ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:oInterstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]oRenal Failure [see Warnings and Precautions (5.2)]oHepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3)]oGastrointestinal Perforation [see Warnings and Precautions (5.4)]oBullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5)]oCerebrovascular Accident [see Warnings and Precautions (5.6)]oMicroangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7)]oOcular Disorders [see Warnings and Precautions (5.8)]oHemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9)]. oInterstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]. oRenal Failure [see Warnings and Precautions (5.2)]. oHepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3)]. oGastrointestinal Perforation [see Warnings and Precautions (5.4)]. oBullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5)]. oCerebrovascular Accident [see Warnings and Precautions (5.6)]. oMicroangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7)]. oOcular Disorders [see Warnings and Precautions (5.8)]. oHemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9)]. The most common adverse reactions (>= 20%) with TARCEVA from pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals, LLC, at 1-800-572-1932 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. The most common adverse reactions with TARCEVA are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of TARCEVA for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea.Non-Small Cell Lung CancerFirst-Line Treatment of Patients with EGFR MutationsThe 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 median time to onset of diarrhea was 32 days.The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients were rash and diarrhea.Dose interruptions 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%).Common adverse reactions in Study 1, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in >= 5% in the TARCEVA-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of TARCEVA treatment was 9.6 months in Study 1.Table 1: Adverse Reactions with an Incidence Rate >= 10% and an Increase of >= 5% in the TARCEVA-Treated Group (Study 1)TARCEVAN 84ChemotherapyPlatinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).N 83Adverse ReactionAll Grades%Grades 3-4%All Grades%Grades 3-4% Rash Rash as composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer. 851450 Diarrhea 625211 Cough 481400 Dyspnea458304 Dry skin 21120 Back pain 19250 Chest pain 181120 Conjunctivitis18000 Mucosal inflammation 18160 Pruritus 16010 Paronychia14000 Arthralgia 13161 Musculoskeletal pain11110Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study [see Warnings and Precautions (5.3)]. Maintenance Treatment Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTCAE v3.0 Grade in Table 2.The most common adverse 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 reduction or 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.Table 2: NSCLC Maintenance Study: 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 3)Adverse ReactionTARCEVAN 433PLACEBON 445Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4%%%%%%Rash Rash as composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer. 6090900Diarrhea2020400Liver test abnormalities including ALT elevations were observed at Grade or greater severity in 3% of TARCEVA-treated patients and 1% of placebo-treated patients. Grade and above bilirubin 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)].Second/Third Line TreatmentAdverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC v2.0 Grade in Table 3.The most common adverse reactions in 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% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was days, and the median time to onset of diarrhea was 12 days.Table 3: NSCLC 2nd/3rd Line Study: 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 4)Adverse ReactionTARCEVA 150 mgN=485PlaceboN=242Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4%%%%%%Rash Rash as composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation. 758<11700Diarrhea546<118<10Anorexia5281385<1Fatigue5214445164Dyspnea411711351511Nausea33302420Infection24401520Stomatitis17<10300Pruritus13<10500Dry skin1200400Conjunctivitis12<102<10Keratoconjunctivitis sicca1200300Liver function test abnormalities [including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were observed in patients receiving single-agent TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade [> 2.5 5.0 upper limit of normal (ULN)] ALT elevations occurred in 4% and 1% of TARCEVA and placebo treated patients, respectively. Grade (> 5.0 20.0 ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.4)].Pancreatic Cancer TARCEVA Administered Concurrently with GemcitabineThis was randomized, double-blind, placebo-controlled study of TARCEVA (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m2 by intravenous infusion) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 5). 