HIGHLIGHTS OF PRESCRIBING INFORMATION
`¢—Hepatotoxicity with or without hepatic impairmentincluding hepatic
`These highlights do not includeall the information needed to use
`failure and hepatorenal syndrome: Monitor periodic liver testing.
`Withhold or discontinue TARCEVAfor severe or worseningliver tests.
`TARCEVA*safely and effectively. See full prescribing information for
`TARCEVA.
`(5.3)
`Gastrointestinal perforations: Discontinue TARCEVA. (5.4)
`Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5)
`Myocardial infarction (MIVischemia: The risk of MI is increased in
`patients with pancreatic cancer. (5.6)
`Cerebrovascular accident (CVA): The risk of CVA is increased in
`patients with pancreatic cancer. (5.7)
` Microangiopathic hemolytic anemia (MAHA): The risk of MAHAis
`increased in patients with pancreatic cancer, (5.8)
`Oculardisorders: Discontinue TARCEVAfor corneal perforation,
`TARCEVA is a kinase inhibitor indicated for:
`ulceration or persistent severe keratitis. (5.9)
`Hemorrhagein patients taking warfarin: Regularly monitor INR in
`e
`First-line treatment of patients with metastatic non-small cell lung
`patients taking warfarin or other coumarin-derivative anticoagulants.
`cancer (NSCLC) whose tumors have epidermal growth factor receptor
`(5.10)
`(EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as
`¢—Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`detected by an FDA-approvedtest. (1.1)
`reproductive potential of potential risk to the fetus and to use highly
`Maintenancetreatmentofpatients with locally advanced or metastatic
`*
`effective contraception. (5.11, 8.6)
`NSCLC whose disease has not progressed after four cycles of platinum-
`based first-line chemotherapy. (1.1)
`woreenerADVERSE REACTIONS-----------------------~--->~
`Treatmentof locally advanced or metastatic NSCLCafter failure of at
`least one prior chemotherapy regimen. (1.1)
`First-line treatment of patients with locally advanced, unresectable or
`metastatic pancreatic cancer, in combination with gemcitabine. (1.2)
`
`e
`
`*
`
`e
`
`TARCEVA(erlotinib) tablets, for oral use
`Initial U.S, Approval: 2004
`weenmeioRECENT MAJOR CHANGES---------------------------
`
`06/2016
`Dosage and Administration (2.1)
`05/2016
`Dosage and Administration, Dose Modifications (2.4)
`aoeenemanaminINDICATIONS AND USAGE.---~-----00eren-ernnneeeene
`
`°
`e
`e
`
`¢
`
`*
`
`¢
`
`°
`
`The most commonadverse reactions (= 20%) with TARCEVAfrom a
`pooled analysis of Studies 1-4 were rash, diarrhea, anorexia, fatigue,
`dyspnea, cough, nausea, and vomiting. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact OSI
`Limitations of Use:
`Pharmaceuticals, LLC, at 1-800-572-1932 or FDA at 1-800-FDA-1088 or
`¢
` TARCEVAis not recommended for use in combination with platinum-
`wwwfdagov/medwatch.
`based chemotherapy.
`weeneneneeenemnennmenmenaDRUG INTERACTIONS.-------------------------++
`«—Safety and efficacy of TARCEVAhavenot been evaluated asfirst-line
`treatmentin patients with metastatic NSCLC whose tumors have EGFR
`¢
`§=CYP3A4inhibitors or a combined CYP3A4 and CYP1A2 inhibitor
`mutations other than exon 19 deletions or exon 21 (L858R)substitution.
`increase erlotinib plasma concentrations. Avoid concomitant use.
`If not
`cateninennnnnDOSAGE AND ADMINISTRATION-+---0--------=----=
`possible, reduce TARCEVAdose(2.4, 7)
`CYP3A4 inducers decrease erlotinib plasma concentrations. Avoid
`concomitantuse. If not possible, increase TARCEVAdose (2.4, 7)
`Cigarette smoking and CYP! A2 inducers decrease erlotinib plasma
`concentrations, Avoid concomitant use. If not possible, increase
`TARCEVAdose (2.4, 7).
`Drugs that increase gastric pH decrease erlotinib plasma concentrations.
