DOSAGE FORMS & STRENGTHS SECTION.


3. DOSAGE FORMS AND STRENGTHS. 25 mg tabletsWhite film-coated tablets for daily oral administration. Round,biconvex face and straight sides, white film-coated, printed inorange with T and 25 on one side and plain on the otherside.100 mg tabletsWhite film-coated tablets for daily oral administration. Round,biconvex face and straight sides, white film-coated, printed in graywith T and 100 on one side and plain on the other side.150 mg tabletsWhite film-coated tablets for daily oral administration. Round,biconvex face and straight sides, white film-coated, printed inmaroon with T and 150 on one side and plain on the otherside.. Tablets: 25 mg,100 mg and 150 mg. (3). Tablets: 25 mg,100 mg and 150 mg. (3).

DRUG INTERACTIONS SECTION.


7. DRUG INTERACTIONS. Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2/3. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice. [see Dosage and Administration (2.3 )].Pre-treatment with the CYP3A4 inducer rifampicin for days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to dose of about 30 to 50 mg in NSCLC patients. In separate study, treatment with rifampicin for 11 days, with co-administration of single 450 mg dose of TARCEVA on day resulted in mean erlotinib exposure (AUC) that was 57.6% of that observed following single 150 mg TARCEVA dose in the absence of rifampicin treatment [see Dose Modifications (2.3 )]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, adjusting the starting dose should be considered. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. Johns Wort [see Dosage and Administration (2.3 )]. Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, cautious increase in the dose of TARCEVA may be considered, while monitoring the patients safety. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking. [see Dosage and Administration(2.3 and Clinical Pharmacology(12.3)]. Pretreatment and co-administration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear.In study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Co-administration of TARCEVA with omeprazole, proton pump inhibitor, decreased the erlotinib AUC by 46%. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TARCEVA should be avoided if possible. The use of antacids may be considered in place of histamine receptor blockers (H2 blockers) or proton pump inhibitors in patients receiving TARCEVA. However, no clinical study has been conducted to evaluate the effect of antacids on erlotinib pharmacokinetics. If an antacid is necessary, the antacid dose and the TARCEVA dose should be separated by several hours [see Clinical Pharmacology (12.3)].. CYP3A4 inhibitors may increase erlotinib plasma concentrations. (7)CYP3A4 inducers may decrease erlotinib plasma concentrations. (7)CYP1A2 inducers may decrease erlotinib plasma concentrations. (7)Erlotinib solubility is pH dependent. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its absorption. (7)Cigarette smoking decreases erlotinib plasma concentrations (7). CYP3A4 inhibitors may increase erlotinib plasma concentrations. (7). CYP3A4 inducers may decrease erlotinib plasma concentrations. (7). CYP1A2 inducers may decrease erlotinib plasma concentrations. (7). Erlotinib solubility is pH dependent. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its absorption. (7). Cigarette smoking decreases erlotinib plasma concentrations (7).

HOW SUPPLIED SECTION.


16. HOW SUPPLIED/STORAGE AND HANDLING. 25 mg TabletsRound, biconvex face and straight sides, white film-coated, printed in orange with T and 25 on one side and plain on the other side; supplied in:Bottles of 30 NDC 54868-5290-0 100 mg TabletsRound, biconvex face and straight sides, white film-coated, printed in gray with T and 100 on one side and plain on the other side; supplied in:Bottles of 30 NDC 54868-5474-0 150 mg TabletsRound, biconvex face and straight sides, white film-coated, printed in maroon with T and 150 on one side and plain on the other side; supplied in:Bottles of 30 NDC 54868-5447-0 Store at 25C (77F); excursions permitted to 15 30C (59 86F). See USP Controlled Room Temperature.

ADVERSE REACTIONS SECTION.


