FULL PRESCRIBING INFORMATION

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use Herceptin sfely nd effectively. See full prescriing informtion for Herceptin. HERCEPTIN (trstuzum) Intrvenous Infusion Initil U.S. Approvl: 1998 WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, nd PULMONARY TOXICITY See full prescriing informtion for complete oxed wrning Crdiomyopthy: Herceptin 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 Herceptin for crdiomyopthy. (5.1, 2.2) Infusion rections, Pulmonry toxicity: Discontinue Herceptin for nphylxis, ngioedem, interstitil pneumonitis, or cute respirtory distress syndrome. (5.2, 5.4) Emryo-Fetl Toxicity: Exposure to Herceptin during pregnncy cn result in oligohydrmnios, in some cses complicted y pulmonry hypoplsi nd neontl deth RECENT MAJOR CHANGES Indictions nd Usge, Metsttic Gstric Cncer (1.3) 10/2010 Dosge nd Administrtion (2.1) 10/2010 Wrnings nd Precutions, Emryo-Fetl Toxicity (5.3) 10/2010 Wrnings nd Precutions, HER2 Testing (5.6) 10/ INDICATIONS AND USAGE Herceptin is HER2/neu receptor ntgonist indicted for: the tretment of HER2 overexpressing rest cncer (1.1, 1.2). the tretment of HER2-overexpressing metsttic gstric or gstroesophgel junction denocrcinom (1.3) 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. Metsttic HER2-overexpressing Gstric Cncer (2.1) Initil dose of 8 mg/kg over 90 minutes IV infusion, followed y 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks DOSAGE FORMS AND STRENGTHS Multidose vil nominlly contining 440 mg Herceptin s lyophilized, sterile powder. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Crdiomyopthy (5.1, 6.1) Infusion Rections (5.2, 6.1) Emryo-fetl Toxicity. Pregnncy registry ville ( ) (5.3, 8.1) Pulmonry Toxicity (5.4, 6.1) Excertion of Chemotherpy-Induced Neutropeni (5.5, 6.1) HER2 testing should e performed using FDA-pproved tests y lortories with demonstrted proficiency. (5.6) ADVERSE REACTIONS Adjuvnt Brest Cncer Most common dverse rections ( 5%) re hedche, dirrhe, nuse, nd chills. (6.1) Metsttic Brest Cncer Most common dverse rections ( 10%) re fever, chills, hedche, infection, congestive hert filure, insomni, cough, nd rsh. (6.1) Metsttic Gstric Cncer Most common dverse rections ( 10%) re neutropeni, dirrhe, ftigue, nemi, stomtitis, weight loss, upper respirtory trct infections, fever, thromocytopeni, mucosl inflmmtion, nsophryngitis, nd dysgeusi. (6.1) USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue nursing or discontinue Herceptin. (8.3) To report SUSPECTED ADVERSE REACTIONS, contct Genentech t or FDA t FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION. Revised: 10/2010 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, PULMONARY TOXICITY 1 INDICATIONS AND USAGE 1.1 Adjuvnt Brest Cncer 1.2 Metsttic Brest Cncer 1.3 Metsttic Gstric 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 Emryo-Fetl Toxicity 5.4 Pulmonry Toxicity 5.5 Excertion of Chemotherpy-Induced Neutropeni 5.6 HER2 Testing 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 6.3 Post-Mrketing Experience 7 DRUG INTERACTIONS 8 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 14.3 Metsttic Gstric 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. FULL PRESCRIBING INFORMATION WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, nd PULMONARY TOXICITY Crdiomyopthy Herceptin dministrtion cn result in su clinicl nd clinicl crdic filure. The incidence nd severity ws highest in ptients receiving Herceptin with nthrcycline contining chemotherpy regimens. Evlute left ventriculr function in ll ptients prior to nd during tretment with Herceptin. Discontinue Herceptin tretment in ptients receiving djuvnt therpy nd withhold Herceptin in ptients with metsttic disese for cliniclly significnt decrese in left ventriculr function. [see Wrnings nd Precutions (5.1) nd Dosge nd Administrtion (2.2)] Infusion Rections; Pulmonry Toxicity Herceptin dministrtion cn result in serious nd ftl infusion rections nd pulmonry toxicity. Symptoms usully occur during or within 24 hours of Herceptin dministrtion. Interrupt Herceptin infusion for dyspne or cliniclly significnt hypotension. Monitor ptients until symptoms completely resolve. Discontinue Herceptin for nphylxis, ngioedem, interstitil pneumonitis, or cute respirtory distress syndrome. [see Wrnings nd Precutions (5.2, 5.4)] Emryo-Fetl Toxicity Exposure to Herceptin during pregnncy cn result in oligohydrmnios nd oligohydrmnios sequence mnifesting s pulmonry hypoplsi, skeletl normlities, nd neontl deth. [see Wrnings nd Precutions (5.3), Use in Specific Popultions (8.1)] 1 INDICATIONS AND USAGE 1.1 Adjuvnt Brest Cncer Herceptin 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 Herceptin 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. 1.3 Metsttic Gstric Cncer Herceptin is indicted, in comintion with cispltin nd cpecitine or 5-fluorourcil, for the tretment of ptients with HER2 overexpressing metsttic gstric or gstroesophgel junction denocrcinom, who hve not received prior tretment 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 Herceptin with other drugs. Adjuvnt Tretment, Brest Cncer: Administer ccording to one of the following doses nd schedules for totl of 52 weeks of Herceptin therpy: During nd following pclitxel, docetxel, or docetxel/cropltin: Initil dose of 4 mg/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 Herceptin, dminister Herceptin t 6 mg/kg s n intrvenous infusion over minutes every three weeks. As single gent within three weeks following completion of multi-modlity, 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 Modifictions (2.2)] Metsttic Tretment, Brest Cncer: Administer Herceptin, 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. Metsttic Gstric Cncer Administer Herceptin t n initil dose of 8 mg/kg s 90 minute intrvenous infusion followed y susequent doses of 6 mg/kg s n intrvenous infusion over minutes every three weeks until disese progression [see Dose Modifictions (2.2)]. 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 Herceptin 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 Herceptin nd t regulr intervls during tretment. Withhold Herceptin 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. Herceptin my e resumed if, within 4 8 weeks, the LVEF returns to norml limits nd the solute decrese from seline is 15%. Permnently discontinue Herceptin for persistent ( > 8 weeks) LVEF decline or for suspension of Herceptin dosing on more thn 3 occsions for crdiomyopthy. 2.3 Preprtion for Administrtion Reconstitution Reconstitute ech 440 mg vil of Herceptin 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.

