HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TARCEVA® safely and effectively. See full prescribing information for
`TARCEVA.
`
`TARCEVA (erlotinib) tablets, for oral use
`Initial U.S. Approval: 2004
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage, Non-Small Cell Lung Cancer (NSCLC) (1.1) 10/2016
`Dosage and Administration (2.1)
`06/2016
`Dosage and Administration, Dose Modifications (2.4)
`05/2016
`Warnings and Precautions, Cerebrovascular Accident (5.6)
`10/2016
`Warnings and Precautions, Embryo-fetal Toxicity (5.10)
`10/2016
`---------------------------INDICATIONS AND USAGE---------------------------
`TARCEVA is a kinase inhibitor indicated for:
`(cid:120) The treatment of patients with metastatic non-small cell lung cancer
`(NSCLC) whose tumors have epidermal growth factor receptor (EGFR)
`exon 19 deletions or exon 21 (L858R) substitution mutations as detected by
`an FDA-approved test receiving first-line, maintenance, or second or
`greater line treatment after progression following at least one prior
`chemotherapy regimen. (1.1)
`(cid:120) First-line treatment of patients with locally advanced, unresectable or
`metastatic pancreatic cancer, in combination with gemcitabine. (1.2)
`Limitations of Use:
`(cid:120) Safety and efficacy of TARCEVA have not been established in patients
`with NSCLC whose tumors have other EGFR mutations. (1.1)
`(cid:120) TARCEVA is not recommended for use in combination with platinum-
`based chemotherapy. (1.1)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`(cid:120) NSCLC: 150 mg orally, on an empty stomach, once daily. (2.2)
`(cid:120) Pancreatic cancer: 100 mg orally, on an empty stomach, once daily. (2.3)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 25 mg, 100 mg, and 150 mg (3)
`-----------------------------CONTRAINDICATIONS-----------------------------
`None. (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`(cid:120) Interstitial 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)
`(cid:120) Renal failure: Monitor renal function and electrolytes, particularly in
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Non-Small Cell Lung Cancer (NSCLC)
`1.2 Pancreatic Cancer
`DOSAGE AND ADMINISTRATION
`2.1 Selection of Patients with Metastatic NSCLC
`2.2 Recommended Dose – NSCLC
`2.3 Recommended Dose – Pancreatic Cancer
`2.4 Dose Modifications
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Interstitial Lung Disease (ILD)
`5.2 Renal Failure
`5.3 Hepatotoxicity with or without Hepatic Impairment
`5.4 Gastrointestinal Perforation
`5.5 Bullous and Exfoliative Skin Disorders
`5.6 Cerebrovascular Accident
`5.7 Microangiopathic Hemolytic Anemia with Thrombocytopenia
`5.8 Ocular Disorders
`5.9 Hemorrhage in Patients Taking Warfarin
`5.10 Embryo-fetal Toxicity
`ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`6.2 Post-Marketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`
`6
`
`7
`8
`
`Reference ID: 4000318
`
`1
`
`patients at risk of dehydration. Withhold TARCEVA for severe renal
`toxicity. (5.2)
`(cid:120) Hepatotoxicity: 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)
`(cid:120) Gastrointestinal perforations: Discontinue TARCEVA. (5.4)
`(cid:120) Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5)
`(cid:120) Cerebrovascular accident (CVA): The risk of CVA is increased in patients
`with pancreatic cancer. (5.6)
`(cid:120) Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is
`increased in patients with pancreatic cancer. (5.7)
`(cid:120) Ocular disorders: Discontinue TARCEVA for corneal perforation,
`ulceration or persistent severe keratitis. (5.8)
`(cid:120) Hemorrhage in patients taking warfarin: Regularly monitor INR in patients
`taking warfarin or other coumarin-derivative anticoagulants. (5.9)
`(cid:120) Embryo-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)
`-----------------------------ADVERSE REACTIONS-----------------------------
`The most common adverse reactions ((cid:149) 20%) with TARCEVA from a 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
`----------------------------DRUG INTERACTIONS----------------------------
`(cid:120) CYP3A4 inhibitors or a combined CYP3A4 and CYP1A2 inhibitor
`increase erlotinib plasma concentrations. Avoid concomitant use. If not
`possible, reduce TARCEVA dose. (2.4, 7)
`(cid:120) CYP3A4 inducers decrease erlotinib plasma concentrations. Avoid
`concomitant use. If not possible, increase TARCEVA dose. (2.4, 7)
`(cid:120) Cigarette smoking and CYP1A2 inducers decrease erlotinib plasma
`concentrations. Avoid concomitant use. If not possible, increase
`TARCEVA dose. (2.4, 7)
`(cid:120) Drugs 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)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`Lactation: Do not breastfeed (8.2)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 10/2016
`
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of
`Patients with EGFR Mutations
`14.2 NSCLC – Lack of Efficacy of TARCEVA in Maintenance
`Treatment of Patients without EGFR Mutations
`14.3 NSCLC – Maintenance Treatment or Second/Third Line Treatment
`14.4 NSCLC – Lack of Efficacy of TARCEVA Administered
`Concurrently with Chemotherapy
`14.5 Pancreatic Cancer – TARCEVA Administered Concurrently with
`Gemcitabine
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed.
`OSI 2030
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1 Non-Small Cell Lung Cancer (NSCLC)
`TARCEVA® is indicated for:
`The treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor
`(cid:120)
`(EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line,
`maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen [see Clinical
`Studies (14.1, 14.3)].
`
`Limitations of use:
`Safety and efficacy of TARCEVA have not been established in patients with NSCLC whose tumors have other EGFR mutations
`(cid:120)
`[see Clinical Studies (14.1, 14.2)].
`TARCEVA is not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies (14.4)].
`
`(cid:120)
`
`1.2 Pancreatic Cancer
`TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or
`metastatic pancreatic cancer [see Clinical Studies (14.5)].
`
`DOSAGE AND ADMINISTRATION
`2
`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 a
`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)].
`
`Reference ID: 4000318
`
`2
`
`

