decrese 11.7% (188) 2.2% (33) 3.8% (64) 1.2% (20) 3.3% (35) 9.8% (105) Asolute LVEF Decrese <20% nd 10% 20% 33.4% (536) 18.3% (272) 22.4% (376) 11.9% (204) 34.5% (364) 44.3% (473) 9.2% (148) 2.4% (36) 3.5% (59) 1.2% (21) 6.3% (67) 13.2% (141) AC T 9.5% 6.6% 3.3% 34% 5.5% (n=1050) (100) (69) (35) (357) (58) For Studies 1, 2 nd 3, events re counted from the eginning of tretment. For Study 4, events re counted from the dte of rndomiztion. Studies 1 nd 2 regimens: doxoruicin nd cyclophosphmide followed y pclitxel (AC T) or pclitxel plus (AC TH) c Study 4 regimens: doxoruicin nd cyclophosphmide followed y docetxel (AC T) or docetxel plus (AC TH); docetxel nd cropltin plus (TCH)

7 Figure 1 Studies 1 nd 2: Cumultive Incidence of Time to First LVEF Decline of 10 Percentge Points from Bseline nd to Below 50% with Deth s Competing Risk Event Time 0 is initition of pclitxel or + pclitxel therpy. Figure 2 Study 3: Cumultive Incidence of Time to First LVEF Decline of 10 Percentge Points from Bseline nd to Below 50% with Deth s Competing Risk Event Time 0 is the dte of rndomiztion. Figure 3 Study 4: Cumultive Incidence of Time to First LVEF Decline of 10 Percentge Points from Bseline nd to Below 50% with Deth s Competing Risk Event Time 0 is the dte of rndomiztion. The incidence of tretment emergent congestive hert filure mong ptients in the metsttic rest cncer trils ws clssified for severity using the New York Hert Assocition clssifiction system (I IV, where IV is the most severe level of crdic filure) (see Tle 2). In the metsttic rest cncer trils the proility of crdic dysfunction ws highest in ptients who received concurrently with nthrcyclines. Infusion Rections During the first infusion with, the symptoms most commonly reported were chills nd fever, occurring in pproximtely 40% of ptients in clinicl trils. Symptoms were treted with cetminophen, diphenhydrmine, nd meperidine (with or without reduction in the rte of infusion); permnent discontinution of for infusionl toxicity ws required in < 1% of ptients. Other signs nd/or symptoms my include nuse, vomiting, pin (in some cses t tumor sites), rigors, hedche, dizziness, dyspne, hypotension, elevted lood pressure, rsh, nd stheni. Infusionl toxicity occurred in 21% nd 35% of ptients, nd ws severe in 1.4% nd 9% of ptients, on second or susequent infusions dministered s monotherpy or in comintion with chemotherpy, respectively. In the post-mrketing setting, severe infusion rections, including hypersensitivity, nphylxis, nd ngioedem hve een reported. Anemi In rndomized controlled clinicl trils, the overll incidence of nemi (30% vs. 21% [Study 5]), of selected NCI-CTC Grde 2 5 nemi (12.5% vs. 6.6% [Study 1]), nd of nemi requiring trnsfusions (0.1% vs. 0 ptients [Study 2]) were incresed in ptients receiving nd chemotherpy compred with those receiving chemotherpy lone. Following the dministrtion of s single gent (Study 6), the incidence of NCI-CTC Grde 3 nemi ws < 1%. Neutropeni In rndomized controlled clinicl trils in the djuvnt setting, the incidence of selected NCI-CTC Grde 4 5 neutropeni (2% vs. 0.7% [Study 2]) nd of selected Grde 2 5 neutropeni (7.1% vs. 4.5 % [Study 1]) were incresed in ptients receiving nd chemotherpy compred with those receiving chemotherpy lone. In rndomized, controlled tril in ptients with metsttic rest cncer, the incidences of NCI-CTC Grde 3/4 neutropeni (32% vs. 22%) nd of ferile neutropeni (23% vs. 17%) were lso incresed in ptients rndomized to in comintion with myelosuppressive chemotherpy s compred to chemotherpy lone. Infection The overll incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grde 2 5 infection/ferile neutropeni (22% vs. 14% [Study 1]) nd of selected Grde 3 5 infection/ferile neutropeni (3.3% vs. 1.4%) [Study 2]), were higher in ptients receiving nd chemotherpy compred with those receiving chemotherpy lone. The most common site of infections in the djuvnt setting involved the upper respirtory trct, skin, nd urinry trct. In study 4, the overll incidence of infection ws higher with the ddition of to AC-T ut not to TCH [44% (AC-TH), 37% (TCH), 38% (AC- T)]. The incidences of NCI-CTC grde 3-4 infection were similr [25% (AC- TH), 21% (TCH), 23% (AC-T)] cross the three rms. In rndomized, controlled tril in tretment of metsttic rest cncer, the reported incidence of ferile neutropeni ws higher (23% vs. 17%) in ptients receiving in comintion with myelosuppressive chemotherpy s compred to chemotherpy lone. Pulmonry Toxicity Adjuvnt Brest Cncer Among women receiving djuvnt therpy for rest cncer, the incidence of selected NCI-CTC Grde 2 5 pulmonry toxicity (14% vs. 5% [Study 1]) nd of selected NCI-CTC Grde 3 5 pulmonry toxicity nd spontneous reported Grde 2 dyspne (3.4 % vs. 1% [Study 2]) ws higher in ptients receiving nd chemotherpy compred with chemotherpy lone. The most common pulmonry toxicity ws dyspne (NCI-CTC Grde 2 5: 12% vs. 4% [Study 1]; NCI-CTC Grde 2 5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonry infiltrtes occurred in 0.7% of ptients receiving compred with 0.3% of those receiving chemotherpy lone. Ftl respirtory filure occurred in 3 ptients receiving, one s component of multi-orgn system filure, s compred to 1 ptient receiving chemotherpy lone. In Study 3, there were 4 cses of interstitil pneumonitis in -treted ptients compred to none in the control rm. Metsttic Brest Cncer Among women receiving for tretment of metsttic rest cncer, the incidence of pulmonry toxicity ws lso incresed. Pulmonry dverse events hve een reported in the post-mrketing experience s prt of the symptom complex of infusion rections. Pulmonry events include ronchospsm, hypoxi, dyspne, pulmonry infiltrtes, pleurl effusions, non-crdiogenic pulmonry edem, nd cute respirtory distress syndrome. For detiled description, see Wrnings nd Precutions (5.4).

8 Thromosis/Emolism In 4 rndomized, controlled clinicl trils, the incidence of thromotic dverse events ws higher in ptients receiving nd chemotherpy compred to chemotherpy lone in three studies (3.0% vs. 1.3% [Study 1], 2.5% nd 3.7% vs. 2.2% [Study 4] nd 2.1% vs. 0% [Study 5]). Dirrhe Among women receiving djuvnt therpy for rest cncer, the incidence of NCI-CTC Grde 2 5 dirrhe (6.2% vs. 4.8% [Study 1]) nd of NCI-CTC Grde 3 5 dirrhe (1.6% vs. 0% [Study 2]), nd of grde 1-4 dirrhe (7% vs. 1% [Study 3]) were higher in ptients receiving s compred to controls. In Study 4, the incidence of Grde 3 4 dirrhe ws higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] nd of Grde 1-4 ws higher [51% AC- TH, 63% TCH vs. 43% AC-T] mong women receiving. Of ptients receiving s single gent for the tretment of metsttic rest cncer, 25% experienced dirrhe. An incresed incidence of dirrhe ws oserved in ptients receiving in comintion with chemotherpy for tretment of metsttic rest cncer. Glomerulopthy In the postmrketing setting, rre cses of nephrotic syndrome with pthologic evidence of glomerulopthy hve een reported. The time to onset rnged from 4 months to pproximtely 18 months from initition of therpy. Pthologic findings included memrnous glomerulonephritis, focl glomerulosclerosis, nd firillry glomerulonephritis. Complictions included volume overlod nd congestive hert filure. 