2 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 Herceptin. 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 Herceptin t 2 8ºC; discrd unused Herceptin fter 28 dys. If Herceptin is reconstituted with SWFI without preservtive, use immeditely nd discrd ny unused portion. Dilution Determine the dose (mg) of Herceptin [see Dosge nd Administrtion (2.1)]. Clculte the volume of the 21 mg/ml reconstituted Herceptin 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 Herceptin cn cuse left ventriculr crdic dysfunction, rrhythmis, hypertension, disling crdic filure, crdiomyopthy, nd crdic deth [see Boxed Wrning: Crdiomyopthy]. Herceptin 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 Herceptin s single gent or in comintion therpy compred with those not receiving Herceptin. The highest solute incidence occurs when Herceptin is dministered with n nthrcycline. Withhold Herceptin 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 Herceptin in ptients with Herceptininduced 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 Herceptin LVEF mesurements every 3 months during nd upon completion of Herceptin Repet LVEF mesurement t 4 week intervls if Herceptin 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 Herceptin s component of djuvnt therpy. In Study 1, 16% (136/844) of ptients discontinued Herceptin due to clinicl evidence of myocrdil dysfunction or significnt decline in LVEF. In Study 3, the numer of ptients who discontinued Herceptin 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 Herceptin 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 Herceptin in ptients with Herceptin-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 Herceptin Control 1 & 2 AC Pclitxel+Herceptin 2% (32/1677) 0.4% (7/1600) 3 Chemo Herceptin 2% (30/1678) 0.3% (5/1708) 4 AC Docetxel+Herceptin 2% (20/1068) 0.3% (3/1050) 4 Docetxel+Cro+Herceptin 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 Incidence NYHA I IV NYHA III IV Study Event Herceptin Control Herceptin Control 5 Crdic (AC) Dysfunction 28% 7% 19% 3% 5 Crdic (pclitxel) Dysfunction 11% 1% 4% 1% 6 Crdic Dysfunction c 7% N/A 5% N/A 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 Herceptin 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 Herceptin 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 Herceptin fter experiencing severe infusion rection. Prior to resumption of Herceptin infusion, the mjority of ptients who experienced severe infusion rection were pre-medicted with ntihistmines nd/or corticosteroids. While some ptients tolerted Herceptin infusions, others hd recurrent severe infusion rections despite pre-medictions. 5.3 Emryo-Fetl Toxicity Herceptin cn cuse fetl hrm when dministered to pregnnt womn. In post-mrketing reports, use of Herceptin during pregnncy resulted in cses of oligohydrmnios nd oligohydrmnios sequence mnifesting s pulmonry hypoplsi, skeletl normlities, nd neontl deth. Advise women of the potentil hzrd to the fetus resulting from Herceptin exposure during pregnncy nd provide contrceptive counseling to women of childering potentil. [see Use in Specific Popultions (8.1), Ptient Counseling Informtion (17)]. 5.4 Pulmonry Toxicity Herceptin 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 Excertion of Chemotherpy-Induced Neutropeni In rndomized, controlled clinicl trils the per-ptient incidences of NCI CTC Grde 3 4 neutropeni nd of ferile neutropeni were higher in ptients receiving Herceptin in comintion with myelosuppressive chemotherpy s compred to those who received chemotherpy lone. The incidence of septic deth ws similr mong ptients who received Herceptin nd those who did not. [see Adverse Rections (6.1)] 5.6 HER2 Testing Detection of HER2 protein overexpression is necessry for selection of ptients pproprite for Herceptin therpy ecuse these re the only ptients studied nd for whom enefit hs een shown. Due to differences in tumor histopthology, use FDA-pproved tests for the specific tumor type (rest or gstric/gstroesophgel denocrcinom) to ssess HER2 protein overexpression nd HER2 gene mplifiction. Tests should e performed y 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 rest cncer nd metsttic gstric cncer ptients for Herceptin therpy. Users should refer to the pckge inserts of specific ssy kits for informtion on the Intended Use, nd the vlidtion nd performnce of ech ssy. Limittions in ssy precision mke it indvisle to rely on single method to rule out potentil Herceptin enefit. Tretment outcomes for djuvnt rest cncer (Studies 2 nd 3) nd for metsttic rest cncer (Study 5) s function of IHC nd FISH testing re provided in Tles 8 nd 10. Assessment of HER2 protein overexpression nd HER2 gene mplifiction in metsttic gstric cncer should e performed using FDA-pproved tests specificlly for gstric cncers due to differences in gstric vs. rest histopthology, including incomplete memrne stining nd more frequent heterogeneous expression of HER2 seen in gstric cncers. Study 7 demonstrted tht gene mplifiction nd protein overexpression were not s well correlted s with rest cncer. Tretment outcomes for metsttic gstric cncer (Study 7), sed on HER2 gene mplifiction (FISH) nd HER2 protein overexpression (IHC) test results re provided in Tle 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)] Emryo-fetl Toxicity [see Wrnings nd Precutions (5.3)] Pulmonry toxicity [see Wrnings nd Precutions (5.4)] Excertion of chemotherpy-induced neutropeni [see Wrnings nd Precutions (5.5)] The most common dverse rections in ptients receiving Herceptin in the djuvnt nd metsttic rest cncer setting 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 Herceptin tretment include CHF, significnt decline in left ventriculr crdic function, severe infusion rections, nd pulmonry toxicity [see Dosge nd Administrtion (2.2)]. In the metsttic gstric cncer setting, the most common dverse rections ( 10%) tht were incresed ( 5% difference) in the Herceptin rm s compred to the chemotherpy lone rm were neutropeni, dirrhe, ftigue, nemi, stomtitis, weight loss, upper respirtory trct infections, fever, thromocytopeni, mucosl inflmmtion, nsophryngitis, nd dysgeusi. The most common dverse rections which resulted in discontinution of tretment on the Herceptin-contining rm in the sence of disese progression were infection, dirrhe, nd ferile neutropeni. 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 Herceptin cross three rndomized, openlel 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 Herceptin 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 : 1 Yer Herceptin Oservtion Adverse Rection (n= 1678) (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 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%)