`For proton pumpinhibitors avoid concomitantuse if possible. For H-2
`receptor antagonists, take TARCEVA 10 hours after H-2 receptor
`antagonist dosing. For use with antacids, separate dosing by several
`hours (2.4, 7)
`
`NSCLC: 150 mgorally, on an empty stomach, once daily. (2.2)
`¢
`Pancreatic cancer: 100 mg orally, on an empty stomach, once daily. (2.3)
`¢
`woereanmnenaewnrnemeDOSAGE FORMS AND STRENGTHS------------------~-~
`
`.
`
`Tablets: 25 mg, 100 mg, and 150 mg. (3)
`cronnomeneeernanneneennCONTRAINDICATIONS.-------------22002022enernen=
`None. (4)
`.
`weeneenoneencernneernnnWARNINGSAND PRECAUTIONS-----------------------
`
`«
`
`e
`
`e
`
`¢
`
`Interstitial Lung Disease (ILD): Occurs in 1.1% ofpatients. Withhold
`TARCEVAfor acute onset of new or progressive unexplained
`pulmonary symptoms, such as dyspnea, cough and fever. Discontinue
`Nursing Mothers: Discontinue drug or nursing. (8.3)
`«
`TARCEVAif ILD is diagnosed. (5.1)
`See 17 for PATIENT COUNSELING INFORMATION.
`Renal Failure: Monitor renal function andelectrolytes, particularly in
`¢
`patients at risk of dehydration. Withhold TARCEVAforsevere renal
`Revised: 09/2016
`toxicity. (5.2)
`
`wetennneenonennnnnanUSE IN SPECIFIC POPULATIONS---------------------------
`
`2
`
`Unmewe
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1.1 Non-Smail Cell Lung Cancer (NSCLC)
`1.2
`Pancreatic Cancer
`DOSAGE AND ADMINISTRATION
`2.1
`Patient Selection
`2.2 Recommended Dose - NSCLC
`2.3 Recommended Dose — Pancreatic Cancer
`24 Dose Modifications
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Interstitial Lung Disease (ILD)
`5.2 Renal:Failure
`5.3 Hepatotoxicity with or without Hepatic Impairment
`5.4 Gastrointestinal Perforation
`5.5 Bullous and Exfoliative Skin Disorders
`5.6 Myocardial Infarction/Ischemia
`5.7 Cerebrovascular Accident
`5.8 Microangiopathic Hemolytic Anemia with Thrombocytopenia
`5.9 Ocular Disorders
`5.10 Hemorrhage in Patients Taking Warfarin
`5.11 Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`
`6
`
`7
`8
`
`6.1 Clinical Trial Experience
`6.2 Post-Marketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`84 Pediatric Use
`8.5 Geriatric Use
`8.6
`Females and Males of Reproductive Potential
`8.7 Patients with Hepatic Impairment
`8.8 Patients with Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13. NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment ofFertility
`14. CLINICAL STUDIES
`14.1 Non-Small Cell Lung Cancer (NSCLC)- First-Line Treatment of
`Patients with EGFR Mutations
`14.2 NSCLC — Maintenance Treatment
`14.3 NSCLC — Second/Third Line Treatment
`
`OSI EXHIBIT 2005
`APOTEXV. OSI
`IPR2016-01284
`
`1
`
`OSI EXHIBIT 2005
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`14.4 NSCLC - Lack of Efficacy of TARCEVA Administered
`Concurrently with Chemotherapy
`14.5 Pancreatic Cancer — TARCEVA Administered Concurrently with
`Gemcitabine
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted fromthe full prescribing information are not listed.
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`1.1. Non-Small Cell Lung Cancer (NSCLC)
`TARCEVA?®is indicatedfor:
`¢
`Thefirst-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor
`receptor (EGFR)exon 19 deletions or exon 21 (L858R)substitution mutations as detected by an FDA-approvedtest /see Clinical
`Studies (14.1)].
`¢ The maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not
`progressed after four cycles of platinum-basedfirst-line chemotherapy /see Clinical Studies (14.2)].
`e The treatment of patients with locally advanced or metastatic non-small cell lung cancerafter failure of at least one prior
`chemotherapy regimen /see Clinical Studies (14.3)].
`
`Limitations ofuse:
`¢
`TARCEVAis not recommended for use in combination with platinum-based chemotherapy /see Clinical Studies (14.4)].
`e
`Safety and efficacy of TARCEVAhave not been evaluatedasfirst-line treatment in patients with metastatic NSCLC whose tumors
`have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution /see Clinical Studies (14.1)].