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 randomized trial of patients with pancreatic cancer (Study 5) were graded according to NCI-CTC v2.0 in Table 4.The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus gemcitabine. Severe adverse reactions (>= Grade NCI-CTC) in the TARCEVA plus 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 (5)].The 150 mg cohort was associated with higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.Table 4: Adverse Reactions Occurring with an Incidence Rate >= 10% and an Increase of >= 5% in TARCEVA-Treated Pancreatic Cancer Patients: 100 mg Cohort (Study 5)Adverse ReactionTARCEVA Gemcitabine1000 mg/m2 IVN=259Placebo Gemcitabine1000 mg/m2 IVN=256Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4%%%%%%Rash Rash as composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, pigmentation disorder, acneiform dermatitis, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer. 70503010Diarrhea485<13620Decreased weight392029<10Infection Infections as composite term include infections with unspecified pathogens as well as bacterial (including chlamydial, rickettsial, mycobacterial and mycoplasmal), parasitic (including helminthic, ectoparasitic and protozoal), viral and fungal infectious disorders. 391333092Pyrexia36303040Stomatitis22<101200Depression192014<10Cough16001100Headache15<101000Ten 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 or thrombotic events, including deep venous thrombosis was 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine. The incidences of liver test abnormalities (>= Grade 2) in Study are provided in Table [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 5)TARCEVA Gemcitabine1000 mg/m2 IVN=259Placebo Gemcitabine1000 mg/m2 IVN=256Grade 2Grade 3Grade 4Grade 2Grade 3Grade 4Bilirubin17%10%<1%11%10%3%ALT31%13%<1%22%9%0%AST24%10%<1%19%9%0%NSCLC and Pancreatic Indications: Selected Low Frequency Adverse ReactionsGastrointestinal DisordersCases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration [see Warnings and Precautions (5.9) and Drug Interactions (7)]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post approval use of TARCEVA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapyEye Disorders: ocular inflammation including uveitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized. 12.3 Pharmacokinetics AbsorptionErlotinib is about 60% absorbed after oral administration. Peak plasma levels occur hours after dosing. Effect of FoodFood increased the bioavailability of erlotinib to approximately 100%. Distribution:Erlotinib is 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters. EliminationErlotinib is eliminated with median half-life of 36.2 hours in patients receiving the single-agent TARCEVA 2nd/3rd line regimen. Time to reach steady state plasma concentration would therefore be 7-8 days. MetabolismErlotinib is metabolized primarily by CYP3A4 and to lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1, in vitro.ExcretionFollowing 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).Specific PopulationsNeither age, body weight, nor gender had clinically significant effect on the systemic exposure of erlotinib in NSCLC patients receiving single-agent TARCEVA for 2nd/3rd line treatment or for maintenance treatment, and in pancreatic cancer patients who received erlotinib plus gemcitabine. The pharmacokinetics of TARCEVA in patients with compromised renal function is unknown.Patients with Hepatic ImpairmentIn vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.Patients That Smoke Tobacco CigarettesIn single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) increased erlotinib clearance and decreased erlotinib AUC0-inf by 64% (95% CI, 46-76%) in current smokers compared with former/never smokers. In NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by 24% increase in apparent erlotinib plasma clearance. In another study which was conducted in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated dose-proportional increase in erlotinib exposure when the TARCEVA dose was increased from 150 mg to 300 mg. [see Dosage and Administration (2.4), Drug Interactions (7) and Patient Counseling Information (17)].Drug Interaction StudiesCo-administration of gemcitabine had no effect on erlotinib plasma clearance. CYP3A4 InhibitorsCo-administration with strong CYP3A4 inhibitor, ketoconazole, increased erlotinib AUC by 67%. Co-administration with combined CYP3A4 and CYP1A2 inhibitor, ciprofloxacin, increased erlotinib exposure [AUC] by 39%, and increased erlotinib maximum concentration [Cmax] by 17%. [see Dose Modifications (2.4), Drug Interactions (7)].CYP3A4 InducersPre-treatment with the CYP3A4 inducer rifampicin, for 7-11 days prior to TARCEVA, decreased erlotinib AUC by 58% to 80% [see Dose Modifications (2.4), Drug Interactions (7)].CYP1A2 Inducers or Smoking TobaccoSee Specific Populations Section [see Dose Modifications (2.4), Drug Interactions (7)].Drugs that Increase Gastric pHErlotinib solubility is pH dependent and decreases as pH increases. When proton pump inhibitor (omeprazole) was co-administered with TARCEVA the erlotinib exposure [AUC] was decreased by 46% and the erlotinib maximum concentration [Cmax] was decreased by 61%. When TARCEVA was administered hours following 300 mg dose of an H-2 receptor antagonist (ranitidine), the erlotinib AUC was reduced by 33% and the erlotinib Cmax was reduced by 54%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 after the previous ranitidine evening dose and h before the ranitidine morning dose), the erlotinib AUC was decreased by 15% and the erlotinib Cmax was decreased by 17% [see Dose Modifications (2.4), Drug Interactions (7)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) First-Line Treatment of Patients with EGFR Mutations Study 1The safety and efficacy of TARCEVA as monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in Study 1, randomized, open-label, clinical trial conducted in Europe. One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n 86) or four cycles of standard platinum-based doublet chemotherapy (n 88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. vs. 2). EGFR mutation status for screening