1 Indications and Usage

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ERBITUX sfely nd effectively. See full prescriing informtion for ERBITUX. ERBITUX (cetuxim) injection, for intrvenous infusion Initil U.S. Approvl: 2004 WARNING: SERIOUS INFUSION REACTIONS nd CARDIOPULMONARY ARREST See full prescriing informtion for complete oxed wrning. Serious infusion rections, some ftl, occurred in pproximtely 3% of ptients. (5.1) Crdiopulmonry rrest nd/or sudden deth occurred in 2% of ptients with squmous cell crcinom of the hed nd neck treted with Eritux nd rdition therpy nd in 3% of ptients with squmous cell crcinom of the hed nd neck treted with cetuxim in comintion with pltinum-sed therpy with 5-fluorourcil (5-FU). Closely monitor serum electrolytes, including serum mgnesium, potssium, nd clcium, during nd fter Eritux dministrtion. (5.2, 5.6) RECENT MAJOR CHANGES Boxed Wrning 11/2011 Indictions nd Usge Squmous Cell Crcinom of the Hed nd Neck (1.1) 11/2011 Colorectl Cncer (1.2) 07/2012 Dosge nd Administrtion Squmous Cell Crcinom of the Hed nd Neck (2.1) 11/2011 Colorectl Cncer (2.2) 07/2012 Wrnings nd Precutions Crdiopulmonry Arrest (5.2) 11/2011 Dermtologic Toxicity (5.4) 01/2012 Hypomgnesemi nd Electrolyte Anormlities (5.6) 11/2011 K-Rs Testing in Metsttic or Advnced Colorectl Cncer Ptients (5.7) 07/2012 INDICATIONS AND USAGE Eritux is n epiderml growth fctor receptor (EGFR) ntgonist indicted for tretment of: Hed nd Neck Cncer Loclly or regionlly dvnced squmous cell crcinom of the hed nd neck in comintion with rdition therpy. (1.1, 14.1) Recurrent locoregionl disese or metsttic squmous cell crcinom of the hed nd neck in comintion with pltinum-sed therpy with 5-FU. (1.1, 14.1) Recurrent or metsttic squmous cell crcinom of the hed nd neck progressing fter pltinum-sed therpy. (1.1, 14.1) Colorectl Cncer K-Rs muttion-negtive (wild-type), EGFR-expressing, metsttic colorectl cncer s determined y FDA-pproved tests in comintion with FOLFIRI for first-line tretment, FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS INFUSION REACTIONS AND CARDIOPULMONARY ARREST 1 Indictions nd Usge 1.1 Squmous Cell Crcinom of the Hed nd Neck (SCCHN) 1.2 K-Rs Muttion-negtive, EGFR-expressing Colorectl Cncer 2 DOSAGE AND ADMINISTRATION 2.1 Squmous Cell Crcinom of the Hed nd Neck 2.2 Colorectl Cncer 2.3 Recommended Premediction 2.4 Dose Modifictions 2.5 Preprtion for Administrtion 3 Dosge Forms nd Strengths 4 Contrindictions 5 Wrnings nd Precutions 5.1 Infusion Rections 5.2 Crdiopulmonry Arrest 5.3 Pulmonry Toxicity 5.4 Dermtologic Toxicity 5.5 Use of Eritux in Comintion With Rdition nd Cispltin 5.6 Hypomgnesemi nd Electrolyte Anormlities 5.7 K-Rs Testing in Metsttic or Advnced Colorectl Cncer Ptients 5.8 Epiderml Growth Fctor Receptor (EGFR) Expression nd Response 6 Adverse Rections 6.1 Clinicl Trils Experience in comintion with irinotecn in ptients who re refrctory to irinotecn-sed chemotherpy, s single gent in ptients who hve filed oxlipltin- nd irinotecn-sed chemotherpy or who re intolernt to irinotecn. (1.2, 5.8, 12.1, 14.2) Limittion of Use: Eritux (cetuxim) is not indicted for tretment of K-Rs muttion-positive colorectl cncer. (5.8, 14.2) DOSAGE AND ADMINISTRATION Premedicte with n H 1 ntgonist. (2.3) Administer 400 mg/m 2 initil dose s 120-minute intrvenous infusion followed y 250 mg/m 2 weekly infused over 60 minutes. (2.1, 2.2) Initite Eritux one week prior to initition of rdition therpy. Complete Eritux dministrtion 1 hour prior to pltinum-sed therpy with 5-FU (2.1) nd FOLFIRI (2.2). Reduce the infusion rte y 50% for NCI CTC Grde 1 or 2 infusion rections nd non-serious NCI CTC Grde 3 infusion rection. (2.4) Permnently discontinue for serious infusion rections. (2.4) Withhold infusion for severe, persistent cneiform rsh. Reduce dose for recurrent, severe rsh. (2.4) DOSAGE FORMS AND STRENGTHS 100 mg/50 ml, single-use vil (3) 200 mg/100 ml, single-use vil (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Infusion Rections: Immeditely stop nd permnently discontinue Eritux for serious infusion rections. Monitor ptients following infusion. (5.1) Crdiopulmonry Arrest: Closely monitor serum electrolytes during nd fter Eritux. (5.2, 5.6) Pulmonry Toxicity: Interrupt therpy for cute onset or worsening of pulmonry symptoms. (5.3) Dermtologic Toxicity: Limit sun exposure. Monitor for inflmmtory or infectious sequele. (2.4, 5.4) hypomgnesemi: Periodiclly monitor during nd for t lest 8 weeks following the completion of Eritux. Replete electrolytes s necessry. (5.6) ADVERSE REACTIONS The most common dverse rections (incidence 25%) re: cutneous dverse rections (including rsh, pruritus, nd nil chnges), hedche, dirrhe, nd infection. (6) To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squi t or FDA t FDA-1088 or USE IN SPECIFIC POPULATIONS Pregnncy: Administer Eritux to pregnnt womn only if the potentil enefit justifies the potentil risk to the fetus. (8.1) Nursing Mothers: Discontinue nursing during nd for 60 dys following tretment with Eritux. (8.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 07/ Immunogenicity 6.3 Postmrketing Experience 7 Drug Interctions 8 Use in Specific Popultions 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 10 Overdosge 11 Description 12 Clinicl Phrmcology 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 Nonclinicl Toxicology 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Phrmcology nd/or Toxicology 14 Clinicl Studies 14.1 Squmous Cell Crcinom of the Hed nd Neck (SCCHN) 14.2 Colorectl Cncer 16 How Supplied/Storge nd Hndling 17 Ptient Counseling Informtion * Sections or susections omitted from the full prescriing informtion re not listed

2 FULL PRESCRIBING INFORMATION WARNING: SERIOUS INFUSION REACTIONS nd CARDIOPULMONARY ARREST Infusion Rections: Serious infusion rections occurred with the dministrtion of Eritux in pproximtely 3% of ptients in clinicl trils, with ftl outcome reported in less thn 1 in [See Wrnings nd Precutions (5.1), Adverse Rections (6).] Immeditely interrupt nd permnently discontinue Eritux infusion for serious infusion rections. [See Dosge nd Administrtion (2.4), Wrnings nd Precutions (5.1).] Crdiopulmonry Arrest: Crdiopulmonry rrest nd/or sudden deth occurred in 2% of ptients with squmous cell crcinom of the hed nd neck treted with Eritux nd rdition therpy in Study 1 nd in 3% of ptients with squmous cell crcinom of the hed nd neck treted with Europen Union (EU)-pproved cetuxim in comintion with pltinum-sed therpy with 5-fluorourcil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum mgnesium, potssium, nd clcium, during nd fter Eritux dministrtion. [See Wrnings nd Precutions (5.2, 5.6), Clinicl Studies (14.1).] 1 Indictions nd Usge 1.1 Squmous Cell Crcinom of the Hed nd Neck (SCCHN) Eritux (cetuxim) is indicted in comintion with rdition therpy for the initil tretment of loclly or regionlly dvnced squmous cell crcinom of the hed nd neck. [See Clinicl Studies (14.1).] Eritux is indicted in comintion with pltinum-sed therpy with 5-FU for the firstline tretment of ptients with recurrent locoregionl disese or metsttic squmous cell crcinom of the hed nd neck. [See Clinicl Studies (14.1).] Eritux, s single gent, is indicted for the tretment of ptients with recurrent or metsttic squmous cell crcinom of the hed nd neck for whom prior pltinum-sed therpy hs filed. [See Clinicl Studies (14.1).] 