6.2 Immunogenicity As with ll therpeutic proteins, there is potentil for immunogenicity. Among 903 women with metsttic rest cncer, humn nti-humn ntiody (HAHA) to ws detected in one ptient using n enzyme-linked immunosorent ssy (ELISA). This ptient did not experience n llergic rection. Smples for ssessment of HAHA were not collected in studies of djuvnt rest cncer. The incidence of ntiody formtion is highly dependent on the sensitivity nd the specificity of the ssy. Additionlly, the oserved incidence of ntiody (including neutrlizing ntiody) positivity in n ssy my e influenced y severl fctors including ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, comprison of the incidence of ntiodies to with the incidence of ntiodies to other products my e misleding. 6.3 Post-Mrketing Experience The following dverse rections hve een identified during post pprovl use of. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Infusion rection [see Wrnings nd Precutions (5.2)] Oligohydrmnios [see Wrnings nd Precutions (5.6)] Glomerulopthy 7 DRUG INTERACTIONS In clinicl studies, dministrtion of pclitxel in comintion with resulted in 1.5-fold increse in trstuzum serum levels [see Clinicl Phrmcology (12)]. In drug interction studies, the phrmcokinetics of docetxel nd pclitxel were not ltered when ech ws dministered in comintion with. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Tertogenic Effects: Ctegory D [see Wrnings nd Precutions (5.6)] cn cuse fetl hrm when dministered to pregnnt womn. Post-mrketing cse reports suggest tht use during pregnncy increses the risk for oligohydrmnios during the second nd third trimester. If is used during pregnncy or if womn ecomes pregnnt while tking, she should e pprised of the potentil hzrd to fetus. In the postmrketing setting, oligohydrmnios ws reported in women who received during pregnncy, either lone or in comintion with chemotherpy. In hlf of these women, mniotic fluid index incresed fter ws stopped. In one cse, ws resumed fter the mniotic fluid index improved, nd oligohydrmnios recurred. Women using during pregnncy should e monitored for oligohydrmnios. If oligohydrmnios occurs, fetl testing should e done tht is pproprite for gesttionl ge nd consistent with community stndrds of cre. Additionl intrvenous (IV) hydrtion hs een helpful when oligohydrmnios hs occurred following dministrtion of other chemotherpy gents, however the effects of dditionl IV hydrtion with tretment re not known. Reproduction studies in cynomolgus monkeys t doses up to 25 times the recommended weekly humn dose of 2 mg/kg trstuzum hve reveled no evidence of hrm to the fetus. However, HER2 protein expression is high in mny emryonic tissues including crdic nd neurl tissues; in mutnt mice lcking HER2, emryos died in erly gesttion. Plcentl trnsfer of trstuzum during the erly (Dys of gesttion) nd lte (Dys of gesttion) fetl development period ws oserved in monkeys. [See Nonclinicl Toxicology (13.2)] Becuse niml reproduction studies re not lwys predictive of humn response, should e used during pregnncy only if the potentil enefit to the mother justifies the potentil risk to the fetus. Registry Pregnnt women with rest cncer who re using re encourged to enroll in MotHER- the Pregnncy Registry: phone Nursing Mothers It is not known whether is excreted in humn milk, ut humn IgG is excreted in humn milk. Pulished dt suggest tht rest milk ntiodies do not enter the neontl nd infnt circultion in sustntil mounts. Trstuzum ws present in the rest milk of lctting cynomolgus monkeys given 12.5 times the recommended weekly