6. ADVERSE REACTIONS. Because clinical trials are conducted under widely varyingconditions, adverse reactions rates observed in the clinical trialsof drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in practice.Safety evaluation of TARCEVA is based on 856 cancer patients whoreceived TARCEVA as monotherapy, 308 patients who received TARCEVA100 or 150 mg plus gemcitabine, and 1228 patients who receivedTARCEVA concurrently with other chemotherapies. There have been reports of serious events, including fatalities,in patients receiving TARCEVA for treatment of NSCLC, pancreaticcancer or other advanced solid tumors [see Warnings andPrecautions (5)and Dosage and Administration (2.3)]. The most common adversereactions (>50%) in NSCLC are rash, diarrhea, anorexia andfatigue. 6.1)The most common adversereactions (>50%) in pancreatic cancer are fatigue, rash, nauseaand anorexia. 6.2)To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals Inc. at 1-800-572-1932or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Non-Small Cell Lung Cancer. Adverse events, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 1.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 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 1: Adverse Reactions Occurring More Frequently (>= 3%) in the Single Agent TARCEVA Group than in the Placebo Group and in >=10% of Patients in the TARCEVA Group.TARCEVA 150 mgN 485PlaceboN 242NCI-CTC GradeAny GradeGrade 3Grade 4Any GradeGrade 3Grade 4MedDRA Preferred Term%%%%%%Rash758<11700Diarrhea546<118<10Anorexia5281385<1Fatigue5214445164Dyspnea411711351511Cough33402920Nausea33302420Infection24401520Vomiting232<11920Stomatitis17<10300Pruritus13<10500Dry skin1200400Conjunctivitis12<102<10Keratoconjunctivitis sicca1200300Abdominal pain112<171<1Liver 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 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 (2.3)] 6.2 Pancreatic Cancer. Adverse events, regardless of causality, that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 2.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 TARCEVA plus gemcitabine-treated 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. 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 2: Adverse Reactions Occurring in >= 10% of TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohortIncludes all MedDRA preferred terms in the Infections and Infestations System Organ ClassTARCEVA Gemcitabine1000 mg/m2 IVN=259Placebo Gemcitabine 1000 mg/m2 IVN=256NCI-CTC GradeAny GradeGrade 3Grade 4Any GradeGrade 3Grade 4MedDRA Preferred Term%%%%%%Fatigue7314270132Rash69503010Nausea60705870Anorexia526<1525<1Diarrhea485<13620Abdominal pain469<14512<1Vomiting427<1414<1Weight decreased392029<10Infection391333092Edema373<1362<1Pyrexia36303040Constipation31313451Bone pain254<12320Dyspnea245<12350Stomatitis22<101200Myalgia211020<10Depression192014<10Dyspepsia17<1013<10Cough16001100Dizziness15<10130<1Headache15<101000Insomnia15<1016<10Alopecia14001100Anxiety131011<10Neuropathy131<110<10Flatulence13009<10Rigors1200900In the pancreatic carcinoma trial, 10 patients in the TARCEVA/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade or thrombotic events, including deep venous thrombosis, was similar in the two treatment arms: 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine.No differences in Grade or Grade hematologic laboratory toxicities were detected between the TARCEVA plus gemcitabine group compared to the placebo plus gemcitabine group.Severe adverse events (>=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)]. Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of TARCEVA plus gemcitabine in patients with pancreatic cancer. Table displays the most severe NCI-CTC grade of liver function abnormalities that developed. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)]. Table 3: Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 100 mg CohortTARCEVA Gemcitabine 1000 mg/m2 IVN 259Placebo Gemcitabine 1000 mg/m2 IVN 256NCI-CTC GradeGrade 2Grade 3Grade 4Grade 2Grade 3Grade 4Bilirubin17 %10%<1%11%10%3%ALT31% 13%<1%22%9%0%AST24%10%<1%19%9%0%. 6.3 NSCLC and Pancreatic Cancer Indications. During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with concomitant warfarin or NSAID administration. [see Warnings and Precautions (5.9)]. These adverse events were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported. [see Warnings and Precautions (5.4)]. Cases of Grade epistaxis were also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.NCI-CTC Grade conjunctivitis and keratitis have been reported infrequently in patients receiving TARCEVA therapy in the NSCLC and pancreatic cancer clinical trials. Corneal ulcerations may also occur. [see Patient Counseling Information (17)]. Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails have been reported in clinical trials and during post-marketing use of TARCEVA.In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade or 4) with desquamation. Associated symptoms may include itching, tenderness and/or burning. Dry skin with or without digital skin fissures may occur. Hepatic failure has been reported in patients treated with single-agent TARCEVA or TARCEVA combined with chemotherapy in clinical studies and during post-marketing use of TARCEVA [see Warnings and Precautions (5.3 )]; it is not possible to reliably estimate the frequency or establish causal relationship to TARCEVA treatment.In general, no notable differences in the safety of TARCEVA monotherapy or in combination with gemcitabine could be discerned between females or males and between patients younger or older than the age of 65 years [s ee Use in Specific Populations (8.4)]. The safety of TARCEVA appears similar in Caucasian and Asian patients.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Erlotinib has not been tested for carcinogenicity.Erlotinib has been tested for genotoxicity in series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage. Erlotinib did not impair fertility in either male or female rats.

CLINICAL PHARMACOLOGY SECTION.