`
`1.2
`
`Pancreatic Cancer
`
`TARCEVAin combination with gemcitabineis indicated for thefirst-line treatmentof patients with locally advanced, unresectable or
`metastatic pancreatic cancer /see Clinical Studies (14.5)).
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Patient Selection
`
`Select patients for thefirst-line treatment of metastatic NSCLC with TARCEVAbased on the presence of EGFR exon 19 deletionsor
`exon 21 (L858R) substitution mutations in tumor or plasma specimens/See Clinical Studies (14.1)]. If these mutationsare not detected
`in a plasmaspecimen,test tumortissue if available. Information on FDA-approvedtests for the detection of EGFR mutations in NSCLC
`is available at: http://www. fda.gov/CompanionDiagnostics.
`
`2.2 Recommended Dose — NSCLC
`
`The recommended daily dose of TARCEVAfor NSCLCis 150 mg taken on an empty stomach,i.e., at least one hour before or two
`hoursafter the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs,
`
`2.3. Recommended Dose ~ Pancreatic Cancer
`
`The recommended daily dose of TARCEVAfor pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take
`TARCEVAon an empty stomach,i.e., at least one hour before or two hoursafter the ingestion of food. Treatment should continueuntil
`disease progression or unacceptable toxicity occurs [see Clinical Studies (14.5)].
`
`2.4 Dose Modifications
`
`Discontinue TARCEVAfor:
`*
`Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)].
`Severe hepatic toxicity that does not improve significantly or resolve within three weeks [see Warnings and Precautions (3.3)].
`Gastrointestinal perforation /see Warnings and Precautions (3.4)].
`Severe bullous, blistering or exfoliating skin conditions [see Warnings and Precautions (5.5)].
`Corneal perforation or severe ulceration [see Warnings and Precautions(5.9)].
`
`Withhold TARCEVA:
`e
`During diagnostic evaluation for possible ILD.
`e
`For severe (CTCAEgrade3 to 4) renal toxicity, and consider discontinuation of TARCEVA [see Warnings and Precautions (5.2)].
`®
`In patients without pre-existing hepatic impairmentfortotal bilirubin levels greater than 3 times the upper limit of normalor
`transaminasesgreater than 5 times the upper limit of normal, and consider discontinuation of TARCEVA /see Warnings and
`Precautions (5.3)].
`Inpatients with pre-existing hepatic impairmentorbiliary obstruction for doubling ofbilirubin ortripling of transaminases values
`over baseline and consider discontinuation of TARCEVA [see Warnings and Precautions (5.3)].
`For persistent severe diarrhea not responsive to medical management (e.g., loperamide).
`For severe rash not responsive to medical management.
`For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks /see Warnings and Precautions (5.9)].
`For acute/worsening oculardisorders such as eye pain, and consider discontinuation of TARCEVA [see Warnings and Precautions
`(6.9)].
`
`*
`
`3
`
`

`

`*
`
`Ifsevere reactions occur with concomitant use of strong CYP3A4 inhibitors or with a combined CYP3A4 and CYP1A2 inhibitor.
`Avoid concomitant use if possible /see Drug Interactions (7)].
`e Whenrestarting therapy following withholding treatmentfor a dose-limiting toxicity that has resolved to baseline or grade < 1.
`
` Reduce TARCEVAby 50 mg decrements:
`
`Increase TARCEVAby 50 mg increments as tolerated for:
`¢ Concomitant use with CYP3A4 inducers. Increase doses by 50 mg increments at 2-weekintervals to a maximum of 450 mg. Avoid
`concomitant use, if possible /see Drug Interactions (7)].
`¢ Concurrent cigarette smoking or concomitant use of moderate CYP1A2 inducers. Increase by 50 mg increments at 2-week intervals
`to a maximumof 300 mg. Immediately reduce the dose of TARCEVAto the recommended dose (150 mg or 100 mg daily) upon
`cessation of smoking {see Drug Interactions (7) and Clinical Pharmacology (1 2.3)].
`
`e
`
`Drugs that Increase Gastric pH
`« Avoid concomitant use of TARCEVA with proton pumpinhibitors if possible. Separation of doses may not eliminate the interaction
`since proton pump inhibitors affect the pH of the upper GI tract for an extended period.
