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 (1.1)
`05/2013
`Dosage and Administration, Patient Selection (2.1)
`05/2013
`---------------------------INDICATIONS AND USAGE---------------------------
`TARCEVA is a kinase inhibitor indicated for:
`First-line treatment of patients with metastatic non-small cell lung
`(cid:120)
`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. (1.1)
`Maintenance treatment of patients with locally advanced or metastatic
`NSCLC whose disease has not progressed after four cycles of platinum-
`based first-line chemotherapy. (1.1)
`Treatment of locally advanced or metastatic NSCLC after failure of at
`least one prior chemotherapy regimen. (1.1)
`First-line treatment of patients with locally advanced, unresectable or
`metastatic pancreatic cancer, in combination with gemcitabine. (1.2)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Limitations of Use:
`TARCEVA is not recommended for use in combination with platinum-
`(cid:120)
`based chemotherapy.
`Safety and efficacy of TARCEVA have not been evaluated as first-line
`treatment in patients with metastatic NSCLC whose tumors have EGFR
`mutations other than exon 19 deletions or exon 21 (L858R) substitution.
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`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)
`(cid:120)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 25 mg, 100 mg, and 150 mg. (3)
`-----------------------------CONTRAINDICATIONS-----------------------------
`None. (4)
`(cid:120)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`Interstitial Lung Disease (ILD): Occurs in 1.1% of patients. Withhold
`TARCEVA for acute onset of new or progressive unexplained
`
`(cid:120)
`
`(cid:120)
`
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`1
`INDICATIONS AND USAGE
`1.1 Non-Small Cell Lung Cancer (NSCLC)
` Pancreatic Cancer
`1.2
` DOSAGE AND ADMINISTRATION
` Patient Selection
`2.1
`2.2 Recommended Dose – NSCLC
`2.3 Recommended Dose – Pancreatic Cancer
` Dose Modifications
`2.4
`
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Interstitial Lung Disease (ILD)
` Renal Failure
`5.2
`5.3 Hepatotoxicity with or without Hepatic Impairment
`5.4 Gastrointestinal Perforation
`5.5 Bullous and Exfoliative Skin Disorders
` Myocardial Infarction/Ischemia
`5.6
` Cerebrovascular Accident
`5.7
` Microangiopathic Hemolytic Anemia with Thrombocytopenia
`5.8
` Ocular Disorders
`5.9
`5.10 Hemorrhage in Patients Taking Warfarin
`5.11 Embryo-Fetal Toxicity
` ADVERSE REACTIONS
`6.1 Clinical Trial Experience
` Post-Marketing Experience
`6.2
` DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`6
`
`
`7
`
`Reference ID: 3308430
`
`1
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`(cid:120)
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
` pulmonary symptoms, such as dyspnea, cough and fever. Discontinue
`TARCEVA if ILD is diagnosed. (5.1)
`Renal Failure: Monitor renal function and electrolytes, particularly in
`patients at risk of dehydration. Withhold TARCEVA for severe renal
`toxicity. (5.2)
`Hepatotoxicity 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)
`Gastrointestinal perforations: Discontinue TARCEVA. (5.4)
`Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5)
`Myocardial infarction (MI)/ischemia: The risk of MI is increased in
`patients with pancreatic cancer. (5.6)
`Cerebrovascular accident (CVA): The risk of CVA is increased in
`patients with pancreatic cancer. (5.7)
`Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is
`increased in patients with pancreatic cancer. (5.8)
`Ocular disorders: Discontinue TARCEVA for corneal perforation,
`ulceration or persistent severe keratitis. (5.9)
`Hemorrhage in patients taking warfarin: Regularly monitor INR in
`patients taking warfarin or other coumarin-derivative anticoagulants.