12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells. 12.3 Pharmacokinetics. Absorption and Distribution:Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of TARCEVA with omeprazole, proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61% respectively [see Drug Interactions (7)].Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.Metabolism and Excretion:A population pharmacokinetic analysis in 591 patients receiving single-agent TARCEVA showed median half-life of 36.2 hours. Time to reach steady state plasma concentration would therefore be - days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had 24% higher rate of erlotinib clearance. second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstrated that covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance.In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. Following 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). Cigarette smoking reduces erlotinib exposure. In the Phase NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which was 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 separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to 1/2 of that in never/former smokers. In another study which was conducted in NSCLC patients (N=35) 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. However, the exact dose to be recommended for patients who currently smoke is unknown [see Drug Interactions (7) and Patient Counseling Information (17)]. Special Populations:Patients with Hepatic ImpairmentPatients with hepatic impairment (total bilirubin ULN or Child Pugh A, and C) should be closely monitored during therapy with TARCEVA. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin 3 ULN [see Warnings and Precautions (5.2 ), Adverse Reactions (6.3), and Dosage and Administration (2.3 )].In 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 with Renal Impairment Less than 9% of single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

CLINICAL STUDIES SECTION.


14. CLINICAL STUDIES. 14.1 Non-Small Cell Lung Cancer NSCLC TARCEVA Administered as Single Agent. The efficacy and safety of single-agent TARCEVA was assessed in 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. Study endpoints 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. Table summarizes the demographic and disease characteristics of the study population. Demographic characteristics were well balanced between the two treatment groups. About two-thirds of the patients were male. Approximately one-fourth had baseline ECOG performance status (PS) of 2, and 9% had baseline ECOG PS of 3. Fifty percent of the patients had received only one prior regimen of chemotherapy. About three quarters of these patients were known to have smoked at some time.Table 4: Demographic and Disease Characteristics Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.TARCEVA(N 488)Placebo(N 243)Characteristicsn(%)n(%)Gender Female173(35)83(34) Male315(65)160(66)Age (years) 65299(61)153(63) >= 65189(39)90(37)Race Caucasian379(78)188(77) Black18(4)12(5) Asian63(13)28(12) Other28(6)15(6)ECOG Performance Status at Baseline 064(13)34(14) 1256(52)132(54) 2126(26)56(23) 342(9)21(9)Weight Loss in Previous Months 5%320(66)166(68) - 10%96(20)36(15) 10%52(11)29(12) Unknown20(4)12(5)Smoking History Never Smoked104(21)42(17) Current or Ex-smoker358(73)187(77) Unknown26(5)14(6)Histological Classification Adenocarcinoma246(50)119(49) Squamous144(30)78(32) Undifferentiated Large Cell41(8)23(9) Mixed Non-Small Cell11(2)2(<1) Other46(9)21(9)Time from Initial Diagnosis to Randomization (Months) 663(13)34(14) - 12157(32)85(35) 12268(55)124(51)Best Response to Prior Therapy at Baseline CR/PR196(40)96(40) PD101(21)51(21) SD191(39)96(40)Number of Prior Regimens at Baseline 1243(50)121(50) 2238(49)119(49) 37(1)3(1)Exposure to Prior Platinum at Baseline Yes454(93)224(92) No34(7)19(8)The results of the study are shown in Table 5.Table 5: Efficacy Results TARCEVAPlaceboHazardRatio ()95% CIp-valueSurvival Median6.7 moMedian4.7 mo0.730.61 0.86<0.001 (Two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.)1-year Survival31.2%21.5%Progression-Free Survival Median9.9 wkMedian7.9 wk0.590.50 0.70<0.001 ()Tumor Response (CR+PR)8.9%0.9%<0.001 ()Response DurationMedian34.3 wkMedian 15.9 wkSurvival was evaluated in the intent-to-treat population. Figure depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.Note: HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. 14.2 NSCLC 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)].. 14.3 Pancreatic Cancer TARCEVA Administered Concurrently with Gemcitabine. The efficacy and safety of TARCEVA in combination with gemcitabine as first-line treatment was assessed in 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 IV (1000 mg/m2, Cycle - Days 1, 8, 15, 22, 29, 36 and 43 of an 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.Table summarizes the demographic and disease characteristics of the study population that was randomized to receive 100 mg of TARCEVA plus gemcitabine or placebo plus gemcitabine. Baseline demographic and disease characteristics of the patients were similar between the treatment groups, except for 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. Most patients presented with metastatic disease at study entry as the initial manifestation of pancreatic cancer.Table 6: Demographic and Disease Characteristics: 100 mg CohortUnknown includes responses of Unknown and missing.Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.TARCEVA+ Gemcitabine (N=261)Placebo Gemcitabine (N=260)Characteristicsn(%)n(%)Gender Female134(51)114(44) Male127(49)146(56)Age (Years) <65136(52)138(53) >=65125(48)122(47)Race Caucasian225(86)231(89) Black8(3)5(2) Asian20(8)14(5) Other8(3)10(3)ECOG Performance Status 082(31)83(32) 1134(51)132(51) 244(17)45(17) Unknown1(<1)0(0)Disease Status at BaselineLocally Advanced61(23)63(24)Distant Metastasis200(77)197(76)The results of the study are shown in Table 7. Table 7: Efficacy Results: 100 mg CohortTARCEVA GemcitabinePlacebo+ GemcitabineHazardRatio ()95% CIp-valueSurvivalMedian6.4 mo250 deathsMedian6.0 mo254 deaths0.810.68 0.970.028 (Two-sided Log-Rank test stratified by ECOG performance status and extent of disease.)1-year Survival23.8%19.4%Progression-Free SurvivalMedian3.8 mo225 eventsMedian3.5 mo232 events0.760.64 0.920.006 ()Tumor Response (CR+PR)8.6%7.9%0.87 ()Response DurationMedian23.9 wkMedian23.3 wkSurvival 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.Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. P-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease.. image of Figure 1. image of Figure 2.