`

`2.4 Dose Modifications
`Adverse Reactions
`
`Pulmonary†
`
`Interstitial Lung Disease (ILD)
`
`Discontinue TARCEVA
`
`During diagnostic evaluation for possible ILD
`
`Withhold TARCEVA*
`
`Severe hepatic toxicity that does not improve
`significantly or resolve within three weeks
`
`Discontinue TARCEVA
`
`Hepatic†
`
`In patients with pre-existing hepatic impairment or
`biliary obstruction for doubling of bilirubin or tripling of
`transaminases values over baseline
`
`Withhold TARCEVA* and consider
`discontinuation
`
`In patients without pre-existing hepatic impairment for
`total bilirubin levels greater than 3 times the upper limit
`of normal or transaminases greater than 5 times the
`upper limit of normal
`
`Renal†
`
`For severe (CTCAE grade 3 to 4) renal toxicity
`
`Gastrointestinal perforation
`For persistent severe diarrhea not responsive to medical
`management (e.g., loperamide)
`Severe bullous, blistering or exfoliating skin conditions
`
`For severe rash not responsive to medical management
`Corneal perforation or severe ulceration
`
`Withhold TARCEVA* and consider
`discontinuation
`
`Withhold TARCEVA* and consider
`discontinuation
`Discontinue TARCEVA
`
`Withhold TARCEVA*
`
`Discontinue TARCEVA
`Withhold TARCEVA*
`Discontinue TARCEVA
`
`Gastrointestinal†
`
`Skin†
`
`Ocular†
`
`Drug Interactions
`
`CYP3A4 inhibitors‡
`
`For keratitis of (NCI-CTC version 4.0) grade 3-4 or for
`grade 2 lasting more than 2 weeks
`
`Withhold TARCEVA*
`
`For acute/worsening ocular disorders such as eye pain
`
`Withhold TARCEVA* and consider
`discontinuation
`
`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)
`
`CYP3A4 inducers‡
`
`Concomitant use with CYP3A4 inducers, such as
`rifampin, rifabutin, rifapentine, phenytoin,
`carbamazepine, phenobarbital, or St. John’s Wort
`
`Concurrent Cigarette
`Smoking ‡§
`
`Concurrent cigarette smoking
`
`Reduce TARCEVA by 50 mg decrements;
`avoid concomitant use if possible
`
`Increase TARCEVA by 50 mg increments at
`2-week intervals to a maximum of 450 mg
`as tolerated. Avoid concomitant use if
`possible
`
`Increase TARCEVA by 50 mg increments at
`2-week intervals to a 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 inhibitors
`
`Separation of doses may not eliminate the interaction
`since proton pump inhibitors affect the pH of the upper
`GI tract for an extended period
`
`Avoid concomitant use if possible
`
`Reference ID: 4000318
`
`3
`
`