1.2 K-Rs Muttion-negtive, EGFR-expressing Colorectl Cncer Eritux is indicted for the tretment of K-Rs muttion-negtive (wild-type), epiderml growth fctor receptor (EGFR)-expressing, metsttic colorectl cncer (mcrc) s determined y FDA-pproved tests for this use [see Dosge nd Administrtion (2.2), Wrnings nd Precutions (5.8), Clinicl Studies (14.2)]. in comintion with FOLFIRI (irinotecn, 5-fluorourcil, leucovorin) for first-line tretment, in comintion with irinotecn in ptients who re refrctory to irinotecn-sed chemotherpy, s single gent in ptients who hve filed oxlipltin- nd irinotecn-sed chemotherpy or who re intolernt to irinotecn. [See Wrnings nd Precutions (5.8), Clinicl Phrmcology (12.1), Clinicl Studies (14.2).] Limittion of Use: Eritux is not indicted for tretment of K-Rs muttion-positive colorectl cncer [see Wrnings nd Precutions (5.8), Clinicl Studies (14.2)]. 2 Dosge nd Administrtion 2.1 Squmous Cell Crcinom of the Hed nd Neck Eritux in comintion with rdition therpy or in comintion with pltinum-sed therpy with 5-FU: The recommended initil dose is 400 mg/m 2 dministered one week prior to initition of course of rdition therpy or on the dy of initition of pltinum-sed therpy with 5-FU s 120-minute intrvenous infusion (mximum infusion rte 10 mg/min). Complete Eritux dministrtion 1 hour prior to pltinum-sed therpy with 5-FU. The recommended susequent weekly dose (ll other infusions) is 250 mg/m 2 infused over 60 minutes (mximum infusion rte 10 mg/min) for the durtion of rdition therpy (6 7 weeks) or until disese progression or uncceptle toxicity when dministered in comintion with pltinum-sed therpy with 5-FU. Complete Eritux dministrtion 1 hour prior to rdition therpy or pltinum-sed therpy with 5-FU. Eritux monotherpy: The recommended initil dose is 400 mg/m 2 dministered s 120-minute intrvenous infusion (mximum infusion rte 10 mg/min). The recommended susequent weekly dose (ll other infusions) is 250 mg/m 2 infused over 60 minutes (mximum infusion rte 10 mg/min) until disese progression or uncceptle toxicity. 2.2 Colorectl Cncer Determine K-Rs muttion nd EGFR-expression sttus using FDA-pproved tests prior to inititing tretment. Only ptients whose tumors re K-Rs muttion-negtive (wild-type) should receive Eritux. The recommended initil dose, either s monotherpy or in comintion with irinotecn or FOLFIRI (irinotecn, 5-fluorourcil, leucovorin), is 400 mg/m 2 dministered s 120-minute intrvenous infusion (mximum infusion rte 10 mg/min). Complete Eritux dministrtion 1 hour prior to FOLFIRI. The recommended susequent weekly dose, either s monotherpy or in comintion with irinotecn or FOLFIRI, is 250 mg/m 2 infused over 60 minutes (mximum infusion rte 10 mg/min) until disese progression or uncceptle toxicity. Complete Eritux dministrtion 1 hour prior to FOLFIRI. Eritux (cetuxim) 2.3 Recommended Premediction Premedicte with n H 1 ntgonist (eg, 50 mg of diphenhydrmine) intrvenously minutes prior to the first dose; premediction should e dministered for susequent Eritux doses sed upon clinicl judgment nd presence/severity of prior infusion rections. 2.4 Dose Modifictions Infusion Rections Reduce the infusion rte y 50% for NCI CTC Grde 1 or 2 nd non-serious NCI CTC Grde 3 infusion rection. Immeditely nd permnently discontinue Eritux for serious infusion rections, requiring medicl intervention nd/or hospitliztion. [See Wrnings nd Precutions (5.1).] Dermtologic Toxicity Recommended dose modifictions for severe (NCI CTC Grde 3 or 4) cneiform rsh re specified in Tle 1. [See Wrnings nd Precutions (5.4).] Tle 1: Eritux Dose Modifiction Guidelines for Rsh Severe Acneiform Rsh Eritux Outcome Eritux Dose Modifiction 1st occurrence Dely infusion 1 to 2 weeks Improvement No Improvement Continue t 250 mg/m 2 Discontinue Eritux 2nd occurrence Dely infusion Improvement Reduce dose to 200 mg/m 2 3rd occurrence 4th occurrence 1 to 2 weeks Dely infusion 1 to 2 weeks Discontinue Eritux No Improvement Improvement No Improvement Discontinue Eritux Reduce dose to 150 mg/m 2 Discontinue Eritux 2.5 Preprtion for Administrtion Do not dminister Eritux s n intrvenous push or olus. Administer vi infusion pump or syringe pump. Do not exceed n infusion rte of 10 mg/min. Administer through low protein inding 0.22-micrometer in-line filter. Prenterl drug products should e inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. The solution should e cler nd colorless nd my contin smll mount of esily visile, white, morphous, cetuxim prticultes. Do not shke or dilute. 3 Dosge Forms nd Strengths 100 mg/50 ml, single-use vil 200 mg/100 ml, single-use vil 4 Contrindictions None 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Rections Serious infusion rections, requiring medicl intervention nd immedite, permnent discontinution of Eritux included rpid onset of irwy ostruction (ronchospsm, stridor, horseness), hypotension, shock, loss of consciousness, myocrdil infrction, nd/ or crdic rrest. Severe (NCI CTC ) infusion rections occurred in 2 5% of 1373 ptients in Studies 1, 3, 5, nd 6 receiving Eritux, with ftl outcome in 1 ptient. [See Clinicl Studies (14.1, 14.2).] Approximtely 90% of severe infusion rections occurred with the first infusion despite premediction with ntihistmines. Monitor ptients for 1 hour following Eritux infusions in setting with resuscittion equipment nd other gents necessry to tret nphylxis (eg, epinephrine, corticosteroids, intrvenous ntihistmines, ronchodiltors, nd oxygen). Monitor longer to confirm resolution of the event in ptients requiring tretment for infusion rections. Immeditely nd permnently discontinue Eritux in ptients with serious infusion rections. [See Boxed Wrning, Dosge nd Administrtion (2.4).] 5.2 Crdiopulmonry Arrest Crdiopulmonry rrest nd/or sudden deth occurred in 4 (2%) of 208 ptients treted with rdition therpy nd Eritux s compred to none of 212 ptients treted with rdition therpy lone in Study 1. Three ptients with prior history of coronry rtery disese died t home, with myocrdil infrction s the presumed cuse of deth. One of these ptients hd rrhythmi nd one hd congestive hert filure. Deth occurred 27, 32, nd 43 dys fter the lst dose of Eritux. One ptient with no prior history of coronry rtery disese died one dy fter the lst dose of Eritux. In Study 2, ftl crdic disorders nd/ or sudden deth occurred in 7 (3%) of 219 ptients treted with EU-pproved cetuxim nd pltinum-sed therpy with 5-FU s compred to 4 (2%) of 215 ptients treted with chemotherpy lone. Five of these 7 ptients in the chemotherpy plus cetuxim rm received concomitnt cispltin nd 2 ptients received concomitnt cropltin. All 4 ptients in the chemotherpy-lone rm received cispltin. Crefully consider use of Eritux in comintion with rdition therpy or pltinum-sed therpy with 5-FU in hed nd neck cncer ptients with history of coronry rtery disese, congestive hert filure, or rrhythmis in light of these risks. Closely monitor serum electrolytes, including serum mgnesium, potssium, nd clcium, during nd fter Eritux. [See Boxed Wrning, Wrnings nd Precutions (5.6).]