`Iftreatment with an H-2 receptor antagonist suchas ranitidine is required, TARCEVA mustbe taken 10 hoursafter the H-2 receptor
`antagonist dosing andat least 2 hours before the next dose of the H-2 receptor antagonist,
`¢ Althoughthe effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the TARCEVA dose
`should be separated by several hours,if an antacid is necessary.
`
`DOSAGE FORMSAND STRENGTHS
`
`25 mgtablets
`White film-coatedtablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange
`with a “T” and “25” on one side and plain on the otherside.
`
`100 mg tablets
`White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with
`“T” and “100” on one side and plain on the otherside.
`
`150 mgtablets
`White film-coated tablets for daily oral administration. Round, biconvex face andstraight sides, white film-coated, printed in maroon
`with “T” and “150” on one side and plain on the otherside.
`
`CONTRAINDICATIONS
`
`None
`
`WARNINGS AND PRECAUTIONS
`
`Interstitial Lung Disease (ILD)
`Cases ofserious ILD, including fatal cases, can occur with TARCEVAtreatment. The overall incidence of ILD in approximately 32,000
`TARCEVA-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with
`ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating TARCEVAtherapy.
`
`Withhold TARCEVAforacute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever
`pendingdiagnostic evaluation. If ILD is confirmed, permanently discontinue TARCEVA [see Dosage and Administration (2.4)].
`
`Renal Failure
`
`Hepatorenal syndrome,severe acute renalfailure including fatal cases, and renal insufficiency can occur with TARCEVAtreatment.
`Renal failure may arise from exacerbation of underlying baseline hepatic impairmentor severe dehydration. The pooled incidence of
`severe renal impairmentin the 3 monotherapy lung cancer studies was 0.5% in the TARCEVAarmsand 0.8% in the control arms. The
`incidence of renal impairment in the pancreatic cancer study was 1.4% in the TARCEVAplus gemcitabine arm and 0.4% in the control
`arm, Withhold TARCEVAin patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring
`of renal function and serumelectrolytes during TARCEVAtreatment /see Adverse Reactions (6.1) and Dosage and Administration
`(2.4)].
`
`5.3
`
`Hepatotoxicity with or without Hepatic Impairment
`Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVAtreatmentin patients with normal hepatic
`function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with
`moderate to severe hepatic impairment were excluded, the pooled incidenceof hepatic failure in the 3 monotherapy lung cancer studies
`was 0.4% in the TARCEVA armsand 0% inthe control arms. The incidence ofhepatic failure in the pancreatic cancer study was 0.4%
`in the TARCEVAplus gemcitabine arm and 0.4% in the control arm, In a pharmacokinetic study in 15 patients with moderate hepatic
`impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 daysofthe last
`TARCEVAdose. One patient died from hepatorenal syndrome, | patient died from rapidly progressingliver failure and the remaining 8
`patients died from progressive disease, Six out of the 10 patients who died hadbaseline total bilirubin > 3 x ULN.
`
`4
`
`

`

`Perform periodic liver testing (transaminases,bilirubin, and alkaline phosphatase) during treatment with TARCEVA.Increased
`frequency of monitoring ofliver function is required for patients with pre-existing hepatic impairmentor biliary obstruction. Withhold
`TARCEVA in patients without pre-existing hepatic impairmentfor total bilirubin levels greater than 3 times the upper limit of normal or
`transaminasesgreater than 5 times the upper limit of normal. Withhold TARCEVAin patients with pre-existing hepatic impairment or
`biliary obstruction for doubling ofbilirubin ortripling of transaminases values over baseline. Discontinue TARCEVAin patients whose
`abnormalliver tests meeting the abovecriteria do not improve significantly or resolve within three weeks /see Dosage and
`Administration (2.4) and Clinical Pharmacology (12.3)].
`
`5.4
`
`Gastrointestinal Perforation
`
`Gastrointestinal perforation, including fatal cases, can occur with TARCEVAtreatment. Patients receiving concomitant anti-angiogenic
`agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease
`maybeat increasedrisk of perforation /see Adverse Reactions(6.1, 6.2)]. The pooled incidence of gastrointestinal perforation in the 3
`monotherapy lung cancer studies was 0.2% in the TARCEVA armsand 0.1% in the contro! arms. The incidence of gastrointestinal
`perforation in the pancreatic cancer study was 0.4% in the TARCEVAplus gemcitabine arm and 0% in the control arm, Permanently
`discontinue TARCEVAin patients who develop gastrointestinal perforation /see Dosage and Administration (2.4)].