and enrollment of patients was determined by clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, cobas(R) EGFR Mutation Test. Baseline demographics of the overall study population were: female (72%), White (99%), age >= 65 years (51%), ECOG PS (53%), with ECOG PS (33%), and ECOG PS (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% Stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition), 93% adenocarcinoma, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by CTA.A statistically significant improvement in investigator-determined PFS (based on RECIST 1.0 or clinical progression) was demonstrated for patients randomized to erlotinib compared to those randomized to chemotherapy (see Table and Figure 1). Similar results for PFS (based on RECIST 1.0) were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients evaluated in Study 1) and in the subgroup of 134 patients (77% of Study population) with EGFR mutations confirmed by the cobas(R) EGFR Mutation Test. protocol-specified analysis of overall survival (OS) conducted at the time of the final analysis of PFS showed no statistically significant difference between the TARCEVA and chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR-tyrosine kinase inhibitor. In the TARCEVA arm, 66% of patients had received at least one subsequent treatment.Table 6: Efficacy Results (Study 1) Efficacy Parameter Erlotinib(N 86)Chemotherapy(N 88)Progression-Free Survival Number of Progressions or Deaths71 (83%)63 (72%) Median PFS in Months (95% CI) 10.4 (8.7, 12.9)5.2 (4.6, 6.0) Hazard Ratio (95% CI) Unstratified Cox regression model. 0.34 (0.23, 0.49) p-value (unstratified log-rank test)< 0.001Overall Survival Number of Deaths (%)55 (64%)54 (61%) Median OS in Months (95% CI) 22.9 (17.0, 26.8)19.5 (17.3, 28.4) Hazard Ratio (95% CI) 0.93 (0.64, 1.35)Objective Response Objective Response Rate (95% CI)65% (54.1%, 75.1%)16% (9.0%, 25.3%)Figure 1: Kaplan-Meier Curves of Investigator-Assessed PFS in Study In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup.. Figure 1: Kaplan-Meier Curves of Investigator-Assessed PFS in Study 1. 14.2 NSCLC Lack of Efficacy of TARCEVA in Maintenance Treatment of Patients without EGFR Mutations. Lack of efficacy of TARCEVA for the maintenance treatment of patients with NSCLC without EGFR activating mutations was demonstrated in Study 2. Study was multicenter, placebo-controlled, randomized trial of 643 patients with advanced NSCLC without an EGFR exon 19 deletion or exon 21 L858R mutation who had not experienced disease progression after four cycles of platinum-based chemotherapy. Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally once daily (322 TARCEVA, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. Baseline characteristics were as follows: median age 61 years (35% age >= 65 years), 75% male, 77% White, 21% Asian, 28% ECOG PS 0, 72% ECOG PS 1, 16% never smokers, 58% current smokers, 57% adenocarcinoma, 35% squamous cell carcinoma, 22% stage IIIB disease not amenable to combined modality treatment, and 78% stage IV disease. Fifty percent of patients randomized to TARCEVA entered the open-label phase and received chemotherapy, while 77% of patients randomized to placebo entered the open-label phase and received TARCEVA. The main efficacy outcome was overall survival (OS). Median OS was 9.7 months in the TARCEVA arm and 9.5 months in the placebo arm; the hazard ratio for OS was 1.02 (95% CI 0.85, 1.22). Median PFS was 3.0 months in the TARCEVA arm and 2.8 months in the placebo arm; the hazard ratio for PFS was 0.94 (95% CI 0.80, 1.11).. 14.3 NSCLC Maintenance Treatment or Second/Third Line Treatment. Two randomized, double-blind, placebo-controlled trials, Studies and 4, examined the efficacy and safety of TARCEVA administered to patients with metastatic NSCLC as maintenance therapy after initial treatment with chemotherapy (Study 3) or with disease progression following initial treatment with chemotherapy (Study 4). Determination of EGFR mutation status was not required for enrollment. Study 3The efficacy and safety of TARCEVA as maintenance treatment of NSCLC were demonstrated in Study 3, randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy. Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally once daily (438 TARCEVA, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of TARCEVA after standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression-free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors. Baseline demographics of the overall study population were as follows: male (74%), age 65 years (66%), ECOG PS (69%), ECOG PS (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%).Table 7: Efficacy Results (Study 3): (ITT Population)Patients with PD prior to randomization were excluded from PFS and TTP analysis. Efficacy ParameterTARCEVA(N 438)Placebo(N 451)Progression-Free Survival (PFS) based on investigator assessment Number of Progression or Deaths (%)349 (80%)400 (89%) Median PFS in Months (95% CI) 2.8 (2.8, 3.1)2.6 (1.9, 2.7) Hazard Ratio (95% CI) Univariate Cox regression model. 