CONTRAINDICATIONS SECTION.


4. CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.


11. DESCRIPTION. TARCEVA (erlotinib), kinase inhibitor, is quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and molecular weight of 429.90. The molecule has pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at pH of less than due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at pH of approximately 2.TARCEVA tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow (25 mg only) for product identification.. image of chemical formula.

DOSAGE & ADMINISTRATION SECTION.


2. DOSAGE AND ADMINISTRATION. Enter section text here. The dose for NSCLC is 150 mg/day. (2.1)The dose for pancreatic cancer is 100 mg/day.(2.2)All doses of TARCEVA should be taken at leastone hour before or two hours after food. (2.1,2.2)Reduce in 50 mgdecrements, when necessary. (2.3). The dose for NSCLC is 150 mg/day. (2.1). The dose for pancreatic cancer is 100 mg/day.(2.2). All doses of TARCEVA should be taken at leastone hour before or two hours after food. (2.1,2.2). Reduce in 50 mgdecrements, when necessary. (2.3). 2.1 Recommended Dose NSCLC. The recommended daily dose of TARCEVA for non-small cell lungcancer is 150 mg taken at least one hour before or two hours afterthe ingestion of food. Treatment should continue until diseaseprogression or unacceptable toxicity occurs. There is no evidencethat treatment beyond progression is beneficial.. 2.2 Recommended Dose Pancreatic Cancer. The recommended daily dose of TARCEVA for pancreatic cancer is 100mg taken at least one hour before or two hours after the ingestion offood, in combination with gemcitabine (see the gemcitabine packageinsert). Treatment should continue until disease progression orunacceptable toxicity occurs.. 2.3 Dose Modifications. In patients who develop an acute onset of new or progressivepulmonary symptoms, such as dyspnea, cough or fever, treatment withTARCEVA should be interrupted pending diagnostic evaluation. IfInterstitial Lung Disease (ILD) is diagnosed, TARCEVA should bediscontinued and appropriate treatment instituted as necessary [seeWarnings and Precautions (5.1)].Diarrhea can usually be managed with loperamide. Patients withsevere diarrhea who are unresponsive to loperamide or who becomedehydrated may require dose reduction or temporary interruption oftherapy. Patients with severe skin reactions may also require dosereduction or temporary interruption of therapy.When dose reduction is necessary, the TARCEVA dose should bereduced in 50 mg decrements.In patients who are taking TARCEVA with strong CYP3A4 inhibitorsuch as, but not limited to, atazanavir, clarithromycin, indinavir,itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,saquinavir, telithromycin, troleandomycin (TAO), voriconazole, orgrapefruit or grapefruit juice, dose reduction should be consideredif severe adverse reactions occur. Similarly, in patients who aretaking TARCEVA with an inhibitor of both CYP3A4 and CYP1A2 likeciprofloxacin, dose reduction of TARCEVA should be considered ifsevere adverse reactions occur. [see Drug Interactions (7)].Pre-treatment with the CYP3A4 inducer rifampicin decreasederlotinib AUC by about 2/3 to 4/5. Use of alternative treatmentslacking CYP3A4 inducing activity is strongly recommended. If analternative treatment is unavailable, an increase in the dose ofTARCEVA should be considered as tolerated at two week intervals whilemonitoring the patients safety. The maximum dose of TARCEVAstudied in combination with rifampicin is 450 mg. If the TARCEVA doseis adjusted upward, the dose will need to be reduced immediately tothe indicated starting dose upon discontinuation of rifampicin orother inducers. Other CYP3A4 inducers include, but are not limited torifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital andSt. Johns Wort. These too should be avoided if possible [seeDrug Interactions (7)].Cigarette smoking has been shown to reduce erlotinibexposure. Patients should be advised to stop smoking. If apatient continues to smoke, cautious increase in the dose ofTARCEVA, not exceeding 300 mg may be considered, while monitoring thepatients safety. However, efficacy and long-term safety (> 14days) of dose higher than the recommended starting doses have notbeen established in patients who continue to smoke cigarettes. If theTARCEVA dose is adjusted upward, the dose should be reducedimmediately to the indicated starting dose upon cessation ofsmoking [see Clinical Pharmacology (12.3)].Erlotinib is eliminated by hepatic metabolism and biliaryexcretion. Although erlotinib exposure was similar in patients withmoderately impaired hepatic function (Child-Pugh B), patients withhepatic impairment (total bilirubin ULN or Child-Pugh A, andC) should be closely monitored during therapy with TARCEVA [seeWARNINGS and PRECAUTIONS (5.2)]. Treatment with TARCEVA should be used with extra caution inpatients with total bilirubin 3 ULN. TARCEVAdosing should be interrupted or discontinued if changes in liverfunction are severe such as doubling of total bilirubin and/ortripling of transaminases in the setting of pretreatment valuesoutside normal range. In the setting of worsening liver functiontests, before they become severe, dose interruption and/or dosereduction with frequent liver function test monitoring should beconsidered. TARCEVA dosing should be interrupted or discontinued iftotal bilirubin is >3 ULN and/or transaminases are >5 ULNin the setting of normal pretreatment values [see Warnings andPrecautions (5.2, 5.3), Adverse Reactions (6.3)and Use in Specific Populations (8.6)].