3 Eritux (cetuxim) 5.3 Pulmonry Toxicity Interstitil lung disese (ILD), including 1 ftlity, occurred in 4 of 1570 (<0.5%) ptients receiving Eritux in Studies 1, 3, nd 6, s well s other studies, in colorectl cncer nd hed nd neck cncer. Interrupt Eritux for cute onset or worsening of pulmonry symptoms. Permnently discontinue Eritux for confirmed ILD. 5.4 Dermtologic Toxicity Dermtologic toxicities, including cneiform rsh, skin drying nd fissuring, pronychil inflmmtion, infectious sequele (for exmple, S. ureus sepsis, scess formtion, cellulitis, lephritis, conjunctivitis, kertitis/ulcertive kertitis with decresed visul cuity, cheilitis), nd hypertrichosis occurred in ptients receiving Eritux therpy. Acneiform rsh occurred in 76 88% of 1373 ptients receiving Eritux in Studies 1, 3, 5, nd 6. Severe cneiform rsh occurred in 1 17% of ptients. Acneiform rsh usully developed within the first two weeks of therpy nd resolved in mjority of the ptients fter cesstion of tretment, lthough in nerly hlf, the event continued eyond 28 dys. Monitor ptients receiving Eritux for dermtologic toxicities nd infectious sequele. Instruct ptients to limit sun exposure during Eritux therpy. [See Dosge nd Administrtion (2.4).] 5.5 Use of Eritux in Comintion With Rdition nd Cispltin The sfety of Eritux in comintion with rdition therpy nd cispltin hs not een estlished. Deth nd serious crdiotoxicity were oserved in single-rm tril with Eritux, rdition therpy, nd cispltin (100 mg/m 2 ) in ptients with loclly dvnced SCCHN. Two of 21 ptients died, one s result of pneumoni nd one of n unknown cuse. Four ptients discontinued tretment due to dverse events. Two of these discontinutions were due to crdic events. 5.6 Hypomgnesemi nd Electrolyte Anormlities In ptients evluted during clinicl trils, hypomgnesemi occurred in 55% of 365 ptients receiving Eritux in Study 5 nd two other clinicl trils in colorectl cncer nd hed nd neck cncer, respectively, nd ws severe (NCI CTC ) in 6 17%. In Study 2, where EU-pproved cetuxim ws dministered in comintion with pltinum-sed therpy, the ddition of cetuxim to cispltin nd 5-FU resulted in n incresed incidence of hypomgnesemi (14% vs. 6%) nd of Grde 3 4 hypomgnesemi (7% vs. 2%) compred to cispltin nd 5-FU lone. In contrst, the incidences of hypomgnesemi were similr for those who received cetuxim, cropltin, nd 5-FU compred to cropltin nd 5-FU (4% vs. 4%). No ptient experienced Grde 3 4 hypomgnesemi in either rm in the cropltin sugroup. The onset of hypomgnesemi nd ccompnying electrolyte normlities occurred dys to months fter initition of Eritux. Periodiclly monitor ptients for hypomgnesemi, hypoclcemi, nd hypoklemi, during nd for t lest 8 weeks following the completion of Eritux. Replete electrolytes s necessry. 5.7 K-Rs Testing in Metsttic or Advnced Colorectl Cncer Ptients Determintion of K-Rs muttionl sttus in colorectl tumors using n FDA-pproved test indicted for this use is necessry for selection of ptients for tretment with Eritux. Eritux is indicted only for ptients with EGFR-expressing K-Rs muttion-negtive (wild-type) mcrc. Eritux is not n effective tretment for ptients with colorectl cncer tht hror somtic muttions in codons 12 nd 13 (exon 2). Studies 4 nd 5, conducted in ptients with colorectl cncer, demonstrted enefit with Eritux tretment only in the suset of ptients whose tumors were K-Rs muttion-negtive (wild-type). Eritux is not effective for the tretment of K-Rs muttion-positive colorectl cncer s determined y n FDA-pproved test for this use. [See Indictions nd Usge (1.2), Clinicl Phrmcology (12.1), Clinicl Studies (14.2)]. Perform the ssessment for K-Rs muttion sttus in colorectl cncer in lortories with demonstrted proficiency in the specific technology eing utilized. Improper ssy performnce cn led to unrelile test results. Refer to n FDA-pproved test s pckge insert for instructions on the identifiction of ptients eligile for the tretment of Eritux. 5.8 Epiderml Growth Fctor Receptor (EGFR) Expression nd Response Becuse expression of EGFR hs een detected in nerly ll SCCHN tumor specimens, ptients enrolled in the hed nd neck cncer clinicl studies were not required to hve immunohistochemicl evidence of EGFR tumor expression prior to study entry. Ptients enrolled in the colorectl cncer clinicl studies were required to hve immunohistochemicl evidence of EGFR tumor expression. Primry tumor or tumor from metsttic site ws tested with the DkoCytomtion EGFR phrmdx test kit. Specimens were scored sed on the percentge of cells expressing EGFR nd intensity (rely/fint, wek-to-moderte, nd strong). Response rte did not correlte with either the percentge of positive cells or the intensity of EGFR expression. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lel: Infusion rections [See Boxed Wrning, Wrnings nd Precutions (5.1).] Crdiopulmonry rrest [See Boxed Wrning, Wrnings nd Precutions (5.2).] Pulmonry toxicity [See Wrnings nd Precutions (5.3).] Dermtologic toxicity [See Wrnings nd Precutions (5.4).] Hypomgnesemi nd Electrolyte Anormlities [See Wrnings nd Precutions (5.6).] The most common dverse rections in Eritux clinicl trils (incidence 25%) include cutneous dverse rections (including rsh, pruritus, nd nil chnges), hedche, dirrhe, nd infection. Eritux (cetuxim) The most serious dverse rections with Eritux re infusion rections, crdiopulmonry rrest, dermtologic toxicity nd rdition dermtitis, sepsis, renl filure, interstitil lung disese, nd pulmonry emolus. Across Studies 1, 3, 5, nd 6, Eritux ws discontinued in 3 10% of ptients ecuse of dverse rections. 