humn dose of 2 mg/kg of. Infnt monkeys with detectle serum levels of trstuzum did not hve ny dverse effects on growth or development from irth to 3 months of ge; however, trstuzum levels in niml rest milk my not ccurtely reflect humn rest milk levels. Becuse mny drugs re secreted in humn milk nd ecuse of the potentil for serious dverse rections in nursing infnts from, decision should e mde whether to discontinue nursing, or discontinue drug, tking into ccount the elimintion hlf-life of trstuzum nd the importnce of the drug to the mother. 8.4 Peditric Use The sfety nd effectiveness of in peditric ptients hs not een estlished. 8.5 Geritric Use hs een dministered to 386 ptients who were 65 yers of ge or over (253 in the djuvnt tretment nd 133 in metsttic rest cncer tretment settings). The risk of crdic dysfunction ws incresed in geritric ptients s compred to younger ptients in oth those receiving tretment for metsttic disese in Studies 5 nd 6, or djuvnt therpy in Studies 1 nd 2. Limittions in dt collection nd differences in study design of the 4 studies of in djuvnt tretment of rest cncer preclude determintion of whether the toxicity profile of in older ptients is different from younger ptients. The reported clinicl experience is not dequte to determine whether the efficcy improvements (ORR, TTP, OS, DFS) of tretment in older ptients is different from tht oserved in ptients <65 yers of ge for metsttic disese nd djuvnt tretment. 10 OVERDOSAGE There is no experience with overdosge in humn clinicl trils. Single doses higher thn 8 mg/kg hve not een tested. 11 DESCRIPTION (trstuzum) is humnized IgG1 kpp monoclonl ntiody tht selectively inds with high ffinity to the extrcellulr domin of the humn epiderml growth fctor receptor 2 protein, HER2. Trstuzum is produced y recominnt DNA technology in mmmlin cell (Chinese Hmster Ovry) culture contining the ntiiotic gentmicin. Gentmicin is not detectle in the finl product. is sterile, white to ple yellow, preservtive-free lyophilized powder for intrvenous dministrtion. Ech multi-use vil of contins 440 mg trstuzum, 400 mg α, α-trehlose dihydrte, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, nd 1.8 mg polysorte 20, USP. Reconstitution with 20 ml of the pproprite diluent (BWFI or SWFI) yields solution contining 21 mg/ml trstuzum, t ph of pproximtely CLINICAL PHARMACOLOGY 12.1 Mechnism of Action The HER2 (or c-erb2) proto-oncogene encodes trnsmemrne receptor protein of 185 kd, which is structurlly relted to the epiderml

9 growth fctor receptor. hs een shown, in oth in vitro ssys nd in nimls, to inhiit the prolifertion of humn tumor cells tht overexpress HER2. is meditor of ntiody-dependent cellulr cytotoxicity (ADCC). In vitro, -medited ADCC hs een shown to e preferentilly exerted on HER2 overexpressing cncer cells compred with cncer cells tht do not overexpress HER Phrmcokinetics The phrmcokinetics of trstuzum were studied in women with metsttic rest cncer. Short durtion intrvenous infusions of 10 to 500 mg once weekly demonstrted dose-dependent phrmcokinetics. Men hlf-life incresed nd clernce decresed with incresing dose level. The hlf-life verged 2 nd 12 dys t the 10 nd 500 mg dose levels, respectively. The volume of distriution of trstuzum ws pproximtely tht of serum volume (44 ml/kg). At the highest weekly dose studied (500 mg), men pek serum concentrtions were 377 mcg/ml. In studies using n initil dose of 4 mg/kg followed y weekly dose of 2 mg/kg, men hlf-life of 6 dys (rnge 1-32 dys) ws oserved. Between weeks 16 nd 32, trstuzum serum concentrtions reched stedy stte with men trough