INDICATIONS & USAGE SECTION.


1. INDICATIONS AND USAGE. Enter section text here. TARCEVA is tyrosinekinase inhibitor indicated for the treatment of:Locally advanced or metastatic non-small celllung cancer (NSCLC) after failure of at least one prior chemotherapyregimen. (1.1)First-linetreatment of patients with locally advanced, unresectable ormetastatic pancreatic cancer, in combination with gemcitabine. (1.2). Locally advanced or metastatic non-small celllung cancer (NSCLC) after failure of at least one prior chemotherapyregimen. (1.1). First-linetreatment of patients with locally advanced, unresectable ormetastatic pancreatic cancer, in combination with gemcitabine. (1.2). 1.1 Non-Small Cell Lung Cancer (NSCLC). TARCEVA monotherapy is indicated for the treatment of patientswith locally advanced or metastatic non-small cell lung cancer afterfailure of at least one prior chemotherapy regimen [see ClinicalStudies (14.1)].Results from two, multicenter, placebo-controlled, randomized,Phase trials conducted in first-line patients with locally advancedor metastatic NSCLC showed no clinical benefit with the concurrentadministration of TARCEVA with platinum-based chemotherapy[carboplatin and paclitaxel or gemcitabine and cisplatin] and its useis not recommended in that setting [see Clinical Studies (14.3)].. 1.2 Pancreatic Cancer. TARCEVA in combination with gemcitabine is indicated for thefirst-line treatment of patients with locally advanced, unresectableor metastatic pancreatic cancer [see Clinical Studies (14.3)].

INFORMATION FOR PATIENTS SECTION.


17. PATIENT COUNSELING INFORMATION. If the following signs or symptoms occur, patients should be advised to seek medical advice promptly [see Warnings and Precautions (5), Adverse Reactions (6) and Dosage and Administration(2.3)]. Onset or worsening of skin rashSevere or persistent diarrhea, nausea, anorexia, or vomitingOnset or worsening of unexplained shortness of breath or coughEye irritationGiven that skin reactions are anticipated when taking TARCEVA, proactive intervention may include alcohol-free emollient cream and sunscreen and the management of rash should be discussed with the patient. This may include topical corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash severity. Women of childbearing potential should be advised to avoid becoming pregnant while taking TARCEVA [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. Smokers should be advised to stop smoking while taking TARCEVA as plasma concentrations of erlotinib are reduced due to the effect of cigarette smoking [see Clinical Pharmacology (12.3 )]. Manufactured for:OSI Pharmaceuticals Inc., Melville, NY 11747Manufactured by:Schwarz Pharma Manufacturing, Seymour, IN 47274Distributed by:Genentech USA, Inc., DNULL Way, South San Francisco, CA 94080-4990. Onset or worsening of skin rash. Severe or persistent diarrhea, nausea, anorexia, or vomiting. Onset or worsening of unexplained shortness of breath or cough. Eye irritation.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

NONCLINICAL TOXICOLOGY SECTION.


13. NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Erlotinib has not been tested for carcinogenicity.Erlotinib has been tested for genotoxicity in series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage. Erlotinib did not impair fertility in either male or female rats.

OVERDOSAGE SECTION.