0.71 (0.62, 0.82) p-value (stratified log-rank test) Unstratified log-rank test. < 0.0001Overall Survival (OS) Number of Deaths298 (68%)350 (78%) Median OS in Months (95% CI)12.0 (10.6, 13.9)11.0 (9.9, 12.1) Hazard Ratio (95% CI) 0.81 (0.70, 0.95) p-value (stratified log-rank test) 0.0088Figure depicts the Kaplan-Meier Curves for Overall Survival (ITT Population).Figure 2: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study Note: HR is from univariate Cox regression model.Study 4The efficacy and safety of single-agent TARCEVA was assessed in Study 4, randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomized 2:1 to receive TARCEVA 150 mg or placebo (488 TARCEVA, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Efficacy outcome measures included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries. Baseline demographics of the overall study population were as follows: male (65%), White (78%), Asian (12%), Black (4%), age 65 years (62%), ECOG PS (53%), ECOG PS (13%), ECOG PS (25%), ECOG PS (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%).The results of the study are shown in Table 8. Table 8: Efficacy Results (Study 4)Efficacy ParameterTARCEVA(N 488)Placebo(N 243)Overall Survival (OS) Number of Deaths378 (77%)209 (86%) Median OS in Months (95% CI) 6.7 (5.5, 7.8)4.7 (4.1, 6.3) Hazard Ratio (95% CI) Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. 0.73 (0.61, 0.86) p-value (stratified log-rank test) Two-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. < 0.001Progression-Free Survival (PFS) Number of Progression or Deaths (%)402 (82%)211 (87%) Median PFS in Months (95% CI)2.3 (1.9, 3.3)1.8 (1.8, 1.9) Hazard Ratio (95% CI) 0.59 (0.50, 0.70)Objective Response Objective Response Rate (95% CI)8.9% (6.4, 12.0)0.9% (0.1, 3.4)Figure depicts the Kaplan-Meier curves for overall survival. Figure 3: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study . Figure 2: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study 3. Figure 3: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study 4. 14.4 NSCLC Lack of Efficacy of TARCEVA Administered Concurrently with Chemotherapy Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel (TARCEVA, = 526) or gemcitabine and cisplatin (TARCEVA, = 580)].. 14.5 Pancreatic Cancer TARCEVA Administered Concurrently with Gemcitabine The efficacy and safety of TARCEVA in combination with gemcitabine as first-line treatment was assessed in Study 5, randomized, double-blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer. Patients were randomized 1:1 to receive TARCEVA (100 mg or 150 mg) or placebo once daily on continuous schedule plus gemcitabine by intravenous infusion (1000 mg/m2, Cycle - Days 1, 8, 15, 22, 29, 36 and 43 of an 8-week cycle; Cycle and subsequent cycles Days 1, and 15 of 4-week cycle [the approved dose and schedule for pancreatic cancer, see the gemcitabine package insert]). TARCEVA or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival. Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18 countries. total of 285 patients were randomized to receive gemcitabine plus TARCEVA (261 patients in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too few patients were treated in the 150 mg cohort to draw conclusions.In the 100 mg cohort, baseline demographics of the overall study population were as follows: male (52%), white (88%), Asian (7%), black (2%), age 65 years (53%), ECOG PS (51%), ECOG PS (32%), and ECOG PS (17%). There was slightly larger proportion of females in the TARCEVA arm (51%) compared with the placebo arm (44%). The median time from initial diagnosis to randomization was approximately 1.0 month. The majority of the patients (76%) had distant metastases at baseline and 24% had locally advanced disease. The results of the study are shown in Table 9.Table 9: Efficacy Results: TARCEVA 100 mg Cohort (Study 5)Efficacy ParameterTARCEVA Gemcitabine(N 261)Placebo Gemcitabine (N 260)Overall Survival (OS) Number of Deaths250254 Median OS in Months (95% CI) 6.5 (6.0, 7.4)6.0 (5.1, 6.7) Hazard Ratio (95% CI) Cox regression model with the following covariates: ECOG performance status and extent of disease. 0.81 (0.68, 0.97) p-value (stratified log-rank test) Two-sided log-rank test stratified by ECOG performance status and extent of disease. 0.028Progression-Free Survival (PFS) Number of Progression or Deaths (%)225232 Median PFS in Months (95% CI)3.8 (3.6, 4.9)3.6 (3.3, 3.8) Hazard Ratio (95% CI) 0.76 (0.64, 0.92)Objective Response Objective Response Rate (95% CI)8.6% (5.4, 12.9)7.9% (4.8, 12.0)Survival was evaluated in the intent-to-treat population. Figure depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and PFS analyses were two-sided log-rank tests stratified by ECOG performance status and extent of disease.Figure 4: Kaplan-Meier Curves for Overall Survival: 100 mg Cohort in Study Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease.. Figure 4: Kaplan-Meier Curves for Overall Survival: 100 mg Cohort in Study 5.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oNSCLC: 150 mg orally, on an empty stomach, once daily. (2.2)oPancreatic cancer: 100 mg orally, on an empty stomach, once daily. (2.3). oNSCLC: 150 mg orally, on an empty stomach, once daily. (2.2). oPancreatic cancer: 100 mg orally, on an empty stomach, once daily. (2.3). 2.1 Selection of Patients with Metastatic NSCLC. Select patients for the treatment of metastatic NSCLC with TARCEVA based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor or plasma specimens [See Clinical Studies (14.1, 14.2)]. If these mutations are not detected in plasma specimen, test tumor tissue if available. Information on FDA-approved tests 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 TARCEVA for NSCLC is 150 mg taken on an empty stomach, i.e., at least one hour before or two hours after 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 TARCEVA for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take TARCEVA on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs [see Clinical Studies (14.5)].. 