`

`H2-receptor antagonists
`
`If 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
`2 hours before the next dose of the H2-
`receptor antagonist
`
`Antacids
`
`The 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
`
`For additional information see Warnings and Precautions (5).
`†
`* Reduce TARCEVA by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to
`(cid:69)(cid:68)(cid:86)(cid:72)(cid:79)(cid:76)(cid:81)(cid:72)(cid:3)(cid:82)(cid:85)(cid:3)(cid:74)(cid:85)(cid:68)(cid:71)(cid:72)(cid:3)(cid:148)(cid:3)(cid:20)(cid:17)
`For additional information see Drug Interactions (7).
`For additional information see Clinical Pharmacology (12.3).
`
`‡
`§
`
`DOSAGE FORMS AND STRENGTHS
`25 mg tablets: round, biconvex face and straight sides, white film-coated, printed in orange with “T” and “25” on one side and plain on
`other side.
`
`100 mg tablets: round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on
`other side.
`
`150 mg tablets: round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain
`on other side.
`
`CONTRAINDICATIONS
`None.
`
`3
`
`4
`
`5
`5.1
`
`WARNINGS AND PRECAUTIONS
`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 5 days to more than 9 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 3 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 3 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 a pharmacokinetic study in 15 patients with moderate hepatic
`impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last
`TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining
`8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x 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 3 times the upper limit of normal or
`transaminases greater than 5 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)].
`
`Reference ID: 4000318
`
`4
`
`

`

`5.4
`
`5.5
`
`5.6
`
`5.7
`
`5.8
`
`5.9
`
`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 3
`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)].
`
`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 3 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)].
`
`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 3 monotherapy lung cancer studies was 0.6% in the
`TARCEVA arms and not higher than that observed in the control arms.
`
`Microangiopathic Hemolytic Anemia with Thrombocytopenia
`The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 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.
`
`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 3
`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)].
`
`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 a pregnant woman. When
`given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures
`approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a
`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)].
`
`6
`
`ADVERSE REACTIONS
`The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:
`Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]
`(cid:120)
`(cid:120) Renal Failure [see Warnings and Precautions (5.2)]
`(cid:120) Hepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3)]
`(cid:120) Gastrointestinal Perforation [see Warnings and Precautions (5.4)]
`(cid:120) Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5)]
`(cid:120) Cerebrovascular Accident [see Warnings and Precautions (5.6)]
`(cid:120) Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7)]
`(cid:120) Ocular Disorders [see Warnings and Precautions (5.8)]
`(cid:120) Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9)]
`
`Reference ID: 4000318
`
`5
`
`

`

`6.1 Clinical Trial Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Cancer
`
`First-Line Treatment of Patients with EGFR Mutations
`
`The most frequent (cid:11)(cid:149) (cid:22)(cid:19)(cid:8)(cid:12) 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
`(cid:76)(cid:81)(cid:3)(cid:149)(cid:3)(cid:24)(cid:8)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72) 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.
`
`(cid:55)(cid:68)(cid:69)(cid:79)(cid:72)(cid:3)(cid:20)(cid:29)(cid:3)(cid:3)(cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:53)(cid:68)(cid:87)(cid:72)(cid:3)(cid:149)(cid:3)(cid:20)(cid:19)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:149)(cid:3)(cid:24)(cid:8)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:55)(cid:36)(cid:53)(cid:38)(cid:40)(cid:57)(cid:36)-Treated Group (Study 1)
`Chemotherapy†
`TARCEVA
`N = 84
`N = 83
`All Grades
`%
`5
`21
`40
`30
`2
`5
`12
`0
`6
`1
`0
`6
`1
`
`Grades 3-4
`All Grades
`%
`%
`Adverse Reaction
`Rash ‡
`14
`85
`5
`62
`Diarrhea
`1
`48
`Cough
`8
`45
`Dyspnea
`1
`21
`Dry skin
`2
`19
`Back pain
`1
`18
`Chest pain
`0
`18
`Conjunctivitis
`1
`18
`Mucosal inflammation
`0
`16
`Pruritus
`0
`14
`Paronychia
`1
`13
`Arthralgia
`1
`11
`Musculoskeletal pain
`† Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).
`‡ Rash as a 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.
`
`Grades 3-4
`%
`0
`1
`0
`4
`0
`0
`0
`0
`0
`0
`0
`1
`0
`
`Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4
`liver test abnormalities in Study 1 [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.
`
`Reference ID: 4000318
`
`6
`
`