10. OVERDOSAGE. Single oral doses of TARCEVA up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent TARCEVA in healthy subjects were poorly tolerated after only few days of dosing. Based on the data from these studies, an unacceptable incidence of severe adverse events, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose [see Dosage and Administration (2)]. In case of suspected overdose, TARCEVA should be withheld and symptomatic treatment instituted.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL PACKAGE LABEL. TARCEVA (erlotinib hydrochloride) tablet25 mg100 mg150 mg. image of 25 mg package label. image of 100 mg package label. image of 150 mg package label.

RECENT MAJOR CHANGES SECTION.


RECENT MAJOR CHANGES. Enter section text here. Warnings andPrecautions, Hepatic Impairment (5.2)09/2008Warnings andPrecautions, Hepatotoxicity (5.3)09/2008Warning andPrecautions, Renal Failure (5.4)09/2008.

SPL UNCLASSIFIED SECTION.


1.1 Non-Small Cell Lung Cancer (NSCLC). TARCEVA monotherapy is indicated for the treatment of patientswith locally advanced or metastatic non-small cell lung cancer afterfailure of at least one prior chemotherapy regimen [see ClinicalStudies (14.1)].Results from two, multicenter, placebo-controlled, randomized,Phase trials conducted in first-line patients with locally advancedor metastatic NSCLC showed no clinical benefit with the concurrentadministration of TARCEVA with platinum-based chemotherapy[carboplatin and paclitaxel or gemcitabine and cisplatin] and its useis not recommended in that setting [see Clinical Studies (14.3)].

USE IN SPECIFIC POPULATIONS SECTION.


8. USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category [See Warnings and Precautions (5.8)]Erlotinib has been shown to cause maternal toxicity with associated embryo/fetal lethality and abortion in rabbits when given at doses that result in plasma drug concentrations of approximately times those in humans (AUCs at 150 mg daily dose). When given during the period of organogenesis to achieve plasma drug concentrations approximately equal to those in humans, based on AUC, there was no increased incidence of embryo/fetal lethality or abortion in rabbits or rats. However, female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the clinical dose, on mg/m2 basis) of erlotinib prior to mating through the first week of pregnancy 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 clinical dose of 150 mg/day on mg/m2 basis).There are no adequate and well-controlled studies in pregnant women using TARCEVA. Women of childbearing potential should be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus. If TARCEVA is used during pregnancy, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy [see Warnings and Precautions (5.8)]. 8.3 Nursing Mothers. It is not known whether erlotinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TARCEVA, decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use. The safety and effectiveness of TARCEVA in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of patients participating in the randomized NSCLC trial, 62% were less than 65 years of age, and 38% of patients were aged 65 years or older. The survival benefit was maintained across both age groups [HR 0.75 (95% CI: 0.6, 0.9) in patients less than 65 years of age, and HR 0.79 (95% CI: 0.6, 1.0) in patients who were 65 years or older]. In the pancreatic cancer study, 53% of patients were younger than 65 years of age and 47% were 65 years of age or older. There were no clinically relevant differences between the age groups [HR 0.78 (95% CI: 0.6, 1.0) in patients less than 65 years of age, and HR 0.94 (95% CI: 0.7, 1.2) in patients who were 65 years or older]. No meaningful differences in safety or pharmacokinetics were observed between younger and older patients in either study. Therefore, no dosage adjustments are recommended in elderly patients. 8.6 Gender Of the total number of patients participating in the randomized NSCLC trial, 65% were males and 35% females. There were no clinically relevant differences in safety and efficacy based on gender [HR 0.76 (95% CI: 0.6, 0.9) in males and HR 0.80 (95% CI: 0.6, 1.1) in females].In the pancreatic cancer study, 52% of patients were males and 48% females. There were no clinically relevant differences in safety and efficacy based on gender [HR 0.74 (95% CI: 0.6, 0.9) in males and HR 1.0 (95% CI: 0.8, 1.3) in females].. 8.7 Race. In the randomized NSCLC trial, 78% of all patients were Caucasian and 12% were Asian. There were no clinically relevant differences in safety and efficacy based on race [HR 0.79 (95% CI: 0.6, 1.0) in Caucasians and HR 0.61 (95% CI: 0.4, 1.0) in Asians].In the pancreatic cancer study, 88% of all patients were Caucasian and 7% were Asian. There were no clinically relevant differences in safety and efficacy based on race [HR 0.88 (95% CI: 0.7, 1.1) in Caucasians and HR 0.61 (95% CI: 0.3, 1.3) in Asians].. 8.8 Patients with Hepatic Impairment. Patients with hepatic impairment (total bilirubin ULN or Child Pugh A, and C) should be closely monitored during therapy with TARCEVA. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin 3 ULN [see Warnings (5.2 ), Adverse Reactions (6.3), and Dosage and Administration (2.3 )].In 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 [see Dosage and Administration (2.3 and Clinical Pharmacology (12.3)]. 8.9 Patients with Renal Impairment Less than 9% of single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

WARNINGS AND PRECAUTIONS SECTION.