3 Tle 3 (cont d) Adverse Rections for Study 3, All Grdes : 1 Yer Herceptin Oservtion Adverse Rection (n= 1678) (n=1708) 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 (0.6%) Nil Disorders 43 (2%) 0 (0%) Pruritis 40 (2%) 10 (0.6%) Generl Disorders Pyrexi 100 (6%) 6 (0.4%) 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 (0.06%) 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, of whom 1635 received Herceptin; the medin tretment durtion ws 50 weeks. The medin ge ws 49 yers (rnge: 24 80); 84% of ptients were White, 7% Blck, 4% Hispnic, nd 4% 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 Herceptin 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 Herceptin tretment. The following non-crdic dverse rections of Grde 2 5 occurred t n incidence of t lest 2% greter mong ptients rndomized to Herceptin 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 Herceptin 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 Herceptin in one rndomized, open-lel 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 4 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 Herceptin followed y 2 mg/kg weekly. The percentges of ptients who received Herceptin 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), 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 Herceptin followed y 2 mg/kg weekly. The percentges of ptients who received Herceptin 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 Herceptin Arm (Studies 5 nd 6) Single Herceptin + Pclitxel Herceptin + AC Agent Pclitxel Alone AC Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body s Whole Pin 47% 61% 62% 57% 42% Astheni 42% 62% 57% 54% 55% Fever 36% 49% 23% 56% 34% Chills 32% 41% 4% 35% 11% Hedche 26% 36% 28% 44% 31% Adominl pin 22% 34% 22% 23% 18% Bck pin 22% 34% 30% 27% 15% Infection 20% 47% 27% 47% 31% Flu syndrome 10% 12% 5% 12% 6% Accidentl injury 6% 13% 3% 9% 4% Allergic rection 3% 8% 2% 4% 2% Tle 4 (cont d) Per-Ptient Incidence of Adverse Rections Occurring in 5% of Ptients in Uncontrolled Studies or t Incresed Incidence in the Herceptin Arm (Studies 5 nd 6) Single Herceptin + Pclitxel Herceptin + AC Agent Pclitxel Alone AC Alone n = 352 n = 91 n = 95 n = 143 n = 135 Crdiovsculr Tchycrdi 5% 12% 4% 10% 5% Congestive hert 7% 11% 1% 28% 7% filure Digestive Nuse 33% 51% 9% 76% 77% Dirrhe 25% 45% 29% 45% 26% Vomiting 23% 37% 28% 53% 49% Nuse nd vomiting 8% 14% 11% 18% 9% Anorexi 14% 24% 16% 31% 26% Heme & Lymphtic Anemi 4% 14% 9% 36% 26% Leukopeni 3% 24% 17% 52% 34% Metolic Peripherl edem 10% 22% 20% 20% 17% Edem 8% 10% 8% 11% 5% Musculoskeletl Bone pin 7% 24% 18% 7% 7% Arthrlgi 6% 37% 21% 8% 9% Nervous Insomni 14% 25% 13% 29% 15% Dizziness 13% 22% 24% 24% 18% Presthesi 9% 48% 39% 17% 11% Depression 6% 12% 13% 20% 12% Peripherl neuritis 2% 23% 16% 2% 2% Neuropthy 1% 13% 5% 4% 4% Respirtory Cough incresed 26% 41% 22% 43% 29% Dyspne 22% 27% 26% 42% 25% Rhinitis 14% 22% 5% 22% 16% Phryngitis 12% 22% 14% 30% 18% Sinusitis 9% 21% 7% 13% 6% Skin Rsh 18% 38% 18% 27% 17% Herpes simplex 2% 12% 3% 7% 9% Acne 2% 11% 3% 3% < 1% Urogenitl Urinry trct infection 5% 18% 14% 13% 7% Dt for Herceptin single gent were from 4 studies, including 213 ptients from Study 6. Anthrcycline (doxoruicin or epiruicin) nd cyclophosphmide. Metsttic Gstric Cncer The dt elow re sed on the exposure of 294 ptients to Herceptin in comintion with fluoropyrimidine (cpecitine or 5-FU) nd cispltin (Study 7). In the Herceptin plus chemotherpy rm, the initil dose of Herceptin 8 mg/kg ws dministered on Dy 1 (prior to chemotherpy) followed y 6 mg/kg every 21 dys until disese progression. Cispltin ws dministered t 80 mg/m 2 on Dy 1 nd the fluoropyrimidine ws dministered s either cpecitine 1000 mg/m 2 orlly twice dy on Dys 1-14 or 5-fluorourcil 800 mg/m 2 /dy s continuous intrvenous infusion Dys 1 through 5. Chemotherpy ws dministered for six 21-dy cycles. Medin durtion of Herceptin tretment ws 21 weeks; medin numer of Herceptin infusions dministered ws eight. Tle 5 Study 7: Per Ptient Incidence of Adverse Rections of All Grdes (Incidence 5% etween Arms) or Grde 3 /4 (Incidence >1% etween Arms) nd Higher Incidence in Herceptin Arm Herceptin +FC FC (N = 294) (N = 290) N (%) N (%) Body System/Adverse Event All Grdes Grdes 3 / 4 All Grdes Grdes 3/ 4 Investigtions Neutropeni 230 (78) 101 (34) 212 (73) 83 (29) Hypoklemi 83 (28) 28 (10) 69 (24) 16 (6) Anemi 81 (28) 36 (12) 61 (21) 30 (10) Thromocytopeni 47 (16) 14 (5) 33 (11) 8 (3) Blood And Lymphtic System Disorders Ferile Neutropeni _ 15 (5) _ 8 (3) Gstrointestinl Disorders Dirrhe 109 (37) 27 (9) 80 (28) 11 (4) Stomtitis 72 (24) 2 (1) 43 (15) 6 (2) Dysphgi 19 (6) 7 (2) 10 ( 3) 1 ( 1) Body s Whole Ftigue 102 (35) 12 (4) 82 (28) 7 (2) Fever 54 (18) 3 (1) 36 (12) 0 (0) Mucosl Inflmmtion 37 (13) 6 (2) 18 (6) 2 (1) Chills 23 (8) 1 ( 1) 0 (0) 0 (0) Metolism And Nutrition Disorders Weight Decrese 69 (23) 6 (2) 40 (14) 7 (2) Infections And Infesttions Upper Respirtory 56 (19) 0 (0) 29 (10) 0 (0) Trct Infections Nsophryngitis 37 (13) 0 (0) 17 (6) 0 (0) Renl And Urinry Disorders Renl Filure nd Impirment 53 (18) 8 (3) 42 (15) 5 (2) Nervous System Disorders Dysgeusi 28 (10) 0 (0) 14 (5) 0 (0) The following susections provide dditionl detil regrding dverse rections oserved in clinicl trils of djuvnt rest, metsttic rest cncer, metsttic gstric 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 followup ws 12.6 months (12.4 months in the oservtion rm; 12.6 months in the 1-yer Herceptin rm); nd in Studies 1 nd 2, 23 months in the AC-T rm, 24 months in the