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. The dt elow reflect exposure to Eritux in 1373 ptients with SCCHN or colorectl cncer in rndomized Phse 3 (Studies 1 nd 5) or Phse 2 (Studies 3 nd 6) trils treted t the recommended dose nd schedule for medins of 7 to 14 weeks. [See Clinicl Studies (14).] Infusion rections: Infusion rections, which included pyrexi, chills, rigors, dyspne, ronchospsm, ngioedem, urticri, hypertension, nd hypotension occurred in 15 21% of ptients cross studies. infusion rections occurred in 2 5% of ptients; infusion rections were ftl in 1 ptient. Infections: The incidence of infection ws vrile cross studies, rnging from 13 35%. Sepsis occurred in % of ptients. Renl: Renl filure occurred in 1% of ptients with colorectl cncer. Squmous Cell Crcinom of the Hed nd Neck Eritux in Comintion with Rdition Therpy Tle 2 contins selected dverse rections in 420 ptients receiving rdition therpy either lone or with Eritux for loclly or regionlly dvnced SCCHN in Study 1. Eritux ws dministered t the recommended dose nd schedule (400 mg/m 2 initil dose, followed y 250 mg/m 2 weekly). Ptients received medin of 8 infusions (rnge 1 11). Tle 2: Incidence of Selected Adverse Rections ( 10%) in Ptients with Locoregionlly Advnced SCCHN Eritux plus Rdition (n=208) Rdition Therpy Alone (n=212) Body System Preferred Term % of Ptients Body s Whole Astheni Fever Hedche 19 <1 8 <1 Infusion Rection Infection Chills Digestive Nuse Emesis Dirrhe Dyspepsi Metolic/Nutritionl Weight Loss Dehydrtion Alnine Trnsminse, high c Asprtte Trnsminse, high c Alkline Phosphtse, high c 33 < Respirtory Phryngitis Skin/Appendges Acneiform Rsh d Rdition Dermtitis Appliction Site Rection Pruritus Includes cses lso reported s infusion rection. Infusion rection is defined s ny event descried t ny time during the clinicl study s llergic rection or nphylctoid rection, or ny event occurring on the first dy of dosing descried s llergic rection, nphylctoid rection, fever, chills, chills nd fever, or dyspne. c Bsed on lortory mesurements, not on reported dverse rections, the numer of sujects with tested smples vried from for Eritux plus Rdition rm; for Rdition lone. d Acneiform rsh is defined s ny event descried s cne, rsh, mculoppulr rsh, pustulr rsh, dry skin, or exfolitive dermtitis. The incidence nd severity of mucositis, stomtitis, nd xerostomi were similr in oth rms of the study.

4 Eritux (cetuxim) Lte Rdition Toxicity The overll incidence of lte rdition toxicities (ny grde) ws higher in Eritux in comintion with rdition therpy compred with rdition therpy lone. The following sites were ffected: slivry glnds (65% versus 56%), lrynx (52% versus 36%), sucutneous tissue (49% versus 45%), mucous memrne (48% versus 39%), esophgus (44% versus 35%), skin (42% versus 33%). The incidence of Grde 3 or 4 lte rdition toxicities ws similr etween the rdition therpy lone nd the Eritux plus rdition tretment groups. Study 2: EU-Approved Cetuxim in Comintion with Pltinum-sed Therpy with 5-Fluorourcil Study 2 used EU-pproved cetuxim. Since U.S.-licensed Eritux provides pproximtely 22% higher exposure reltive to the EU-pproved cetuxim, the dt provided elow my underestimte the incidence nd severity of dverse rections nticipted with Eritux for this indiction. However, the tolerility of the recommended dose is supported y sfety dt from dditionl studies of Eritux [see Clinicl Phrmcology (12.3)]. Tle 3 contins selected dverse rections in 434 ptients with recurrent locoregionl disese or metsttic SCCHN receiving EU-pproved cetuxim in comintion with pltinum-sed therpy with 5-FU or pltinum-sed therpy with 5-FU lone in Study 2. Cetuxim ws dministered t 400 mg/m 2 for the initil dose, followed y 250 mg/m 2 weekly. Ptients received medin of 17 infusions (rnge 1 89). Tle 3: Incidence of Selected Adverse Rections ( 10%) in Ptients with Recurrent Locoregionl Disese or Metsttic SCCHN EU-Approved Cetuxim plus Pltinum-sed Therpy with 5-FU (n=219) Pltinum-sed Therpy with 5-FU Alone (n=215) System Orgn Clss Preferred Term % of Ptients Eye Disorders Conjunctivitis Gstrointestinl Disorders Nuse Dirrhe Generl Disorders nd Administrtion Site Conditions Pyrexi Infusion Rection 10 2 <1 0 Infections nd Infesttions Infection Metolism nd Nutrition Disorders Anorexi Hypoclcemi Hypoklemi Hypomgnesemi Skin nd Sucutneous Tissue Disorders Acneiform Rsh c Rsh Acne Dermtitis Acneiform Dry Skin 14 0 <1 0 Alopeci Infusion rection defined s ny event of nphylctic rection, hypersensitivity, fever nd/or chills, dyspne, or pyrexi on the first dy of dosing. Infection this term excludes sepsis-relted events which re presented seprtely. c Acneiform rsh defined s ny event descried s cne, dermtitis cneiform, dry skin, exfolitive rsh, rsh, rsh erythemtous, rsh mculr, rsh ppulr, or rsh pustulr. Chemotherpy = cispltin + 5-fluorourcil or cropltin + 5-fluorourcil For crdic disorders, pproximtely 9% of sujects in oth the EU-pproved cetuxim plus chemotherpy nd chemotherpy-only tretment rms in Study 2 experienced crdic event. The mjority of these events occurred in ptients who received cispltin/5-fu, with or without cetuxim s follows: 11% nd 12% in ptients who received cispltin/5-fu with or without cetuxim, respectively, nd 6% or 4% in ptients who received cropltin/5-fu with or without cetuxim, respectively. In oth rms, the incidence of crdiovsculr events ws higher in the cispltin with 5-FU contining sugroup. Deth ttriuted to crdiovsculr event or sudden deth ws reported in 3% of the ptients in the cetuxim plus pltinum-sed therpy with 5-FU rm nd 2% in the pltinum-sed chemotherpy with 5-FU lone rm. Eritux (cetuxim) Colorectl Cncer Study 4: EU-Approved Cetuxim in Comintion with FOLFIRI Study 4 used EU-pproved cetuxim. U.S.-licensed Eritux provides pproximtely 22% higher exposure to cetuxim reltive to the EU-pproved cetuxim. The dt provided elow for Study 4 is consistent in incidence nd severity of dverse rections with those seen for Eritux in this indiction. The tolerility of the recommended dose is supported y sfety dt from dditionl studies of Eritux [see Clinicl Phrmcology (12.3)]. Tle 4 contins selected dverse rections in 667 ptients with K-Rs muttion-negtive (wild-type), EGFR-expressing, metsttic colorectl cncer receiving EU-pproved cetuxim plus FOLFIRI or FOLFIRI lone in Study 4 [see Wrnings nd Precutions (5.8)]. Cetuxim ws dministered t the recommended dose nd schedule (400 mg/m 2 initil dose, followed y 250 mg/m 2 weekly). Ptients received medin of 26 infusions (rnge 1 224). Tle 4: Body System Preferred Term Incidence of Selected Adverse Rections Occurring in 10% of Ptients with K-Rs Muttion-negtive (Wild-type) nd EGFR-expressing, Metsttic Colorectl Cncer EU-Approved Cetuxim plus FOLFIRI FOLFIRI Alone (n=317) (n=350) % of Ptients