5. WARNINGS AND PRECAUTIONS. Enter section text here. Interstitial Lung Disease (ILD)-like events,including fatalities have been infrequently reported. InterruptTARCEVA if acute onset of new or progressive unexplained pulmonarysymptoms, such as dyspnea, cough and fever occur. DiscontinueTARCEVA if ILD is diagnosed. (5.1)Monitor patients with hepatic impairmentclosely. Interrupt or discontinue TARCEVA if changes in liverfunction are severe (5.2)Cases of hepatic failure and hepatorenalsyndrome (including fatalities) have been reported. Monitor periodicliver function testing. Interrupt or discontinue TARCEVA if liverfunction changes are severe. (5.3)Cases of acute renal failure (includingfatalities), and renal insufficiency have been reported. InterruptTARCEVA in the event of dehydration. Monitor renal function andelectrolytes in patients at risk of dehydration. (5.4)Myocardial infarction/ischemia has beenreported, including fatalities, in patients with pancreatic cancer.(5.5)Cerebrovascular accidents, including afatality, have been reported in patients with pancreatic cancer.(5.6)Microangiopathic Hemolytic Anemia withthrombocytopenia has been reported in patients with pancreaticcancer. (5.7)Women should be advised to avoid pregnancywhile on TARCEVA. Treatment should only be continued if thepotential benefit to the mother outweighs the risk to the fetus.(5.8)InternationalNormalized Ratio (INR) elevations and bleeding events, someassociated with concomitant warfarin administration have beenreported. Monitor patients taking warfarin or othercoumarin-derivative anticoagulants. (5.9). Interstitial Lung Disease (ILD)-like events,including fatalities have been infrequently reported. InterruptTARCEVA if acute onset of new or progressive unexplained pulmonarysymptoms, such as dyspnea, cough and fever occur. DiscontinueTARCEVA if ILD is diagnosed. (5.1). Monitor patients with hepatic impairmentclosely. Interrupt or discontinue TARCEVA if changes in liverfunction are severe (5.2). Cases of hepatic failure and hepatorenalsyndrome (including fatalities) have been reported. Monitor periodicliver function testing. Interrupt or discontinue TARCEVA if liverfunction changes are severe. (5.3). Cases of acute renal failure (includingfatalities), and renal insufficiency have been reported. InterruptTARCEVA in the event of dehydration. Monitor renal function andelectrolytes in patients at risk of dehydration. (5.4). Myocardial infarction/ischemia has beenreported, including fatalities, in patients with pancreatic cancer.(5.5). Cerebrovascular accidents, including afatality, have been reported in patients with pancreatic cancer.(5.6). Microangiopathic Hemolytic Anemia withthrombocytopenia has been reported in patients with pancreaticcancer. (5.7). Women should be advised to avoid pregnancywhile on TARCEVA. Treatment should only be continued if thepotential benefit to the mother outweighs the risk to the fetus.(5.8). InternationalNormalized Ratio (INR) elevations and bleeding events, someassociated with concomitant warfarin administration have beenreported. Monitor patients taking warfarin or othercoumarin-derivative anticoagulants. (5.9). 5.1 Pulmonary Toxicity. There have been infrequent reports of serious Interstitial LungDisease (ILD)-like events, including fatalities, in patientsreceiving TARCEVA for treatment of NSCLC, pancreatic cancer or otheradvanced solid tumors. In the randomized single-agent NSCLC study[see CLINICAL STUDIES (14.1)],the incidence of ILD-like events (0.8%) was the same in both theplacebo and TARCEVA groups. In the pancreatic cancer study incombination with gemcitabine [see Clinical Studies(14.3)], theincidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabinegroup vs. 0.4% in the placebo plus gemcitabine group. The overall incidence of ILD-like events in approximately 4900TARCEVA-treated patients from all studies (including uncontrolledstudies and studies with concurrent chemotherapy) was approximately0.7%. Reported diagnoses in patients suspected of having ILD-likeevents included pneumonitis, radiation pneumonitis, hypersensitivitypneumonitis, interstitial pneumonia, interstitial lung disease,obliterative bronchiolitis, pulmonary fibrosis, Acute RespiratoryDistress Syndrome and lung infiltration. Symptoms started from daysto more than months (median 39 days) after initiating TARCEVAtherapy. In the lung cancer trials most of the cases were associatedwith confounding or contributing factors such as concomitant/priorchemotherapy, prior radiotherapy, pre-existing parenchymal lungdisease, metastatic lung disease, or pulmonary infections. In the event of an acute onset of new or progressive unexplainedpulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapyshould be interrupted pending diagnostic evaluation. If ILD isdiagnosed, TARCEVA should be discontinued and appropriate treatmentinstituted as needed [see Dosage and Administration (2.3)]. 