`
`5.5
`
`Bullous and Exfoliative Skin Disorders
`
`Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis,
`which in somecases were fatal, can occur with TARCEVAtreatment /see Adverse Reactions (6.1, 6.2)]. The pooled incidence of
`bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the TARCEVAarms and 0% in the control
`arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the TARCEVAplus
`gemcitabine arm and 0% in the control arm. Discontinue TARCEVAtreatmentif the patient develops severe bullous, blistering or
`exfoliating conditions /see Dosage and Administration (2.4)].
`
`5.6
`
`Myocardial Infarction/Ischemia
`
`In the pancreatic carcinomatrial, six patients (incidence of 2.1%) in the TARCEVA/gemcitabine group developed myocardial
`infarction/ischemia. Oneof these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group
`developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial
`infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the TARCEVA armsand 0.4% in the control arms.
`
`5.7
`
`Cerebrovascular Accident
`
`In the pancreatic carcinomatrial, seven patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence:
`2.5%). One of these was hemorrhagic and wastheonly fatal event. In comparison,in the placebo/gemcitabine group there were no
`cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the
`TARCEVAarmsand 0.9% in the control arms.
`
`5.8
`
`Microangiopathic Hemolytic Anemia with Thrombocytopenia
`The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancerstudies was 0%
`in the TARCEVAarmsand 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in
`the pancreatic cancer study was 1.4% in the TARCEVAplus gemcitabine arm and 0% in the control arm,
`
`Ocular Disorders
`
`Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with TARCEVAtreatment and
`can lead to corneal perforation or ulceration [see Adverse Reactions (6.1) and (6.2)]. The pooled incidenceof ocular disorders in the 3
`monotherapy lung cancerstudies was 17.8% in the TARCEVAarmsand 4% in the control arms. The incidence of ocular disorders in
`the pancreatic cancer study was 12.8% in the TARCEVAplus gemcitabine arm and 11.4% in the control arm.Interrupt or discontinue
`TARCEVAtherapyif patients present with acute or worsening ocular disorders such as eye pain {see Dosage and Administration (2.4)].
`
`5.10
`
`Hemorrhagein Patients Taking Warfarin
`
`Severe and fatal hemorrhage associated with International Normalized Ratio (INR)elevations can occur when TARCEVAandwarfarin
`are administered concurrently. Regularly monitor prothrombin time and INR during TARCEVAtreatmentin patients taking warfarin or
`other coumarin-derivative anticoagulants [see Adverse Reactions (6.1) and Drug Interactions (7)).
`
`Embryo-Fetal Toxicity
`
`Based on its mechanism of action, TARCEVAcan cause fetal harm when administered to a pregnant woman. When given during
`organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the
`recommended human daily dose of 150 mg. If TARCEVAis used during pregnancy,orif the patient becomes pregnant while taking
`this drug, the patient should be apprised of the potential hazard to a fetus /see Use in Specific Populations (8.1)],
`
`Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeksafter the last dose
`of TARCEVA.Advisepatients to contact their healthcare providerif they become pregnant,or if pregnancy is suspected, while taking
`TARCEVA[see Use in Specific Populations (8.1) and (8.6)].
`
`ADVERSE REACTIONS
`
`5
`
`

`

`The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sectionsof the labeling:
`Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]
`Renal Failure /see Warnings and Precautions (3.2)]
`Hepatotoxicity with or without Hepatic Impairment /see Warnings and Precautions (5.3)]
`Gastrointestinal Perforation /see Warnings and Precautions (5.4)]
`Bullous and Exfoliative Skin Disorders /see Warnings and Precautions (3.5)]
`Myocardial Infarction/Ischemia /see Warnings and Precautions (5.6)]
`Cerebrovascular Accident /see Warnings and Precautions (5.7)]
`Microangiopathic Hemolytic Anemia with Thrombocytopenia /see Warnings and Precautions (5,8)]
`Ocular Disorders [see Warnings and Precautions (5.9)]
`Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.10)]
`
`oeoesee#e#ee#e#sesee?e¢@¢#
`
`6.1
`
`Clinical Trial Experience
`
`Because clinicaltrials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug
`cannotbe directly comparedto rates in the clinical trials of another drug and maynotreflect the rates observed in practice.