Blood nd Lymphtic System Disorders Neutropeni Eye Disorders Conjunctivitis 18 <1 3 0 Gstrointestinl Disorders Dirrhe Stomtitis Dyspepsi Generl Disorders nd Administrtion Site Conditions Infusion-relted Rection c 14 2 <1 0 Pyrexi Infections nd Infesttions Pronychi 20 4 <1 0 Investigtions Weight Decresed Metolism nd Nutrition Disorders Anorexi Skin nd Sucutneous Tissue Disorders Acne-like Rsh d <1 Rsh Dermtitis Acneiform 26 5 <1 0 Dry Skin Acne Pruritus Plmr-plntr <1 Erythrodysesthesi Syndrome Skin Fissures Adverse rections occurring in t lest 10% of Eritux comintion rm with frequency t lest 5% greter thn tht seen in the FOLFIRI rm. Adverse rections were grded using the NCI CTC, V 2.0. c Infusion relted rection is defined s ny event meeting the medicl concepts of llergy/nphylxis t ny time during the clinicl study or ny event occurring on the first dy of dosing nd meeting the medicl concepts of dyspne nd fever or y the following events using MedDRA preferred terms: cute myocrdil infrction, ngin pectoris, ngioedem, utonomic seizure, lood pressure norml, lood pressure decresed, lood pressure incresed, crdic filure, crdiopulmonry filure, crdiovsculr insufficiency, clonus, convulsion, coronry no-reflow phenomenon, epilepsy, hypertension, hypertensive crisis, hypertensive emergency, hypotension, infusion relted rection, loss of consciousness, myocrdil infrction, myocrdil ischemi, prinzmetl ngin, shock, sudden deth, syncope, or systolic hypertension. d Acne-like rsh is defined y the events using MedDRA preferred terms nd included cne, cne pustulr, utterfly rsh, dermtitis cneiform, drug rsh with eosinophili nd systemic symptoms, dry skin, erythem, exfolitive rsh, folliculitis, genitl rsh, mucocutneous rsh, pruritus, rsh, rsh erythemtous, rsh folliculr, rsh generlized, rsh mculr, rsh mculoppulr, rsh mculovesiculr, rsh morilliform, rsh ppulr, rsh ppulosqumous, rsh pruritic, rsh pustulr, rsh ruelliform, rsh scrltiniform, rsh vesiculr, skin exfolition, skin hyperpigmenttion, skin plque, telngiectsi, or xerosis.

5 Eritux (cetuxim) Eritux Monotherpy Tle 5 contins selected dverse rections in 242 ptients with K-Rs muttion-negtive (wild-type), EGFR-expressing, metsttic colorectl cncer who received est supportive cre (BSC) lone or with Eritux in Study 5 [see Wrnings nd Precutions (5.8)]. Eritux ws dministered t the recommended dose nd schedule (400 mg/m 2 initil dose, followed y 250 mg/m 2 weekly). Ptients received medin of 17 infusions (rnge 1 51). Tle 5: Body System Preferred Term Incidence of Selected Adverse Rections Occurring in 10% of Ptients with K-Rs Muttion-negtive (Wild-type), EGFR-expressing, Metsttic Colorectl Cncer Treted with Eritux Monotherpy Eritux plus BSC BSC lone (n=118) (n=124) % of Ptients Dermtology/Skin Rsh/Desqumtion Dry Skin Pruritus Other-Dermtology Nil Chnges Constitutionl Symptoms Ftigue Fever Infusion Rections c Rigors, Chills Pin Pin-Other Hedche Bone Pin Pulmonry Dyspne Cough Gstrointestinl Nuse Constiption Dirrhe Vomiting Stomtitis Other-Gstrointestinl Dehydrtion Mouth Dryness Tste Disturnce Infection Infection without neutropeni Musculoskeletl Arthrlgi Neurology Neuropthy-sensory Insomni Confusion Anxiety Depression Adverse rections occurring in t lest 10% of Eritux plus BSC rm with frequency t lest 5% greter thn tht seen in the BSC lone rm. Adverse rections were grded using the NCI CTC, V 2.0. c Infusion rection is defined s ny event (chills, rigors, dyspne, tchycrdi, ronchospsm, chest tightness, swelling, urticri, hypotension, flushing, rsh, hypertension, nuse, ngioedem, pin, sweting, tremors, shking, drug fever, or other hypersensitivity rection) recorded y the investigtor s infusion-relted. Eritux in Comintion with Irinotecn The most frequently reported dverse rections in 354 ptients treted with Eritux plus irinotecn in clinicl trils were cneiform rsh (88%), stheni/mlise (73%), dirrhe (72%), nd nuse (55%). The most common 3 4 dverse rections included dirrhe (22%), leukopeni (17%), stheni/mlise (16%), nd cneiform rsh (14%). Eritux (cetuxim) 6.2 Immunogenicity As with ll therpeutic proteins, there is potentil for immunogenicity. Immunogenic responses to cetuxim were ssessed using either doule ntigen rdiometric ssy or n ELISA ssy. Due to limittions in ssy performnce nd smpling timing, the incidence of ntiody development in ptients receiving Eritux hs not een dequtely determined. Non-neutrlizing nti-cetuxim ntiodies were detected in 5% (49 of 1001) of evlule ptients without pprent effect on the sfety or ntitumor ctivity of Eritux. The incidence of ntiody formtion is highly dependent on the sensitivity nd 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 Eritux with the incidence of ntiodies to other products my e misleding. 6.3 Postmrketing Experience The following dverse rection hs een identified during post-pprovl use of Eritux. Becuse this rection ws reported from popultion of uncertin size, it ws not lwys possile to relily estimte its frequency or estlish cusl reltionship to drug exposure. Aseptic meningitis 7 Drug Interctions A drug interction study ws performed in which Eritux ws dministered in comintion with irinotecn. There ws no evidence of ny phrmcokinetic interctions etween Eritux nd irinotecn. 8 Use in Specific Popultions 8.1 Pregnncy Pregnncy Ctegory C There re no dequte nd well-controlled studies of Eritux in pregnnt women. Bsed on niml models, EGFR hs een implicted in the control of prentl development nd my e essentil for norml orgnogenesis, prolifertion, nd differentition in the developing emryo. Humn IgG is known to cross the plcentl rrier; therefore, Eritux my e trnsmitted from the mother to the developing fetus, nd hs the potentil to cuse fetl hrm when dministered to pregnnt women. Eritux should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. Pregnnt cynomolgus monkeys were treted weekly with 0.4 to 4 times the recommended humn dose of cetuxim (sed on ody surfce re) during the period of orgnogenesis (gesttion dy [GD] 20 48). Cetuxim ws detected in the mniotic fluid nd in the serum of emryos from treted dms t GD 49. No fetl mlformtions or other tertogenic effects occurred in offspring. However, significnt increses in emryolethlity nd ortions occurred t doses of pproximtely 1.6 to 4 times the recommended humn dose of cetuxim (sed on totl ody surfce re). 