2.4 Dose Modifications. Adverse ReactionsPulmonaryFor additional information see Warnings and Precautions (5). Interstitial Lung Disease (ILD)Discontinue TARCEVADuring diagnostic evaluation for possible ILDWithhold TARCEVAReduce TARCEVA by 50 mg decrements when restarting therapy following withholding treatment for dose-limiting toxicity that has resolved to baseline or grade <= 1. Hepatic Severe hepatic toxicity that does not improve significantly or resolve within three weeksDiscontinue TARCEVAIn patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baselineWithhold TARCEVA and consider discontinuationIn patients without pre-existing hepatic impairment for total bilirubin levels greater than times the upper limit of normal or transaminases greater than times the upper limit of normalWithhold TARCEVA and consider discontinuationRenal For severe (CTCAE grade to 4) renal toxicityWithhold TARCEVA and consider discontinuationGastrointestinal Gastrointestinal perforationDiscontinue TARCEVAFor persistent severe diarrhea not responsive to medical management (e.g., loperamide)Withhold TARCEVA Skin Severe bullous, blistering or exfoliating skin conditionsDiscontinue TARCEVAFor severe rash not responsive to medical managementWithhold TARCEVA OcularCorneal perforation or severe ulcerationDiscontinue TARCEVAFor keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade lasting more than weeksWithhold TARCEVA For acute/worsening ocular disorders such as eye pain Withhold TARCEVA and consider discontinuation Drug InteractionsCYP3A4 inhibitorsFor additional information see Drug Interactions (7). If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin)Reduce TARCEVA by 50 mg decrements; avoid concomitant use if possibleCYP3A4 inducers Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. Johns Wort Increase TARCEVA by 50 mg increments at 2-week intervals to maximum of 450 mg as tolerated. Avoid concomitant use if possibleConcurrent Cigarette Smoking For additional information see Clinical Pharmacology (12.3).Concurrent cigarette smoking Increase TARCEVA by 50 mg increments at 2-week intervals to maximum of 300 mg. Immediately reduce the dose of TARCEVA to the recommended dose (150 mg or 100 mg daily) upon cessation of smoking Proton Pump inhibitorsSeparation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended periodAvoid concomitant use if possibleH2-receptor antagonistsIf treatment with an H2-receptor antagonist such as ranitidine is required, separate dosing.TARCEVA must be taken 10 hours after the H2-receptor antagonist dosing and at least hours before the next dose of the H2-receptor antagonistAntacidsThe 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS CYP3A4 InhibitorsCo-administration of TARCEVA with strong CYP3A4 inhibitor or combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity [see Clinical Pharmacology (12.3)].Avoid co-administering TARCEVA with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin). Reduce the TARCEVA dosage when co-administering with strong CYP3A4 inhibitor or combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable [see Dosage and Administration (2.4)].CYP3A4 InducersPre-treatment with CYP3A4 inducer prior to TARCEVA decreased erlotinib exposure [see Clinical Pharmacology (12.3)]. Increase the TARCEVA dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St. Johns wort) is unavoidable [see Dosage and Administration (2.4)]. CYP1A2 Inducers and Cigarette SmokingCigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of TARCEVA with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the TARCEVA dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].Drugs the Increase Gastric pHCo-administration of TARCEVA with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure [see Clinical Pharmacology (12.3)]. For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule [see Dosage and Administration (2.4)]. Increasing the dose of TARCEVA when co-administered with gastric PH elevating agents is not likely to compensate for the loss of exposure.AnticoagulantsInteraction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving TARCEVA. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of TARCEVA are not recommended [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].. oCYP3A4 inhibitors or combined CYP3A4 and CYP1A2 inhibitor increase erlotinib plasma concentrations. Avoid concomitant use. If not possible, reduce TARCEVA dose. (2.4, 7)oCYP3A4 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase TARCEVA dose. (2.4, 7)oCigarette smoking and CYP1A2 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase TARCEVA dose. (2.4, 7)oDrugs that increase gastric pH decrease erlotinib plasma concentrations. For proton pump inhibitors avoid concomitant use 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). oCYP3A4 inhibitors or combined CYP3A4 and CYP1A2 inhibitor increase erlotinib plasma concentrations. Avoid concomitant use. If not possible, reduce TARCEVA dose. (2.4, 7). oCYP3A4 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase TARCEVA dose. (2.4, 7). oCigarette smoking and CYP1A2 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase TARCEVA dose. (2.4, 7). oDrugs that increase gastric pH decrease erlotinib plasma concentrations. For proton pump inhibitors avoid concomitant use 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Skin rash, bullous and exfoliative skin disordersoAdvise patients that skin reactions can occur or worsen on sun-exposed areas while taking TARCEVA, and proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure. Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash [see Adverse Reactions (6.1)]. oAdvise patients that TARCEVA can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions [see Warnings and Precautions (5.5)].DiarrheaAdvise patients that diarrhea can usually be managed with loperamide and to contact their healthcare provider for severe or persistent diarrhea [see Adverse Reactions (6.1)]. Interstitial lung diseaseAdvise patients of the risk of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new of worsening unexplained shortness of breath or coughing [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Renal failureAdvise patients of the risk of developing renal failure. Inform patients of the need for the healthcare provider to monitor kidney function and electrolytes [see Warnings and Precautions (5.2)].HepatotoxicityAdvise patients to immediately report signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.3)]. Gastrointestinal perforationsAdvise patients that TARCEVA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)].Cerebrovascular accidentAdvise patients of the risk of cerebrovascular accident and see immediate medical attention [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)]. Ocular disordersAdvise patients promptly to contact their healthcare provider if they develop eye signs or symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye, or changes in vision [see Dosage and Administration (2.4) and Warnings and Precautions (5.8)]. Hemorrhage in patients taking warfarinAdvise patients who are receiving warfarin of the need to monitor INR or other coumarin-derivative anticoagulants [see Warnings and Precautions (5.9) and Drug Interactions (7)].Hair and nail disordersAdvise patients that hair and nail disorders, including hirsutism and brittle and loose nails, have been reported [see Adverse Reactions (6.1)].Embryo-fetal toxicityoAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].oAdvise females of reproductive potential to use effective contraception during treatment with TARCEVA, and for month after the last dose [see Use in Specific Populations (8.3)].LactationoAdvise women not to breastfeed during treatment with TARCEVA and for weeks after the final dose [see Use in Specific Populations (8.2)].SmokingoAdvise patients to contact their health care provider for any changes in smoking status and that the dose of TARCEVA may need to be adjusted if they smoke [see Drug Interactions (7) and Clinical Pharmacology (12.3)]oAdvise patients to stop smoking [see Clinical Pharmacology (12.3)].Manufactured for: OSI Pharmaceuticals, LLC, Northbrook, IL 60062an affiliate of Astellas Pharma US, Inc.Product of Japan or Italy See bottle label for originDistributed by: Genentech USA, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990For further information please call 1-877-TARCEVA (1-877-827-2382).TARCEVA(R) is registered trademark of OSI Pharmaceuticals, LLC. Other trademarks listed belong to their respective owners.(C)2016 Astellas Pharma US, Inc., and Genentech, Inc. All rights reserved.15J080-TAR-SPL. oAdvise patients that skin reactions can occur or worsen on sun-exposed areas while taking TARCEVA, and proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure. Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash [see Adverse Reactions (6.1)]. oAdvise patients that TARCEVA can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions [see Warnings and Precautions (5.5)].. oAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].. oAdvise females of reproductive potential to use effective contraception during treatment with TARCEVA, and for month after the last dose [see Use in Specific Populations (8.3)].. oAdvise women not to breastfeed during treatment with TARCEVA and for weeks after the final dose [see Use in Specific Populations (8.2)].. oAdvise patients to contact their health care provider for any changes in smoking status and that the dose of TARCEVA may need to be adjusted if they smoke [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. oAdvise patients to stop smoking [see Clinical Pharmacology (12.3)].. Logo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics AbsorptionErlotinib is about 60% absorbed after oral administration. Peak plasma levels occur hours after dosing. Effect of FoodFood increased the bioavailability of erlotinib to approximately 100%. Distribution:Erlotinib is 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters. EliminationErlotinib is eliminated with median half-life of 36.2 hours in patients receiving the single-agent TARCEVA 2nd/3rd line regimen. Time to reach steady state plasma concentration would therefore be 7-8 days. MetabolismErlotinib is metabolized primarily by CYP3A4 and to lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1, in vitro.ExcretionFollowing 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).Specific PopulationsNeither age, body weight, nor gender had clinically significant effect on the systemic exposure of erlotinib in NSCLC patients receiving single-agent TARCEVA for 2nd/3rd line treatment or for maintenance treatment, and in pancreatic cancer patients who received erlotinib plus gemcitabine. The pharmacokinetics of TARCEVA in patients with compromised renal function is unknown.Patients with Hepatic ImpairmentIn vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.Patients That Smoke Tobacco CigarettesIn single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) increased erlotinib clearance and decreased erlotinib AUC0-inf by 64% (95% CI, 46-76%) in current smokers compared with former/never smokers. In NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by 24% increase in apparent erlotinib