nd pek concentrtions of pproximtely 79 mcg/ml nd 123 mcg/ml, respectively. In study of women receiving djuvnt therpy for rest cncer, men hlf-life of trstuzum of 16 dys (rnge: dys) ws oserved fter n initil dose of 8 mg/kg followed y dose of 6 mg/kg every three weeks. Between weeks 6 nd 37, trstuzum serum concentrtions reched stedy-stte with men trough nd pek concentrtions of 63 mcg/ml nd 216 mcg/ml, respectively. Sixty-four percent (286/447) of women with metsttic rest cncer hd detectle circulting extrcellulr domin of the HER2 receptor (shed ntigen), which rnged s high s 1880 ng/ml (medin 11 ng/ml). Ptients with higher seline shed ntigen levels were more likely to hve lower serum trough concentrtions. Dt suggest tht the disposition of trstuzum is not ltered sed on ge or serum cretinine ( 2.0 mg cretinine/dl). Men serum trough concentrtions of trstuzum, when dministered in comintion with pclitxel, were consistently elevted pproximtely 1.5-fold s compred with serum concentrtions of trstuzum when used in comintion with nthrcycline plus cyclophosphmide. In clinicl studies in HER2+ metsttic rest cncer where ws dministered in comintion with pclitxel, in comintion with docetxel, or in comintion with pclitxel nd doxoruicin, did not pper to lter the plsm concentrtions of these chemotherpeutic gents, or the metolites tht were nlyzed. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility hs not een tested for crcinogenic potentil. No evidence of mutgenic ctivity ws oserved when trstuzum ws tested in the stndrd Ames cteril nd humn peripherl lood lymphocyte mutgenicity ssys, t concentrtions of up to 5000 mcg/ml. In n in vivo micronucleus ssy, no evidence of chromosoml dmge to mouse one mrrow cells ws oserved following olus intrvenous doses of up to 118 mg/kg. A fertility study conducted in femle cynomolgus monkeys t doses up to 25 times the weekly recommended humn dose of 2 mg/kg trstuzum nd hs reveled no evidence of impired fertility, s mesured y menstrul cycle durtion nd femle sex hormone levels. Studies to evlute the effects of trstuzum on mle fertility hve not een conducted Animl Toxicology nd/or Phrmcology Reproductive Toxicology Studies Reproductive toxicology studies hve een conducted in cynomolgus monkeys t doses up to 25 times the weekly recommended humn dose of 2 mg/kg nd hve reveled no evidence of impired fertility or hrm to the fetus. However, HER2 protein expression is high in mny emryonic tissues including crdic nd neurl tissues; in mutnt mice lcking HER2, emryos died in erly gesttion. Plcentl trnsfer of during the erly (Dys of gesttion) nd lte (Dys of gesttion) fetl development period ws oserved in monkeys. 14 CLINICAL STUDIES 14.1 Adjuvnt Brest Cncer The sfety nd efficcy of in women receiving djuvnt chemotherpy for HER2 overexpressing rest cncer, were evluted in n integrted nlysis of two rndomized, open-lel, clinicl trils (Studies 1 nd 2) with totl of 3752 women, third rndomized, open-lel, clinicl tril (Study 3) with totl of 3386 women, nd fourth rndomized, openlel clinicl tril with totl of 3222 ptients (Study 4). Studies 1 nd 2 In Studies 1 nd 2, rest tumor specimens were required to show HER2 overexpression (3+ y IHC) or gene mplifiction (y FISH). HER2 testing ws verified y centrl lortory prior to rndomiztion (Study 2) or ws required to e performed t reference lortory (Study 1). Ptients with history of ctive crdic disese sed on symptoms, norml electrocrdiogrphic, rdiologic, or left ventriculr ejection frction findings or uncontrolled hypertension (distolic > 100 mmhg or systolic > 200 mmhg) were not eligile. Ptients