8.3 Nursing Mothers It is not known whether Eritux is secreted in humn milk. IgG ntiodies, such s Eritux, cn e excreted in humn milk. Becuse mny drugs re excreted in humn milk nd ecuse of the potentil for serious dverse rections in nursing infnts from Eritux, decision should e mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother. If nursing is interrupted, sed on the men hlf-life of cetuxim [see Clinicl Phrmcology (12.3)], nursing should not e resumed erlier thn 60 dys following the lst dose of Eritux. 8.4 Peditric Use The sfety nd effectiveness of Eritux in peditric ptients hve not een estlished. The phrmcokinetics of cetuxim, in comintion with irinotecn, were evluted in peditric ptients with refrctory solid tumors in n open-lel, single-rm, dose-finding study. Eritux ws dministered once-weekly, t doses up to 250 mg/m 2, to 27 ptients rnging from 1 to 12 yers old; nd in 19 ptients rnging from 13 to 18 yers old. No new sfety signls were identified in peditric ptients. The phrmcokinetic profiles of cetuxim etween the two ge groups were similr t the 75 nd 150 mg/m 2 single dose levels. The volume of the distriution ppered to e independent of dose nd pproximted the vsculr spce of 2 3 L/m 2. Following single dose of 250 mg/m 2, the geometric men AUC 0-inf (CV%) vlue ws 17.7 mg h/ml (34%) in the younger ge group (1 12 yers, n=9) nd 13.4 mg h/ml (38%) in the dolescent group (13 18 yers, n=6). The men hlf-life of cetuxim ws 110 hours (rnge 69 to 188 hours) for the younger ge group, nd 82 hours (rnge 55 to 117 hours) for the dolescent ge group. 8.5 Geritric Use Of the 1662 ptients who received Eritux with irinotecn, FOLFIRI or Eritux monotherpy in six studies of dvnced colorectl cncer, 588 ptients were 65 yers of ge or older. No overll differences in sfety or efficcy were oserved etween these ptients nd younger ptients. Clinicl studies of Eritux conducted in ptients with hed nd neck cncer did not include sufficient numer of sujects ged 65 nd over to determine whether they respond differently from younger sujects. 10 Overdosge The mximum single dose of Eritux dministered is 1000 mg/m 2 in one ptient. No dverse events were reported for this ptient.

6 Eritux (cetuxim) 11 Description Eritux (cetuxim) is recominnt, humn/mouse chimeric monoclonl ntiody tht inds specificlly to the extrcellulr domin of the humn epiderml growth fctor receptor (EGFR). Cetuxim is composed of the Fv regions of murine nti-egfr ntiody with humn IgG1 hevy nd kpp light chin constnt regions nd hs n pproximte moleculr weight of 152 kd. Cetuxim is produced in mmmlin (murine myelom) cell culture. Eritux is sterile, cler, colorless liquid of ph 7.0 to 7.4, which my contin smll mount of esily visile, white, morphous cetuxim prticultes. Eritux is supplied t concentrtion of 2 mg/ml in either 100 mg (50 ml) or 200 mg (100 ml), single-use vils. Cetuxim is formulted in solution with no preservtives, which contins 8.48 mg/ml sodium chloride, 1.88 mg/ml sodium phosphte disic hepthydrte, 0.41 mg/ml sodium phosphte monosic monohydrte, nd Wter for Injection, USP. 12 Clinicl Phrmcology 12.1 Mechnism of Action The epiderml growth fctor receptor (EGFR, HER1, c-erb-1) is trnsmemrne glycoprotein tht is memer of sufmily of type I receptor tyrosine kinses including EGFR, HER2, HER3, nd HER4. The EGFR is constitutively expressed in mny norml epithelil tissues, including the skin nd hir follicle. Expression of EGFR is lso detected in mny humn cncers including those of the hed nd neck, colon, nd rectum. Cetuxim inds specificlly to the EGFR on oth norml nd tumor cells, nd competitively inhiits the inding of epiderml growth fctor (EGF) nd other lignds, such s trnsforming growth fctor-lph. In vitro ssys nd in vivo niml studies hve shown tht inding of cetuxim to the EGFR locks phosphoryltion nd ctivtion of receptor-ssocited kinses, resulting in inhiition of cell growth, induction of poptosis, nd decresed mtrix metlloproteinse nd vsculr endothelil growth fctor production. Signl trnsduction through the EGFR results in ctivtion of wild-type K-Rs protein. However, in cells with ctivting K-Rs somtic muttions, the mutnt K-Rs protein is continuously ctive nd ppers independent of EGFR regultion. In vitro, cetuxim cn medite ntiody-dependent cellulr cytotoxicity (ADCC) ginst certin humn tumor types. In vitro ssys nd in vivo niml studies hve shown tht cetuxim inhiits the growth nd survivl of tumor cells tht express the EGFR. No nti-tumor effects of cetuxim were oserved in humn tumor xenogrfts lcking EGFR expression. The ddition of cetuxim to rdition therpy or irinotecn in humn tumor xenogrft models in mice resulted in n increse in nti-tumor effects compred to rdition therpy or chemotherpy lone Phrmcodynmics Effects on Electrocrdiogrm (ECG) The effect of cetuxim on QT intervl ws evluted in n open-lel, single-rm, monotherpy tril in 37 sujects with dvnced mlignncies who received n initil dose of 400 mg/m 2, followed y weekly infusions of 250 mg/m 2 for totl of 5 weeks. No lrge chnges in the men QT intervl of >20 ms from seline were detected in the tril sed on Friderici correction method. A smll increse in the men QTc intervl of <10 ms cnnot e excluded ecuse of the limittions in the tril design Phrmcokinetics Eritux dministered s monotherpy or in comintion with concomitnt chemotherpy or rdition therpy exhiits nonliner phrmcokinetics. The re under the concentrtion time curve (AUC) incresed in greter thn dose proportionl mnner while clernce of cetuxim decresed from 0.08 to 0.02 L/h/m 2 s the dose incresed from 20 to 200 mg/m 2, nd t doses >200 mg/m 2, it ppered to plteu. The volume of the distriution for cetuxim ppered to e independent of dose nd pproximted the vsculr spce of 2 3 L/m 2. Following the recommended dose regimen (400 mg/m 2 initil dose; 250 mg/m 2 weekly dose), concentrtions of cetuxim reched stedy-stte levels y the third weekly infusion with men pek nd trough concentrtions cross studies rnging from 168 to 235 nd 41 to 85 μg/ml, respectively. The men hlf-life of cetuxim ws pproximtely 112 hours (rnge hours). The phrmcokinetics of cetuxim were similr in ptients with SCCHN nd those with colorectl cncer. Eritux hd n pproximtely 22% (90% confidence intervl; 6%, 38%) higher systemic exposure reltive to the EU-pproved cetuxim used in Studies 2 nd 4 sed on popultion phrmcokinetic nlysis. [See Clinicl Studies (14.1).] 