4 AC-TH rm. In Studies 1 nd 2, 6% of ptients were not permitted to initite Herceptin 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 Herceptin therpy, the incidence of new-onset dose-limiting myocrdil dysfunction ws higher mong ptients receiving Herceptin nd pclitxel s compred to those receiving pclitxel lone in Studies 1 nd 2, nd in ptients receiving Herceptin monotherpy compred to oservtion in Study 3 (see Tle 6, Figures 1 nd 2). Tle 6 Per-ptient Incidence of New Onset Myocrdil Dysfunction (y LVEF) Studies 1, 2, 3 nd 4 LVEF <50% nd Asolute Decrese from Bseline Asolute LVEF Decrese LVEF 10% 16% <20% nd <50% decrese decrese 10% 20% Studies 1 & 2 AC TH 22.8% 18.3% 11.7% 33.4% 9.2% (n=1606) (366) (294) (188) (536) (148) AC T 9.1% 5.4% 2.2% 18.3% 2.4% (n=1488) (136) (81) (33) (272) (36) Study 3 Herceptin 8.6% 7.0% 3.8% 22.4% 3.5% (n=1678) (144) (118) (64) (376) (59) Oservtion 2.7% 2.0% 1.2% 11.9% 1.2% (n=1708) (46) (35) (20) (204) (21) Study 4 c TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n=1056) (90) (62) (35) (364) (67) AC TH 17% 13.3% 9.8% 44.3% 13.2% (n=1068) (182) (142) (105) (473) (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 Herceptin 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 Herceptin (AC TH). c Study 4 regimens: doxoruicin nd cyclophosphmide followed y docetxel (AC T) or docetxel plus Herceptin (AC TH); docetxel nd cropltin plus Herceptin (TCH). 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 Herceptin + 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 Herceptin concurrently with nthrcyclines. In Study 7, 5.0% of ptients in the Herceptin plus chemotherpy rm compred to 1.1% of ptients in the chemotherpy lone rm hd LVEF vlue elow 50% with 10% solute decrese in LVEF from pretretment vlues. Infusion Rections During the first infusion with Herceptin, 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 Herceptin infusion); permnent discontinution of Herceptin 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 Herceptin infusions dministered s monotherpy or in comintion with chemotherpy, respectively. In the postmrketing 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 Herceptin nd chemotherpy compred with those receiving chemotherpy lone. Following the dministrtion of Herceptin s single gent (Study 6), the incidence of NCI-CTC Grde 3 nemi ws < 1%. In Study 7 (metsttic gstric cncer) on the Herceptin contining rm s compred to the chemotherpy lone rm the overll incidence of nemi ws 28% compred 21% nd of NCI CTC Grde 3/4 nemi ws 12.2% compred to 10.3%. 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 Herceptin 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 Herceptin in comintion with myelosuppressive chemotherpy s compred to chemotherpy lone. In Study 7 (metsttic gstric cncer) on the Herceptin contining rm s compred to the chemotherpy lone rm, the incidence of NCI CTC Grde 3/4 neutropeni ws 36.8% compred to 28.9%; ferile neutropeni 5.1% compred to 2.8%. 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 Herceptin 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 Herceptin 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 Herceptin 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 Herceptin 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 Herceptin compred with 0.3% of those receiving chemotherpy lone. Ftl respirtory filure occurred in 3 ptients receiving Herceptin, 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 Herceptin-treted ptients compred to none in the control rm. Metsttic Brest Cncer Among women receiving Herceptin 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). Thromosis/Emolism In 4 rndomized, controlled clinicl trils, the incidence of thromotic dverse events ws higher in ptients receiving Herceptin 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 Herceptin 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 Herceptin. Of ptients receiving Herceptin s single gent for the tretment of metsttic rest cncer, 25% experienced dirrhe. An incresed incidence of dirrhe ws oserved in ptients receiving Herceptin in comintion with chemotherpy for tretment of metsttic rest cncer. Renl Toxicity In Study 7 (metsttic gstric cncer) on the Herceptin-contining rm s compred to the chemotherpy lone rm the incidence of renl impirment ws 18% compred to 14.5%. Severe (Grde 3/4) renl filure ws 2.7% on the Herceptincontining rm compred to 1.7% on the chemotherpy only rm. Tretment discontinution for renl insufficiency/filure ws 2% on the Herceptin-contining rm nd 0.3% on the chemotherpy only rm. 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 Herceptin 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 Herceptin 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 Herceptin 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 Herceptin. 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 or oligohydrmnios sequence, including pulmonry hypoplsi, skeletl normlities, nd neontl deth [see Wrnings nd Precutions (5.3)] Glomerulopthy [see Adverse Rections (6.1)]

5 7 DRUG INTERACTIONS In Study 5, the men serum trough concentrtion of trstuzum ws consistently elevted pproximtely 1.5-fold, when dministered in comintion with pclitxel s compred to trough concentrtions of trstuzum when dministered in comintion with n nthrcycline nd cyclophosphmide. In other phrmcokinetic studies, where Herceptin ws dministered in comintion with pclitxel, docetxel or doxoruicin, Herceptin did not lter the plsm concentrtions of these chemotherpeutic gents, or the metolites tht were nlyzed. In drug interction sustudy conducted in ptients in Study 7, the phrmcokinetics of cispltin, cpecitine nd their metolites were not ltered when dministered in comintion with Herceptin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy: Ctegory D [see Wrnings nd Precutions (5.3), Nonclinicl Toxicology (13.2)] Herceptin cn cuse fetl hrm when dministered to pregnnt womn. In post-mrketing reports use of