`
`Safety evaluation of TARCEVAis based on more than 1200 cancer patients who received TARCEVAas monotherapy, more than 300
`patients who received TARCEVA100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVAconcurrently with other
`chemotherapies. The most commonadverse reactions with TARCEVAare rash and diarrhea usually with onset during the first month of
`treatment. The incidences of rash and diarrhea from clinical studies of TARCEVAfor the treatment of NSCLC and pancreatic cancer
`were 70% for rash and 42% for diarrhea.
`
`Non-Small Cell Lung Cancer
`
`First-Line Treatment ofPatients with EGFR Mutations
`
`The most frequent ( 30%) adverse reactions in TARCEVA-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased
`appetite. In TARCEVA-treated patients the median time to onset of rash was 15 days and the mediantime to onset of diarrhea was 32
`days,
`
`The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients were rash and diarrhea.
`
`Doseinterruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA-
`treated patients discontinued therapy due to adverse reactions. In TARCEVA-treated patients, the most frequently reported adverse
`reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).
`
`Selected, commonadverse reactionsin Study 4, occurring in at least 10% of patients who received TARCEVAor chemotherapy and an
`increase in > 5% in the TARCEVA-treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of
`TARCEVAtreatment was 9.6 months in Study 4.
`
`6
`
`

`

`Study 4
`
`
`
` QorooToOoSojS|Oo
`
`Arthralgia
`
`Musculoskeletal pain
`
`13
`
`li
`
`o
`
`
`
`Platinum-based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel)
`* Rash as a composite term includes: rash, acne,folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia
`syndrome, exfoliative rash, rash erythematous,rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.
`
`Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4
`liver test abnormalities in Study 4 [see Warnings and Precautions (5.3)].
`
`Maintenance Treatment
`
`Adversereactions, regardless of causality, that occurred in at least 3% ofpatients treated with single-agent TARCEVAat 150 mg and at
`least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0)
`Grade in Table 2.
`
`The most commonadverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3-4 rash and
`diarrhea occurred in 9% and 2%,respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1%
`and 0.5% of TARCEVA-treated patients, respectively. Dose reductionor interruption for rash and diarrhea was needed in 5% and 3% of
`patients, respectively. In TARCEVA-treated patients the median time to onset of rash was 10 days, and the median time to onset of
`diarrhea was 15 days.
`
`N = 433
`
`
`Table 2: NSCLC Maintenance Study: Selected Adverse Reactions Occurring with an Incidence Rate 2 10%and an Increase of
`> 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study3)
`
`TARCEVA
`PLACEBO
`
`N = 445
`
`
`
`NCI-CTC Grade Any Grade|Grade3|Grade4|Any Grade|Grade3|Grade4
`
`MedDRAPreferred Term
`~
`%
`%
`%
`
`
`
`
`
`Rash
`60
`9
`0
`
`
`Diarrhea
`
`
`220 0
`t Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin
`exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, skin hyperpigmentation,
`skin reaction, skin ulcer.
`
`Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% ofTARCEVA-treated patients
`and 1% ofplacebo-treated patients. Grade 2 and abovebilirubin elevations were observed in 5% of TARCEVA-treated patients and in
`< 1% in the placebo group /see Dosage and Administration (2.4) and Warnings and Precautions (5.3)].
`
`—
`
`Table 1: Selected Adverse Reactions with an Incidence Rate > 10% and an Increase of > 5% in the TARCEVA-treated Group
`
`Chemotherapy
`TARCEVA
`N = 83
`N = 84
`
`All Grades
`Grades 3-4
`All Grades
`Grades 3-4
`
`%
`%
`%
`MedDRA Preferred Term
`
`Rash?
`85
`14
`5
`
`Diarrhea
`62
`5
`21
`
`Cough
`48
`]
`40
`
`
`45
`Dyspnea
`
`Dry skin
`21
`
`
`Back pain 19
`
`Chest pain 18
`
`Conjunctivitis 18
`Mucosalinflammation
`18
`
`Pruritus
`16
`
`
`
`Paronychia 14
`
`7
`
`

`

`Second/Third Line Treatment
`
`Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVAat 150 mg and
`at least 5% more often than in the placebo group in the randomizedtrial of patients with NSCLC are summarized by NCI-CTC (version
`2,0) Grade in Table 3.
`
`The most common adverse reactionsin this patient population were rash and diarrhea, Grade 3-4 rash and diarrhea occurred in 9% and
`6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated
`patients, Six percent and 1% ofpatients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was
`8 days, and the median time to onset of diarrhea was 12 days.