13 Nonclinicl Toxicology 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Long-term niml studies hve not een performed to test cetuxim for crcinogenic potentil, nd no mutgenic or clstogenic potentil of cetuxim ws oserved in the Slmonell-Escherichi coli (Ames) ssy or in the in vivo rt micronucleus test. Menstrul cyclicity ws impired in femle cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the humn dose of cetuxim (sed on totl ody surfce re). Cetuxim-treted nimls exhiited incresed incidences of irregulr or sent cycles, s compred to control nimls. These effects were initilly noted eginning week 25 of cetuxim tretment nd continued through the 6-week recovery period. In this sme study, there were no effects of cetuxim tretment on mesured mle fertility prmeters (ie, serum testosterone levels nd nlysis of sperm counts, viility, nd motility) s compred to control mle monkeys. It is not known if cetuxim cn impir fertility in humns. Eritux (cetuxim) 13.2 Animl Phrmcology nd/or Toxicology In cynomolgus monkeys, cetuxim, when dministered t doses of pproximtely 0.4 to 4 times the weekly humn exposure (sed on totl ody surfce re), resulted in dermtologic findings, including inflmmtion t the injection site nd desqumtion of the externl integument. At the highest dose level, the epithelil mucos of the nsl pssge, esophgus, nd tongue were similrly ffected, nd degenertive chnges in the renl tuulr epithelium occurred. Deths due to sepsis were oserved in 50% (5/10) of the nimls t the highest dose level eginning fter pproximtely 13 weeks of tretment. 14 Clinicl Studies Studies 2 nd 4 were conducted outside the U.S. using n EU-pproved cetuxim s the clinicl tril mteril. Eritux provides pproximtely 22% higher exposure reltive to the EU-pproved cetuxim used in Studies 2 nd 4; these phrmcokinetic dt, together with the results of Studies 2, 4, nd other clinicl tril dt estlish the efficcy of Eritux t the recommended dose in SCCHN nd mcrc [see Clinicl Phrmcology (12.3)] Squmous Cell Crcinom of the Hed nd Neck (SCCHN) Study 1 ws rndomized, multicenter, controlled tril of 424 ptients with loclly or regionlly dvnced SCCHN. Ptients with Stge III/IV SCCHN of the orophrynx, hypophrynx, or lrynx with no prior therpy were rndomized (1:1) to receive either Eritux plus rdition therpy or rdition therpy lone. Strtifiction fctors were Krnofsky performnce sttus (60 80 versus ), nodl stge (N0 versus N+), tumor stge (T1 3 versus T4 using Americn Joint Committee on Cncer 1998 stging criteri), nd rdition therpy frctiontion (concomitnt oost versus once-dily versus twice-dily). Rdition therpy ws dministered for 6 7 weeks s once-dily, twice-dily, or concomitnt oost. Eritux ws dministered s 400 mg/m 2 initil dose eginning one week prior to initition of rdition therpy, followed y 250 mg/m 2 weekly dministered 1 hour prior to rdition therpy for the durtion of rdition therpy (6 7 weeks). Of the 424 rndomized ptients, the medin ge ws 57 yers, 80% were mle, 83% were Cucsin, nd 90% hd seline Krnofsky performnce sttus 80. There were 258 ptients enrolled in U.S. sites (61%). Sixty percent of ptients hd orophryngel, 25% lryngel, nd 15% hypophryngel primry tumors; 28% hd AJCC T4 tumor stge. Fifty-six percent of the ptients received rdition therpy with concomitnt oost, 26% received once-dily regimen, nd 18% twice-dily regimen. The min outcome mesure of this tril ws durtion of locoregionl control. Overll survivl ws lso ssessed. Results re presented in Tle 6. Tle 6: Study 1: Clinicl Efficcy in Locoregionlly Advnced SCCHN Eritux + Rdition (n=211) Rdition Alone (n=213) Hzrd Rtio (95% CI ) Strtified Log-rnk p-vlue Locoregionl Control Medin durtion (months) ( ) Overll Survivl Medin durtion (months) ( ) 0.03 CI = confidence intervl Study 2 ws n open-lel, rndomized, multicenter, controlled tril of 442 ptients with recurrent locoregionl disese or metsttic SCCHN. Ptients with no prior therpy for recurrent locoregionl disese or metsttic SCCHN were rndomized (1:1) to receive EU-pproved cetuxim plus cispltin or cropltin nd 5-FU, or cispltin or cropltin nd 5-FU lone. Choice of cispltin or cropltin ws t the discretion of the treting physicin. Strtifiction fctors were Krnofsky performnce sttus (<80 versus 80) nd previous chemotherpy. Cispltin (100 mg/m 2, Dy 1) or cropltin (AUC 5, Dy 1) plus intrvenous 5-FU (1000 mg/m 2 /dy, Dys ) were dministered every 3 weeks (1 cycle) for mximum of 6 cycles in the sence of disese progression or uncceptle toxicity. Cetuxim ws dministered t 400 mg/m 2 initil dose, followed y 250 mg/m 2 weekly dose in comintion with chemotherpy. Ptients demonstrting t lest stle disese on cetuxim in comintion with chemotherpy were to continue cetuxim monotherpy t 250 mg/m 2 weekly, in the sence of disese progression or uncceptle toxicity fter completion of 6 plnned courses of pltinum-sed therpy. For ptients where tretment ws delyed ecuse of the toxic effects of chemotherpy, weekly cetuxim ws continued. If chemotherpy ws discontinued for toxicity, cetuxim could e continued s monotherpy until disese progression or uncceptle toxicity. Of the 442 rndomized ptients, the medin ge ws 57 yers, 90% were mle, 98% were Cucsin, nd 88% hd seline Krnofsky performnce sttus 80. Thirty-four percent of ptients hd orophryngel, 25% lryngel, 20% orl cvity, nd 14% hypophryngel primry tumors. Fifty-three percent of ptients hd recurrent locoregionl disese only nd 47% hd metsttic disese. Fifty-eight percent hd AJCC Stge IV disese nd 21% hd Stge III disese. Sixty-four percent of ptients received cispltin therpy nd 34% received cropltin s initil therpy. Approximtely fifteen percent of the ptients in the cispltin lone rm switched to cropltin during the tretment period. The min outcome mesure of this tril ws overll survivl. Results re presented in Tle 7 nd Figure 1.