Herceptin during pregnncy resulted in cses of oligohydrmnios nd of oligohydrmnios sequence, mnifesting s pulmonry hypoplsi, skeletl normlities, nd neontl deth. These cse reports descried oligohydrmnios in pregnnt women who received Herceptin either lone or in comintion with chemotherpy. In some cse reports, mniotic fluid index incresed fter Herceptin ws stopped. In one cse, Herceptin therpy resumed fter the mniotic fluid index improved, nd oligohydrmnios recurred. Monitor women exposed to Herceptin during pregnncy for oligohydrmnios. If oligohydrmnios occurs, perform fetl testing tht is pproprite for gesttionl ge nd consistent with community stndrds of cre. The efficcy of IV hydrtion in mngement of oligohydrmnios due to Herceptin exposure is not known. Advise women of the potentil hzrd to the fetus resulting from Herceptin exposure during pregnncy. Encourge pregnnt women with rest cncer who re using Herceptin to enroll in MotHER-the Herceptin Pregnncy Registry: phone [see Ptient Counseling Informtion (17)]. No tertogenic effects were oserved in offspring from reproduction studies in cynomolgus monkeys t doses up to 25 times the recommended weekly humn dose of 2 mg/kg trstuzum. In mutnt mice lcking HER2, emryos died in erly gesttion. Trstuzum exposure ws reported t delivery in offspring of cynomolgus monkeys treted during the erly (Dys of gesttion) or lte (Dys of gesttion) fetl development periods, t levels of 15 to 28% of the mternl lood levels. 8.3 Nursing Mothers It is not known whether Herceptin 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 Herceptin. 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 Herceptin, 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 Herceptin in peditric ptients hs not een estlished. 8.5 Geritric Use Herceptin 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 Herceptin in djuvnt tretment of rest cncer preclude determintion of whether the toxicity profile of Herceptin 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 Herceptin tretment in older ptients is different from tht oserved in ptients <65 yers of ge for metsttic disese nd djuvnt tretment. In Study 7 (metsttic gstric cncer), of the 294 ptients treted with Herceptin 108 (37%) were 65 yers of ge or older, while 13 (4.4%) were 75 nd over. No overll differences in sfety or effectiveness were oserved. 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 Herceptin (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. Herceptin is sterile, white to ple yellow, preservtive-free lyophilized powder for intrvenous dministrtion. Ech multi-use vil of Herceptin 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 growth fctor receptor. Herceptin hs een shown, in oth in vitro ssys nd in nimls, to inhiit the prolifertion of humn tumor cells tht overexpress HER2. Herceptin is meditor of ntiody-dependent cellulr cytotoxicity (ADCC). In vitro, Herceptin-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 Herceptin 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 hlflife 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. In ptients with metsttic gstric cncer (Study 7), men serum trstuzum trough concentrtions t stedy stte were 24 to 63% lower s compred to the concentrtions oserved in ptients with rest cncer receiving tretment for metsttic disese in comintion with pclitxel, s monotherpy for metsttic disese, or s djuvnt monotherpy. 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). 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Herceptin 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 Herceptin. 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 Herceptin 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 trstuzum ws detected t Cesren section in offspring from pregnnt cynomolgus monkeys dosed during the erly (Dys of gesttion) or lte (Dys of gesttion) fetl development periods. 14 CLINICAL STUDIES 14.1 Adjuvnt Brest Cncer The sfety nd efficcy of Herceptin 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, open-lel 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 Herceptin (AC pclitxel + Herceptin). 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. Herceptin 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. Herceptin 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 Herceptin 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. Herceptin 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 were required to hve either node-positive disese, or node-negtive disese with t lest one of the following high-risk fetures: ER/PR-negtive, tumor size > 2 cm, ge < 35 yers, or histologic nd/or nucler Grde 2 or 3. Ptients with history of CHF, myocrdil infrction, Grde 3 or 4 crdic rrhythmi, ngin requiring mediction, cliniclly significnt vlvulr hert disese, poorly controlled hypertension (distolic > 100 mmhg), ny T4 or N2 or known N3 or M1 rest cncer were not eligile. Ptients were rndomized (1:1:1) to receive doxoruicin nd cyclophosphmide followed y docetxel (AC-T), doxoruicin nd cyclophosphmide followed y docetxel plus Herceptin (AC-TH), or docetxel nd cropltin plus Herceptin (TCH). In oth the AC-T nd AC-TH rms, doxoruicin 60 mg/m 2 nd cyclophosphmide 600 mg/m 2 were dministered every 3 weeks for four cycles; docetxel 100 mg/m 2 ws dministered every 3 weeks for four cycles. In the TCH rm, docetxel 75 mg/m 2 nd cropltin (t trget AUC of 6 mg/ml/min s 30- to 60-minute infusion) were dministered every 3 weeks for six cycles. Herceptin ws dministered weekly (initil dose of 4 mg/kg followed y weekly dose of 2 mg/kg) concurrently with either T or TC, nd then every 3 weeks (6 mg/kg) s monotherpy for totl of 52 weeks. Rdition therpy, if dministered, ws initited fter completion of chemotherpy. Ptients with ER+ nd/or PR+ tumors received hormonl therpy. Disese-free survivl (DFS) ws the min outcome mesure. Among the 3222 ptients rndomized, the medin ge ws 49 (rnge 22 to 74 yers; 6% 65 yers). Disese chrcteristics included 54% ER+ nd/or PR+ nd 71% node positive. Prior to rndomiztion, ll ptients underwent primry surgery for rest cncer.