`
`Table 3: NSCLC 2"4/3™ Line Study: Selected Adverse Reactions Occurring with an Incidence Rate = 10% and an Increase of
`> 5% in the Single-Agent TARCEVA Group compared to the Placebo Group
`(Study
`1
`TARCEVA150 mg
`Placebo
`N=485
`N=242
`
`
`
`NCI-CTC Grade Any Grade|Grade3|Grade4|Any Grade|Grade3|Graded
`
`MedDRA Preferred Term
`
`
`Diarrhea
`Anorexia
`
`Nausea
`Infection
`
`Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome,acne, skin disorder, pigmentation disorder, erythema,
`skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.
`
`Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin)
`were observedin patients receiving single-agent TARCEVA 150 mg. These elevations were mainly transient or associated with liver
`metastases. Grade 2 (> 2.5 — 5.0 x ULN) ALTelevations occurred in 4% and < 1% of TARCEVAandplacebo-treated patients,
`respectively, Grade 3 (> 5.0 ~ 20.0 x ULN)elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be
`interrupted or discontinued if changesin liver function are severe [see Dosage and Administration (2.4)].
`
`Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine
`
`This was a randomized, double-blind placebo-controlled study of TARCEVA(150 mg or 100 mgdaily) or placebo plus gemcitabine
`(1000 mg/m? IV)in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2), The safety population
`comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo
`group (256 in the 100 mg cohort and 24 in the 150 mg cohort).
`
`Adverse reactions that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomizedtrial of
`patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4.
`
`The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine werefatigue, rash,
`nausea, anorexia and diarrhea. In the TARCEVAplus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of
`patients. The median timeto onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose
`reductionsin 2% ofpatients, and resulted in study discontinuation in up to 1% ofpatients receiving TARCEVAplus gemcitabine,
`Severe adverse reactions (> Grade 3 NCI-CTC) in the TARCEVAplus gemcitabine group with incidences < 5% included syncope,
`arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial
`infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency /see Warnings and Precautions
`(S)].
`
`The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more
`frequent dose reduction or interruption.
`
`8
`
`

`

`Table 4: Selected Adverse Reactions Occurring with an Incidence Rate > 10% and an Increase of = 5%in TARCEVA-treated
`Pancreatic Cancer Patients: 100 mg cohort
`(Study
`2
`TARCEVA+ Gemcitabine
`
`
`
`
`
`1000 mg/m? IV
`N=259
`
` Placebo + Gemcitabine
`
`1000 mg/m’ IV
`
`
`
` Infection
`
`
`
`
` %% %
`%
`%
`%
`MedDRA Preferred Term
`70
`Rash?
`0
`30
`1
`
`“ 5
`
`
`
`48
`
`39
`
`2
`
`39
`
`1
`
`3
`
`3
`
`36 ef 30
`Pyrexia
`3
`somanesa
`Daven
`Cough
`16
`0
`
`30
`
`ll
`
`9
`
`0
`
`“Includes all MedDRA preferred termsin the Infections and Infestations System Organ Class
`* Rash asa composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, pigmentation disorder, dermatitis acneiform,folliculitis,
`photosensitivity reaction, Stevens-Johnson syndrome,urticaria, erythematous rash, skin disorder, skin ulcer,
`
`Ten patients (4%) in the TARCEVA/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep
`venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for TARCEVA
`plus gemcitabine and 9% for placebo plus gemcitabine.
`
`The incidences ofliver test abnormalities (= Grade 2) in Study 2 are provided in Table 5 [see Dosage and Administration (2.4) and
`Warnings and Precautions (5.3)].
`
`
`Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 2)
`TARCEVA+ Gemcitabine
`Placebo + Gemcitabine
`
`
`
`
`1000 mg/m’ IV
`N=259
`
`1000 mg/m? IV
`N=256
`
`
`
`
`
`NCI-CTC
`
`Grade
`
`
`
`Grade 2 Grade3|Grade4|Grade2 Grade 3
`
` Grade 4
`
`AST
`
`
`
`24%
`
`10%
`
`<1%
`
`19%
`
`9%
`
`NSCLCand Pancreatic Indications: Selected Low Frequency Adverse Reactions
`Gastrointestinal Disorders
`Cases ofgastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID
`administration /see Warnings and Precautions (5.10