7 Eritux (cetuxim) Tle 7: Study 2: Clinicl Efficcy in Recurrent Locoregionl Disese or Metsttic SCCHN EU-Approved Cetuxim + Pltinum-sed Therpy + 5-FU (n=222) Pltinum-sed Therpy + 5-FU (n=220) Hzrd Rtio (95% CI ) Strtified Log-rnk p-vlue Overll Survivl Medin durtion (months) (0.64, 0.98) Progression-free Survivl Medin durtion (months) (0.46, 0.72) < EU-Approved Cetuxim + Pltinum-sed Therpy + 5-FU (n=222) Pltinum-sed Therpy + 5-FU (n=220) Odds Rtio CMH test (95% CI ) p-vlue Ojective Response Rte 35.6% 19.5% 2.33 (1.50, 3.60) CI = confidence intervl CMH = Cochrn-Mntel-Henszel Figure 1: Proportion Alive Kpln-Meier Curve for Overll Survivl in Ptients with Recurrent Locoregionl Disese or Metsttic Squmous Cell Crcinom of the Hed nd Neck CET+CT CT Time (months) Ptients t Risk CET+CT CT CT = Pltinum-sed therpy with 5-FU CET = EU-pproved cetuxim In explortory sugroup nlyses of Study 2 y initil pltinum therpy (cispltin or cropltin), for ptients (N=284) receiving cetuxim plus cispltin with 5-FU compred to cispltin with 5-FU lone, the difference in medin overll survivl ws 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in medin progression-free survivl ws 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The ojective response rte ws 39% nd 23%, respectively (OR 2.18; 95% CI 1.29, 3.69). For ptients (N=149) receiving cetuxim plus cropltin with 5-FU compred to cropltin with 5-FU lone, the difference in medin overll survivl ws 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in medin progression-free survivl ws 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The ojective response rte ws 30% nd 15%, respectively (OR 2.45; 95% CI 1.10, 5.46). Study 3 ws single-rm, multicenter clinicl tril in 103 ptients with recurrent or metsttic SCCHN. All ptients hd documented disese progression within 30 dys of pltinum-sed chemotherpy regimen. Ptients received 20-mg test dose of Eritux on Dy 1, followed y 400 mg/m 2 initil dose, nd 250 mg/m 2 weekly until disese progression or uncceptle toxicity. The medin ge ws 57 yers, 82% were mle, 100% Cucsin, nd 62% hd Krnofsky performnce sttus of 80. The ojective response rte ws 13% (95% confidence intervl 7% 21%). Medin durtion of response ws 5.8 months (rnge months) Colorectl Cncer Eritux Clinicl Trils in K-Rs Muttion-negtive (Wild-type), EGFR-expressing, Metsttic Colorectl Cncer Study 4 ws rndomized, open-lel, multicenter, study of 1217 ptients with EGFR-expressing, metsttic colorectl cncer. Ptients were rndomized (1:1) to receive either EU-pproved cetuxim in comintion with FOLFIRI or FOLFIRI lone s first-line tretment. Strtifiction fctors were Estern Coopertive Oncology Group (ECOG) performnce sttus (0 nd 1 versus 2) nd region (sites in Western Europe versus Estern Europe versus other). Eritux (cetuxim) FOLFIRI regimen included 14-dy cycles of irinotecn (180 mg/m 2 dministered intrvenously on Dy 1), folinic cid (400 mg/m 2 [rcemic] or 200 mg/m 2 [L-form] dministered intrvenously on Dy 1), nd 5-FU (400 mg/m 2 olus on Dy 1 followed y 2400 mg/m 2 s 46-hour continuous infusion). Cetuxim ws dministered s 400 mg/m 2 initil dose on Dy 1, Week 1, followed y 250 mg/m 2 weekly dministered 1 hour prior to chemotherpy. Study tretment continued until disese progression or uncceptle toxicity occurred. Of the 1217 rndomized ptients, the medin ge ws 61 yers, 60% were mle, 86% were Cucsin, nd 96% hd seline ECOG performnce sttus 0 1, 60% hd primry tumor loclized in colon, 84% hd 1 2 metsttic sites nd 20% hd received prior djuvnt nd/or neodjuvnt chemotherpy. Demogrphics nd seline chrcteristics were similr etween study rms. K-Rs muttion sttus ws ville for 1079/1217 (89%) of the ptients: 676 (63%) ptients hd K-Rs muttion-negtive (wild-type) tumors nd 403 (37%) ptients hd K-Rs muttion-positive tumors where testing ssessed for the following somtic muttions in codons 12 nd 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see Wrnings nd Precutions (5.8)]. Bseline chrcteristics nd demogrphics in the K-Rs muttion-negtive (wildtype) suset were similr to tht seen in the overll popultion [see Wrnings nd Precutions (5.8)]. The min outcome mesure of this tril ws progression-free survivl ssessed y n independent review committee (IRC). Overll survivl nd response rte were lso ssessed. A sttisticlly significnt improvement in PFS ws oserved for the cetuxim plus FOLFIRI rm compred with the FOLFIRI rm (medin PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-vlue=0.036). Overll survivl ws not significntly different t the plnned, finl nlysis sed on 838 events [HR=0.93, 95% CI (0.8, 1.1), p-vlue 0.327]. Results of the plnned PFS nd ORR nlysis in ll rndomized ptients nd post-hoc PFS nd ORR nlysis in sugroups of ptients defined y K-Rs muttion sttus, nd post-hoc nlysis of updted OS sed on dditionl follow-up (1000 events) in ll rndomized ptients nd in sugroups of ptients defined y K-Rs muttion sttus re presented in Tle 8 nd Figure 2. The tretment effect in the ll-rndomized popultion for PFS ws driven y tretment effects limited to ptients who hve K-Rs muttion-negtive (wild-type) tumors. There is no evidence of effectiveness in the sugroup of ptients with K-Rs muttion-positive tumors. Tle 8: Clinicl Efficcy in First-line EGFR-expressing, Metsttic Colorectl Cncer (All Rndomized nd K-Rs Sttus) K-Rs All Rndomized Muttion-negtive (Wild-type) K-Rs Muttion-positive EU- Approved Cetuxim plus FOLFIRI (N=608) FOLFIRI (n=609) EU- Approved Cetuxim plus FOLFIRI FOLFIRI (n=320) (n=356) EU- Approved Cetuxim plus FOLFIRI FOLFIRI (n=216) (n=187) Progression-Free Survivl Numer of Events (%) 343 (56) 371 (61) 165 (52) 214 (60) 138 (64) 112 (60) Medin (months) (95% CI) 8.9 (8.0, 9.4) 8.1 (7.6, 8.8) 9.5 (8.9, 11.1) 8.1 (7.4, 9.2) 7.5 (6.7, 8.7) 8.2 (7.4, 9.2) HR (95% CI) 0.85 (0.74, 0.99) 0.70 (0.57, 0.86) 1.13 (0.88, 1.46) p-vlue Overll Survivl Numer of Events (%) 491 (81) 509 (84) 244 (76) 292 (82) 189 (88) 159 (85) Medin (months) (95% CI) 19.6 (18, 21) 18.5 (17, 20) 23.5 (21, 26) 19.5 (17, 21) 16.0 (15, 18) 16.7 (15, 19) HR (95% CI) 0.88 (0.78, 1.0) 0.80 (0.67, 0.94) 1.04 (0.84, 1.29) Ojective Response Rte ORR (95% CI) 46% (42, 50) 38% (34, 42) 57% (51, 62) 39% (34, 44) 31% (25, 38) Bsed on the Strtified Log-rnk test. Post-hoc updted OS nlysis, results sed on n dditionl 162 events. 35% (28, 43)

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