were rndomized (1:1) to receive doxoruicin nd cyclophosphmide followed y pclitxel (AC pclitxel) lone or pclitxel plus (AC pclitxel + ). In oth trils, ptients received four 21-dy cycles of doxoruicin 60 mg/m 2 nd cyclophosphmide 600 mg/m 2. Pclitxel ws dministered either weekly (80 mg/m 2 ) or every 3 weeks (175 mg/m 2 ) for totl of 12 weeks in Study 1; pclitxel ws dministered only y the weekly schedule in Study 2. ws dministered t 4 mg/kg on the dy of initition of pclitxel nd then t dose of 2 mg/kg weekly for totl of 52 weeks. tretment ws permnently discontinued in ptients who developed congestive hert filure, or persistent/recurrent LVEF decline [see Dosge nd Administrtion (2.2)]. Rdition therpy, if dministered, ws initited fter the completion of chemotherpy. Ptients with ER+ nd/or PR+ tumors received hormonl therpy. Disese-free survivl (DFS), defined s the time from rndomiztion to recurrence, occurrence of contrlterl rest cncer, other second primry cncer, or deth, ws the min outcome mesure of the comined efficcy nlysis. A totl of 3752 ptients were included in the efficcy nlyses. The dt from oth rms in Study 1 nd two of the three study rms in Study 2 were pooled for efficcy nlyses. Of these ptients, the medin ge ws 49 yers (rnge, yers; 6% > 65 yers), 84% were white, 7% lck, 4% Hispnic, nd 4% Asin/Pcific Islnder. Disese chrcteristics included 90% infiltrting ductl histology, 38% T1, 91% nodl involvement, 27% intermedite nd 66% high grde pthology, nd 53% ER+ nd/or PR+ tumors. At the time of rndomiztion 53% of the popultion were to receive pclitxel on weekly regimen, nd the reminder were to receive q3 week schedule of pclitxel. Study 3 In Study 3, rest tumor specimens were required to show HER2 overexpression (3+ y IHC) or gene mplifiction (y FISH) s determined t centrl lortory. Ptients with node-negtive disese were required to hve T1c primry tumor. Ptients with history of congestive hert filure or LVEF <55%, uncontrolled rrhythmis, ngin requiring mediction, cliniclly significnt vlvulr hert disese, evidence of trnsmurl infrction on ECG, poorly controlled hypertension (systolic > 180 mm Hg or distolic > 100 mm Hg) were not eligile. Ptients were rndomized (1:1) upon completion of definitive surgery, nd t lest four cycles of chemotherpy to receive no dditionl tretment (n = 1693) or 1 yer of tretment (n = 1693). Ptients undergoing lumpectomy hd lso completed stndrd rdiotherpy. Ptients with ER+ nd/or PgR+ disese received systemic djuvnt hormonl therpy t investigtor discretion. ws dministered with n initil dose of 8 mg/kg followed y susequent doses of 6 mg/kg once every three weeks for totl of 52 weeks. The min outcome mesure ws disese-free survivl (DFS), defined s in Studies 1 nd 2. Among the 3386 ptients rndomized to the two tretment rms, the medin ge ws 49 yers (rnge 21 80), 83% were Cucsin, nd 13% were Asin. Disese chrcteristics: 94% infiltrting ductl crcinom, 50% ER+ nd/or PgR+, 57% node positive, 32% node negtive, nd in 11% of ptients, nodl sttus ws not ssessle due to prior neo-djuvnt chemotherpy. Ninety-six percent (1055/1098) of ptients with node-negtive disese hd high-risk fetures: mong the 1098 ptients with node-negtive disese, 49% (543) were ER nd PgR, nd 47% (512) were ER nd/or PgR + nd hd t lest one of the following high-risk fetures: pthologicl tumor size greter thn 2 cm, Grde 2 3, or ge < 35 yers. Prior to rndomiztion, 94% of ptients hd received nthrcycline-sed chemotherpy regimens. Study 4 In Study 4, rest tumor specimens were required to show HER2 gene mplifiction (FISH+ only) s determined t centrl lortory. Ptients