plasma clearance. In another study which was conducted in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated dose-proportional increase in erlotinib exposure when the TARCEVA dose was increased from 150 mg to 300 mg. [see Dosage and Administration (2.4), Drug Interactions (7) and Patient Counseling Information (17)].Drug Interaction StudiesCo-administration of gemcitabine had no effect on erlotinib plasma clearance. CYP3A4 InhibitorsCo-administration with strong CYP3A4 inhibitor, ketoconazole, increased erlotinib AUC by 67%. Co-administration with combined CYP3A4 and CYP1A2 inhibitor, ciprofloxacin, increased erlotinib exposure [AUC] by 39%, and increased erlotinib maximum concentration [Cmax] by 17%. [see Dose Modifications (2.4), Drug Interactions (7)].CYP3A4 InducersPre-treatment with the CYP3A4 inducer rifampicin, for 7-11 days prior to TARCEVA, decreased erlotinib AUC by 58% to 80% [see Dose Modifications (2.4), Drug Interactions (7)].CYP1A2 Inducers or Smoking TobaccoSee Specific Populations Section [see Dose Modifications (2.4), Drug Interactions (7)].Drugs that Increase Gastric pHErlotinib solubility is pH dependent and decreases as pH increases. When proton pump inhibitor (omeprazole) was co-administered with TARCEVA the erlotinib exposure [AUC] was decreased by 46% and the erlotinib maximum concentration [Cmax] was decreased by 61%. When TARCEVA was administered hours following 300 mg dose of an H-2 receptor antagonist (ranitidine), the erlotinib AUC was reduced by 33% and the erlotinib Cmax was reduced by 54%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 after the previous ranitidine evening dose and h before the ranitidine morning dose), the erlotinib AUC was decreased by 15% and the erlotinib Cmax was decreased by 17% [see Dose Modifications (2.4), Drug Interactions (7)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed (8.2) 8.1 Pregnancy Risk SummaryBased on animal data and its mechanism of action, TARCEVA can cause fetal harm when administered to pregnant woman. Limited available data on use of TARCEVA in pregnant women are not sufficient to inform risk of major birth defects or miscarriage. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. DataAnimal DataErlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the recommended daily dose, on mg/m2 basis) of erlotinib had an increase in early resorptions that resulted in decrease in the number of live fetuses. No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 times the recommended dose of 150 mg/day on mg/m2 basis).. 8.2 Lactation Risk SummaryThere are no data on the presence of erlotinib in human milk, or the effects of erlotinib on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from TARCEVA, including interstitial lung disease, hepatotoxicity, bullous and exfoliative skin disorders, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, and diarrhea. Advise lactating woman not to breastfeed during treatment with TARCEVA and for weeks after the final dose. 8.3 Females and Males of Reproductive Potential ContraceptionFemalesTARCEVA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TARCEVA and for one month after the last dose of TARCEVA.. 8.4 Pediatric Use The safety and effectiveness of TARCEVA in pediatric patients have not been established. In an open-label, multicenter trial, 25 pediatric patients (median age 14 years, range 3-20 years) with recurrent or refractory ependymoma were randomized (1:1) to TARCEVA or etoposide. Thirteen patients received TARCEVA at dose of 85 mg/m2/day orally until disease progression, death, patient request, investigator decision to discontinue study drug, or intolerable toxicity. Four patients randomized to etoposide also received TARCEVA following disease progression. The trial was terminated prematurely for lack of efficacy; there were no objective responses observed in these 17 TARCEVA-treated patients.No new adverse events were identified in the pediatric population. Based on the population pharmacokinetics analysis conducted in 105 pediatric patients (2 to 21 years old) with cancer, the geometric mean estimates of CL/F/BSA (apparent clearance normalized to body surface area) were comparable across the three age groups: 2-6 years (n 29), 7-16 years (n 59), and 17-21 years (n 17).. 8.5 Geriatric Use Of the 1297 subjects in clinical studies of TARCEVA for the treatment of NSCLC and pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65.. 8.6 Hepatic Impairment Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVA treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment [see Warnings and Precautions (5.3), Adverse Reactions (6.1, 6.2), and Dosage and Administration]. Monitor patients with hepatic impairment (total bilirubin greater than upper limit of normal (ULN) or Child-Pugh A, and C) during therapy with TARCEVA. Treatment with TARCEVA should be used with increased monitoring in patients with total bilirubin greater than x ULN [see Warnings and Precautions (5.3), Adverse Reactions (6.1, 6.2), and Dosage and Administration (2.4)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oInterstitial lung disease (ILD): Occurs in 1.1% of patients. Withhold TARCEVA for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue TARCEVA if ILD is diagnosed. (5.1)oRenal failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold TARCEVA for severe renal toxicity. (5.2)oHepatotoxicity: Occurs with or without hepatic impairment, including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. (5.3)oGastrointestinal perforations: Discontinue