6 Tle 7 Efficcy Results from Adjuvnt Tretment of Brest Cncer (Studies 1 + 2, Study 3, nd Study 4) Hzrd rtio DFS (95% CI) Hzrd rtio events p vlue Deths p vlue Studies e AC TH (n =1872) (0.39, 0.59) p=ns d p=< AC T (n = 1880) Study 3 Chemo Herceptin (0.44, 0.67) p=ns d (n =1693 ) p=< c Chemo Oservtion (n = 1693) Study 4 f TCH (n=1075) ( ) p=0.0006,g AC TH (n=1074) ( ) p=< ,g AC T (n=1073) CI = confidence intervl. Hzrd rtio estimted y Cox regression strtified y clinicl tril, intended pclitxel schedule, numer of positive nodes, nd hormone receptor sttus. strtified log-rnk test. c log-rnk test. d NS= non-significnt. e Studies 1 nd 2 regimens: doxoruicin nd cyclophosphmide followed y pclitxel (AC T) or pclitxel plus Herceptin (AC TH). f Study 4 regimens: doxoruicin nd cyclophosphmide followed y docetxel (AC T) or docetxel plus Herceptin (AC TH); docetxel nd cropltin plus Herceptin (TCH). g A two-sided lph level of for ech comprison. The results for DFS for the integrted nlysis of Studies 1 nd 2, Study 3, nd Study 4 re presented in Tle 7. The durtion of DFS for Studies 1 nd 2 is presented in Figure 4, nd the durtion of DFS for Study 4 is presented in Figure 5. Across ll four studies, there were insufficient numers of ptients within ech of the following sugroups to determine if the tretment effect ws different from tht of the overll ptient popultion: ptients with low tumor grde, ptients within specific ethnic/ rcil sugroups (Blck, Hispnic, Asin/Pcific Islnder ptients), nd ptients > 65 yers of ge. Figure 4 Durtion of Disese-Free Survivl in Ptients with Adjuvnt Tretment of Brest Cncer (Studies 1 nd 2) Figure 5 Durtion of Disese-Free Survivl in Ptients with Adjuvnt Tretment of Brest Cncer (Study 4) Tle 8 Tretment Outcomes in Studies 2 nd 3 s Function of HER2 Overexpression or Amplifiction Study 2 Study 3 Numer Hzrd Rtio Numer Hzrd Rtio HER2 Assy of DFS of DFS Result Ptients (95% CI) Ptients (95% CI) IHC 3+ FISH (+) (0.27, 0.64) (0.13, 2.50) FISH ( ) (0.04, 11.79) FISH Unknown (0.09, 5.14) (0.41, 0.69) IHC < 3+ / FISH (+) (0.18, 5.65) (0.20, 1.42) IHC unknown / FISH (+) (0.38, 0.93) IHC y HercepTest, FISH y PthVysion (HER2/CEP17 rtio 2.0) s performed t centrl lortory. All cses in this ctegory in Study 3 were IHC Metsttic Brest Cncer The sfety nd efficcy of Herceptin in tretment of women with metsttic rest cncer were studied in rndomized, controlled clinicl tril in comintion with chemotherpy (Study 5, n=469 ptients) nd n open-lel single gent clinicl tril (Study 6, n=222 ptients). Both trils studied ptients with metsttic rest cncer whose tumors overexpress the HER2 protein. Ptients were eligile if they hd 2 or 3 levels of overexpression (sed on 0 to 3 scle) y immunohistochemicl ssessment of tumor tissue performed y centrl testing l. Previously Untreted Metsttic Brest Cncer (Study 5) Study 5 ws multicenter, rndomized, open-lel clinicl tril conducted in 469 women with metsttic rest cncer who hd not een previously treted with chemotherpy for metsttic disese. Tumor specimens were tested y IHC (Clinicl Tril Assy, CTA) nd scored s 0, 1+, 2+, or 3+, with 3+ indicting the strongest positivity. Only ptients with 2+ or 3+ positive tumors were eligile (out 33% of those screened). Ptients were rndomized to receive chemotherpy lone or in comintion with Herceptin given intrvenously s 4 mg/kg loding dose followed y weekly doses of Herceptin t 2 mg/kg. For those who hd received prior nthrcycline therpy in the djuvnt setting, chemotherpy consisted of pclitxel (175 mg/m 2 over 3 hours every 21 dys for t lest six cycles); for ll other ptients, chemotherpy consisted of nthrcycline plus cyclophosphmide (AC: doxoruicin 60 mg/m 2 or epiruicin 75 mg/m 2 plus 600 mg/m 2 cyclophosphmide every 21 dys for six cycles). Sixty-five percent of ptients rndomized to receive chemotherpy lone in this study received Herceptin t the time of disese progression s prt of seprte extension study. Bsed upon the determintion y n independent response evlution committee the ptients rndomized to Herceptin nd chemotherpy experienced significntly longer medin time to disese progression, higher overll response rte (ORR), nd longer medin durtion of response, s compred with ptients rndomized to chemotherpy lone. Ptients rndomized to Herceptin nd chemotherpy lso hd longer medin survivl (see Tle 9). These tretment effects were oserved oth in ptients who received Herceptin plus pclitxel nd in those who received Herceptin plus AC; however the mgnitude of the effects ws greter in the pclitxel sugroup. Tle 9 Study 5: Efficcy Results in First-Line Tretment for Metsttic Brest Cncer Comined Results Pclitxel Sugroup AC Sugroup Herceptin + All Chemo- All Chemo- Herceptin + Herceptin + therpy therpy Pclitxel Pclitxel AC AC (n = 235) (n = 234) (n = 92) (n = 96) (n = 143) (n = 138) Primry Endpoint Medin TTP(mos),c 95% CI 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 p-vlue d < < Secondry Endpoints Overll Response Rte 95% CI 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p-vlue e < < Medin Resp Durtion (mos),c 25%, 75% Qurtile 6, 15 4, 8 5,11 4, 7 6, 15 4, 8 Med Survivl (mos) c 95% CI 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 p-vlue d AC = Anthrcycline (doxoruicin or epiruicin) nd cyclophosphmide. Assessed y n independent Response Evlution Committee. c Kpln-Meier Estimte. d log-rnk test. e χ2-test. Dt from Study 5 suggest tht the eneficil tretment effects were lrgely limited to ptients with the highest level of HER2 protein overexpression (3+) (see Tle 10). Tle 10 Tretment Effects in Study 5 s Function of HER2 Overexpression or Amplifiction Explortory nlyses of DFS s function of HER2 overexpression or gene mplifiction were conducted for ptients in Studies 2 nd 3, where centrl lortory testing dt were ville. The results re shown in Tle 8. The numer of events in Study 2 ws smll with the exception of the IHC 3+/FISH+ sugroup, which constituted 81% of those with dt. Definitive conclusions cnnot e drwn regrding efficcy within other sugroups due to the smll numer of events. The numer of events in Study 3 ws dequte to demonstrte significnt effects on DFS in the IHC 3+/FISH unknown nd the FISH +/IHC unknown sugroups. Numer of Reltive Risk for Time Reltive Risk for HER2 Assy Ptients to Disese Progression Mortlity Result (N) (95% CI) (95% CI) CTA 2+ or (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+) (0.34, 0.57) 0.70 (0.53, 0.91) FISH ( ) (0.42, 0.94) 1.06 (0.70, 1.63) CTA (0.50, 1.15) 1.26 (0.82, 1.94) FISH (+) (0.21, 1.35) 1.31 (0.53, 3.27) FISH ( ) (0.48, 1.25) 1.11 (0.68, 1.82) CTA (0.33, 0.54) 0.70 (0.51, 0.90) FISH (+) (0.32, 0.55) 0.67 (0.51, 0.89) FISH ( ) (0.20, 0.94) 0.88 (0.39, 1.98) FISH testing results were ville for 451 of the 469 ptients enrolled on study. The reltive risk represents the risk of progression or deth in the Herceptin plus chemotherpy rm versus the chemotherpy rm.

7 Previously Treted Metsttic Brest Cncer (Study 6) Herceptin ws studied s single gent in multicenter, open-lel, single-rm clinicl tril (Study 6) in ptients with HER2 overexpressing metsttic rest cncer who hd relpsed following one or two prior chemotherpy regimens for metsttic disese. Of 222 ptients enrolled, 66% hd received prior djuvnt chemotherpy, 68% hd received two prior chemotherpy regimens for metsttic disese, nd 25% hd received prior myeloltive tretment with hemtopoietic rescue. Ptients were treted with loding dose of 4 mg/kg IV followed y weekly doses of Herceptin t 2 mg/kg IV. The ORR (complete response+prtil response), s determined y n independent Response Evlution Committee, ws 14%, with 2% complete response rte nd 12% prtil response rte. Complete responses were oserved only in ptients with disese limited to skin nd lymph nodes. The overll response rte in ptients whose tumors tested s CTA 3+ ws 18% while in those tht tested s CTA 2+, it ws 6% Metsttic Gstric Cncer The sfety nd efficcy of Herceptin in comintion with cispltin nd fluoropyrimidine (cpecitine or 5-fluorourcil) were studied in ptients previously untreted for metsttic gstric or gstroesophgel junction denocrcinom (Study 7). In this open-lel, multi-center tril, 594 ptients were rndomized 1:1 to Herceptin in comintion with cispltin nd fluoropyrimidine (FC+H) or chemotherpy lone (FC). Rndomiztion ws strtified y extent of disese (metsttic vs. loclly dvnced), primry site (gstric vs. gstroesophgel junction), tumor mesurility (yes vs. no), ECOG performnce sttus (0,1 vs. 2), nd fluoropyrimidine (cpecitine vs. 5-fluorourcil). All ptients were either HER2 gene mplified (FISH+) or HER2 overexpressing (IHC 3+). Ptients were lso required to hve dequte crdic function (e.g., LVEF > 50%). On the Herceptin-contining rm, Herceptin ws dministered s n IV infusion t n initil dose of 8 mg/kg followed y 6 mg/kg every 3 weeks until disese progression. On oth study rms cispltin ws dministered t dose of 80 mg/m 2 Dy 1 every 3 weeks for 6 cycles s 2 hour IV infusion. On oth study rms cpecitine ws dministered t 1000 mg/m 2 dose orlly twice dily (totl dily dose 2000 mg/m 2 ) for 14 dys of ech 21 dy cycle for 6 cycles. Alterntively continuous intrvenous infusion (CIV) 5-fluorourcil ws dministered t dose of 800 mg/m 2 /dy from Dy 1 through Dy 5 every three weeks for 6 cycles. The medin ge of the study popultion ws 60 yers (rnge: 21 83); 76% were