5.2 Patients with Hepatic Impairment. In pharmacokinetic study in patients with moderate hepaticimpairment (Child-Pugh B) associated with significant liver tumorburden, 10 out of 15 patients died on treatment or within 30 days ofthe last TARCEVA dose. One patient died from hepatorenal syndrome, 1patient died from rapidly progressing liver failure and the remaining8 patients died from progressive disease. Six out of the 10 patientswho died had baseline total bilirubin 3 ULN suggesting severehepatic impairment. Treatment with TARCEVA should be used with extracaution in patients with total bilirubin 3 ULN. Patients withhepatic impairment (total bilirubin ULN or Child-Pugh A, andC) should be closely monitored during therapy with TARCEVA. TARCEVAdosing should be interrupted or discontinued if changes in liverfunction are severe such as doubling of total bilirubin and/ortripling of transaminases in the setting of pretreatment valuesoutside normal range [see Clinical Pharmacology (12.3)and Dosage and Administration (2.3)].. 5.3 Hepatotoxicity. Cases of hepatic failure and hepatorenal syndrome (includingfatalities) have been reported during use of TARCEVA, particularly inpatients with baseline hepatic impairment. Therefore, periodic liverfunction testing (transaminases, bilirubin, and alkaline phosphatase)is recommended. In the setting of worsening liver function tests,dose interruption and/or dose reduction with frequent liver functiontest monitoring should be considered. TARCEVA dosing should beinterrupted or discontinued if total bilirubin is >3 ULN and/ortransaminases are >5 ULN in the setting of normal pretreatmentvalues [see Adverse Reactions (6.3)and Dosage and Administration (2.3)].. 5.4 Renal Failure. Cases of hepatorenal syndrome, acute renal failure (includingfatalities), and renal insufficiency have been reported. Some weresecondary to baseline hepatic impairment while others were associatedwith severe dehydration due to diarrhea, vomiting, and/or anorexia orconcurrent chemotherapy use. In the event of dehydration,particularly in patients with contributing risk factors for renalfailure (eg, pre-existing renal disease, medical conditions ormedications that may lead to renal disease, or other predisposingconditions including advanced age), TARCEVA therapy should beinterrupted and appropriate measures should be taken to intensivelyrehydrate the patient. Periodic monitoring of renal function andserum electrolytes is recommended in patients at risk of dehydration[see Adverse Reactions (6.3)and Dosage and Administration (2.3)].. 5.5 Myocardial infarction/ischemia. In the pancreatic carcinoma trial, six patients (incidence of2.3%) in the TARCEVA/gemcitabine group developed myocardialinfarction/ischemia. One of these patients died due to myocardialinfarction. In comparison, patients in the placebo/gemcitabinegroup developed myocardial infarction (incidence 1.2%) and one dieddue to myocardial infarction.. 5.6 Cerebrovascular accident. In the pancreatic carcinoma trial, six patients in theTARCEVA/gemcitabine group developed cerebrovascular accidents(incidence: 2.3%). One of these was hemorrhagic and was the onlyfatal event. In comparison, in the placebo/gemcitabine group therewere no cerebrovascular accidents.. 5.7 Microangiopathic Hemolytic Anemia with Thrombocytopenia. In the pancreatic carcinoma trial, two patients in theTARCEVA/gemcitabine group developed microangiopathic hemolytic anemiawith thrombocytopenia (incidence: 0.8%). Both patients receivedTARCEVA and gemcitabine concurrently. In comparison, in theplacebo/gemcitabine group there were no cases of microangiopathichemolytic anemia with thrombocytopenia.. 5.8 Use in Pregnancy. Pregnancy Category Women of childbearing potential should avoid becoming pregnantwhile being treated with TARCEVA. Erlotinib administered to rabbitsduring organogenesis at doses that result in plasma drugconcentrations of approximately times those in humans (AUCs at 150mg daily dose) was associated with embryo/fetal lethality andabortion. When erlotinib was administered to female rats prior tomating and through the first week of pregnancy, at doses 0.3 or 0.7times the clinical dose of 150 mg, on mg/m2 basis, there was anincrease in early resorptions that resulted in decrease in thenumber of live fetuses. [see Use in Specific Populations (8.1)]. 5.9 Elevated International Normalized Ratio and Potential Bleeding. International Normalized Ratio (INR) elevations and infrequentreports of bleeding events including gastrointestinal andnon-gastrointestinal bleedings have been reported in clinicalstudies, some associated with concomitant warfarin administration.Patients taking warfarin or other coumarin-derivative anticoagulantsshould be monitored regularly for changes in prothrombin time orINR. [see Adverse Reactions (6.3)].