`

`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.
`
`Adverse Reaction
`
`Table 2: (cid:49)(cid:54)(cid:38)(cid:47)(cid:38)(cid:3)(cid:48)(cid:68)(cid:76)(cid:81)(cid:87)(cid:72)(cid:81)(cid:68)(cid:81)(cid:70)(cid:72)(cid:3)(cid:54)(cid:87)(cid:88)(cid:71)(cid:92)(cid:29)(cid:3) (cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:50)(cid:70)(cid:70)(cid:88)(cid:85)(cid:85)(cid:76)(cid:81)(cid:74)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:53)(cid:68)(cid:87)(cid:72)(cid:3)(cid:149)(cid:3)(cid:20)(cid:19)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:149)(cid:3)(cid:24)(cid:8)(cid:3)(cid:76)(cid:81)(cid:3)
`the Single-Agent TARCEVA Group compared to the Placebo Group (Study 3)
`PLACEBO
`TARCEVA
`N = 445
`N = 433
`Any Grade Grade 3 Grade 4
`Any Grade Grade 3 Grade 4
`%
`%
`%
`%
`%
`%
`Rash †
`9
`0
`0
`60
`9
`0
`4
`0
`0
`20
`2
`0
`Diarrhea
`† Rash as a 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.
`
`Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of TARCEVA-treated patients
`and 1% of placebo-treated patients. Grade 2 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 Treatment
`
`Adverse 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
`8 days, and the median time to onset of diarrhea was 12 days.
`
`Adverse Reaction
`
`Table 3: NSCLC 2nd/3rd (cid:47)(cid:76)(cid:81)(cid:72)(cid:3)(cid:54)(cid:87)(cid:88)(cid:71)(cid:92)(cid:29)(cid:3) (cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:50)(cid:70)(cid:70)(cid:88)(cid:85)(cid:85)(cid:76)(cid:81)(cid:74)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:53)(cid:68)(cid:87)(cid:72)(cid:3)(cid:149)(cid:3)(cid:20)(cid:19)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:68)(cid:81)(cid:3)(cid:44)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:149)(cid:3)5% in
`the Single-Agent TARCEVA Group Compared to the Placebo Group (Study 4)
`Placebo
`TARCEVA 150 mg
`N=242
`N=485
`Any Grade Grade 3 Grade 4
`Any Grade Grade 3 Grade 4
`%
`%
`%
`%
`%
`%
`Rash †
`17
`0
`0
`75
`8
`<1
`18
`<1
`0
`54
`6
`<1
`Diarrhea
`38
`5
`<1
`52
`8
`1
`Anorexia
`45
`16
`4
`52
`14
`4
`Fatigue
`35
`15
`11
`41
`17
`11
`Dyspnea
`24
`2
`0
`33
`3
`0
`Nausea
`15
`2
`0
`24
`4
`0
`Infection
`3
`0
`0
`17
`<1
`0
`Stomatitis
`5
`0
`0
`13
`<1
`0
`Pruritus
`4
`0
`0
`12
`0
`0
`Dry skin
`2
`<1
`0
`12
`<1
`0
`Conjunctivitis
`3
`0
`0
`12
`0
`0
`Keratoconjunctivitis sicca
`† Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema,
`skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.
`
`Liver 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 [> 2.5 – 5.0 x upper limit of normal (ULN)] ALT elevations occurred in 4% and < 1% of TARCEVA and placebo
`
`Reference ID: 4000318
`
`7
`
`

`

`treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA
`dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.4)].
`
`Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine
`
`This was a randomized, double–blind, placebo-controlled study of TARCEVA (150 mg or 100 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 ons