mle; 53% were Asin, 38% Cucsin, 5% Hispnic, 5% other rcil/ethnic groups; 91% hd ECOG PS of 0 or 1; 82% hd primry gstric cncer nd 18% hd primry gstroesophgel denocrcinom. Of these ptients, 23% hd undergone prior gstrectomy, 7% hd received prior neodjuvnt nd/or djuvnt therpy, nd 2% hd received prior rdiotherpy. The min outcome mesure of Study 7 ws overll survivl (OS), nlyzed y the unstrtified log-rnk test. The finl OS nlysis sed on 351 deths ws sttisticlly significnt (nominl significnce level of ). An updted OS nlysis ws conducted t one yer fter the finl nlysis. The efficcy results of oth the finl nd the updted nlyses re summrized in Tle 11 nd Figure 6. Tle 11 Study 7: Overll Survivl in ITT Popultion FC Arm FC + H Arm N= 296 N=298 Definitive (Second Interim) Overll Survivl No. Deths (%) 184 (62.2%) 167 (56.0%) Medin % CI (mos.) (9.4, 12.5) (11.7, 15.7) Hzrd Rtio % CI (0.60, 0.91) p-vlue*, two-sided Updted Overll Survivl No. Deths (%) 227 (76.7%) 221 (74.2%) Medin % CI (mos.) (10.3, 13.0) (11.9, 15.1) Hzrd Rtio % CI (0.67, 0.97) * Compring with the nominl significnce level of Figure 6 Updted Overll Survivl in Ptients with Metsttic Gstric Cncer (Study 7) Five ptients on the Herceptin-contining rm who were FISH+, ut IHC sttus unknown were excluded from the explortory sugroup nlyses. c Includes 6 ptients on chemotherpy rm, 10 ptients on Herceptin rm with FISH-, IHC3+ nd 8 ptients on chemotherpy rm, 8 ptients on Herceptin rm with FISH sttus unknown, IHC HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Herceptin is supplied in multi-use vil contining 440 mg trstuzum s lyophilized sterile powder, under vcuum. Ech crton contins one vil Herceptin nd one vil (20 ml) of Bcteriosttic Wter for Injection (BWFI), USP, contining 1.1% enzyl lcohol s preservtive. NDC Stility nd Storge Vils of Herceptin re stle t 2 8 C (36 46 F) prior to reconstitution. Do not use eyond the expirtion dte stmped on the vil. A vil of Herceptin reconstituted with BWFI, s supplied, is stle for 28 dys fter reconstitution when stored refrigerted t 2 8 C (36 46 F). Discrd ny remining multi-dose reconstituted solution fter 28 dys. A vil of Herceptin reconstituted with unpreserved SWFI (not supplied) should e used immeditely nd ny unused portion discrded. Do Not Freeze Herceptin following reconstitution or dilution. The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene gs contining 0.9% Sodium Chloride Injection, USP, should e stored t 2 8 C (36 46 F) for no more thn 24 hours prior to use. 17 PATIENT COUNSELING INFORMATION Advise ptients to contct helth cre professionl immeditely for ny of the following: new onset or worsening shortness of reth, cough, swelling of the nkles/legs, swelling of the fce, plpittions, weight gin of more thn 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Wrning Crdiomyopthy]. Advise pregnnt women nd women of childering potentil tht Herceptin exposure cn result in fetl hrm [see Wrnings nd Precutions (5.3) nd Use in Specific Popultions (8.1)]. Advise women of childering potentil to use effective contrceptive methods during tretment nd for minimum of six months following Herceptin [see Wrnings nd Precutions (5.3)]. Advise nursing mothers treted with Herceptin to discontinue nursing or discontinue Herceptin, tking into ccount the importnce of the drug to the mother [see Use in Specific Popultions (8.3)]. Encourge women who re exposed to Herceptin during pregnncy to enroll in MotHER- the Herceptin Pregnncy Registry ( ) [see Wrnings nd Precutions (5.3) nd Use in Specific Popultions (8.1)]. HERCEPTIN [trstuzum] Mnufctured y: Genentech, Inc. A Memer of the Roche Group 1 DNA Wy South Sn Frncisco, CA Initil US Approvl: Septemer 1998 Revision Dte: Octoer 2010 Herceptin is registered trdemrk of Genentech, Inc. HER Genentech, Inc. An explortory nlysis of OS in ptients sed on HER2 gene mplifiction (FISH) nd protein overexpression (IHC) testing is summrized in Tle 12. Tle 12 Explortory Anlyses y HER2 Sttus using Updted Overll Survivl Results FC (N= 296) FC+H (N=298) FISH+ / IHC 0, 1+ sugroup (N=133) No. Deths / n (%) 57/71 (80%) 56/62 (90%) Medin OS Durtion (mos.) % CI (mos.) (6.4, 11.7) (6.2, 10.7) Hzrd rtio (95% CI) 1.33 (0.92, 1.92) FISH+ / IHC2+ sugroup (N=160) No. Deths / n (%) 65/80 (81%) 64/80 (80%) Medin OS Durtion (mos.) % CI (mos.) (6.8, 12.8) (9.5, 15.7) Hzrd rtio (95% CI) 0.78 (0.55, 1.10) FISH+ or FISH-/IHC3+ c sugroup (N=294) No. Deths / n (%) 104/143 (73%) 96/151 (64%) Medin OS Durtion (mos.) % CI (mos.) ( ) (15.5, 21.2) Hzrd rtio (95% CI) 0.66 (0.50, 0.87) Two ptients on the FC rm who were FISH+ ut IHC sttus unknown were excluded from the explortory sugroup nlyses.