TARCEVA. (5.4)oBullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5)oCerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.6)oMicroangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. (5.7)oOcular disorders: Discontinue TARCEVA for corneal perforation, ulceration or persistent severe keratitis. (5.8)oHemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. (5.9)oEmbryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.10, 8.1, 8.3). oInterstitial lung disease (ILD): Occurs in 1.1% of patients. Withhold TARCEVA for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue TARCEVA if ILD is diagnosed. (5.1). oRenal failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold TARCEVA for severe renal toxicity. (5.2). oHepatotoxicity: Occurs with or without hepatic impairment, including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. (5.3). oGastrointestinal perforations: Discontinue TARCEVA. (5.4). oBullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5). oCerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.6). oMicroangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. (5.7). oOcular disorders: Discontinue TARCEVA for corneal perforation, ulceration or persistent severe keratitis. (5.8). oHemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. (5.9). oEmbryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.10, 8.1, 8.3). 5.1 Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with TARCEVA treatment. 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 days to more than months (median 39 days) after initiating TARCEVA therapy.Withhold TARCEVA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue TARCEVA [see Dosage and Administration (2.4)].. 5.2 Renal Failure. Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with TARCEVA treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the monotherapy lung cancer studies was 0.5% in the TARCEVA arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the TARCEVA plus gemcitabine arm and 0.4% in the control arm. Withhold TARCEVA in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during TARCEVA treatment [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 TARCEVA treatment in 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 incidence of hepatic failure in the monotherapy lung cancer studies was 0.4% in the TARCEVA arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the TARCEVA plus gemcitabine arm and 0.4% in the control arm. In 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 days of the last TARCEVA dose. One patient died from hepatorenal syndrome, patient died from rapidly progressing liver failure and the remaining patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin 3 ULN.Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with TARCEVA. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold TARCEVA in patients without pre-existing hepatic impairment for total bilirubin levels greater than times the upper limit of normal or transaminases greater than times the upper limit of normal. Withhold TARCEVA in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue TARCEVA in patients whose abnormal liver tests meeting the above criteria 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 TARCEVA treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation [see Adverse Reactions (6.1, 6.2)]. The pooled incidence of gastrointestinal perforation in the monotherapy lung cancer studies was 0.2% in the TARCEVA arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm. Permanently discontinue TARCEVA in 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 some cases were fatal, can occur with TARCEVA treatment [see Adverse Reactions (6.1, 6.2)]. The pooled incidence of bullous and exfoliative skin disorders in the monotherapy lung cancer studies was 1.2% in the TARCEVA arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm. Discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and Administration (2.4)].. 5.6 Cerebrovascular Accident. In the pancreatic carcinoma trial, seven patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the monotherapy lung cancer studies was 0.6% in the TARCEVA arms and not higher than that observed in the control arms.. 5.7 Microangiopathic Hemolytic Anemia with Thrombocytopenia. The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the monotherapy lung cancer studies was 0% in the TARCEVA arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm.. 5.8 Ocular Disorders. Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with TARCEVA treatment and can lead to corneal perforation or ulceration [see Adverse Reactions (6.1) and (6.2)]. The pooled incidence of ocular disorders in the monotherapy lung cancer studies was 17.8% in the TARCEVA arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the TARCEVA plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue TARCEVA therapy if patients present with acute or worsening ocular disorders such as eye pain [see Dosage and Administration (2.4)].. 5.9 Hemorrhage in Patients Taking Warfarin. Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when TARCEVA and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during TARCEVA treatment in patients taking warfarin or other coumarin-derivative anticoagulants [see Adverse Reactions (6.1) and Drug Interactions (7)].. 5.10 Embryo-fetal Toxicity. Based on animal data and its mechanism of action, TARCEVA can cause fetal harm when administered to pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to fetus.Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of TARCEVA [see Use in Specific Populations (8.1) and 8.3), Clinical Pharmacology (12.1)].