`(5.10)
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`reproductive potential of potential risk to the fetus and to use highly
`effective contraception (5.11, 8.6)
`-----------------------------ADVERSE REACTIONS-----------------------------
`The most common adverse reactions ((cid:149) 20%) with TARCEVA from a
`pooled analysis of Studies 1-4 were rash, diarrhea, anorexia, fatigue,
`dyspnea, cough, nausea, and vomiting. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact OSI
`Pharmaceuticals, LLC, at 1-800-572-1932 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`----------------------------DRUG INTERACTIONS----------------------------
`CYP3A4 inhibitors increase erlotinib plasma concentrations. (7)
`(cid:120)
`CYP3A4 inducers decrease erlotinib plasma concentrations. (7)
`(cid:120)
`Drugs affecting gastric pH decrease erlotinib plasma concentrations. (7)
`(cid:120)
`Cigarette smoking decreases erlotinib plasma concentrations. (7)
`(cid:120)
`--------------------USE IN SPECIFIC POPULATIONS---------------------------
`Nursing Mothers: Discontinue drug or nursing. (8.3)
`(cid:120)
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: [05/2013]
`
`(cid:120)
`
`
`
`
`
`
`13
`
`14
`
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
` Nursing Mothers
`8.3
` Pediatric Use
`8.4
` Geriatric Use
`8.5
`8.6 Females and Males of Reproductive Potential
`8.7 Patients with Hepatic Impairment
`8.8 Patients with Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` CLINICAL STUDIES
`14.1 Non-Small Cell Lung Cancer (NSCLC) –First-Line Treatment of
`Patients with EGFR Mutations
`14.2 NSCLC – Maintenance Treatment
`14.3 NSCLC – Second/Third Line Treatment
`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 2029
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1 Non-Small Cell Lung Cancer (NSCLC)
`TARCEVA is indicated for:
`(cid:120)
`The first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor
`receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical
`Studies (14.1)].
`The maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not
`progressed after four cycles of platinum-based first-line chemotherapy [see Clinical Studies (14.2)].
`The treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior
`chemotherapy regimen [see Clinical Studies (14.3)].
`
`(cid:120)
`
`(cid:120)
`
`Limitations of use:
`TARCEVA is not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies (14.4)].
`(cid:120)
`Safety and efficacy of TARCEVA have not been evaluated as first-line treatment in patients with metastatic NSCLC whose tumors
`(cid:120)
`have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution [see Clinical Studies (14.1)].
`
`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 Patient Selection
`Select patients for the first-line treatment of metastatic NSCLC with TARCEVA based on the presence of EGFR exon 19 deletions or
`exon 21 (L858R) substitution mutations in tumor specimens [See Clinical Studies (14.1)]. 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
`Discontinue TARCEVA for:
`Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)].
`(cid:120)
`(cid:120) Severe hepatic toxicity that does not improve significantly or resolve within three weeks [see Warnings and Precautions (5.3)].
`(cid:120) Gastrointestinal perforation [see Warnings and Precautions (5.4)].
`(cid:120) Severe bullous, blistering or exfoliating skin conditions [see Warnings and Precautions (5.5)].
`(cid:120) Corneal perforation or severe ulceration [see Warnings and Precautions (5.9)].
`
`Withhold TARCEVA:
`(cid:120) During diagnostic evaluation for possible ILD.
`(cid:120) For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of TARCEVA [see Warnings and Precautions (5.2)].
`In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or
`(cid:120)
`transaminases greater than 5 times the upper limit of normal, and consider discontinuation of TARCEVA [see Warnings and
`Precautions (5.3)].
`In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values
`over baseline and consider discontinuation of TARCEVA [see Warnings and Precautions (5.3)].
`(cid:120) For persistent severe diarrhea not responsive to medical management (e.g., loperamide).
`(cid:120) For severe rash not responsive to medical management.
`(cid:120) For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks [see Warnings and Precautions (5.9)].
`(cid:120) For acute/worsening ocular disorders such as eye pain, and consider discontinuation of TARCEVA [see Warnings and Precautions
`(5.9)].
`
`(cid:120)
`
`Reference ID: 3308430
`
`2
`
`

`

`Reduce TARCEVA by 50 mg decrements:
`If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir,
`(cid:120)
`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).
`Avoid concomitant use if possible [see Drug Interactions (7)].
`(cid:120) When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade (cid:148) 1.
`
`Increase TARCEVA by 50 mg increments as tolerated for:
`(cid:120) Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or
`St. John’s Wort. Increase doses by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use, if
`possible [see Drug Interactions (7)].
`(cid:120) Concurrent cigarette smoking. Increase 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 [see Drug Interactions (7) and
`Clinical Pharmacology (12.3)].
`
`Drugs Affecting Gastric pH
`(cid:120) Avoid concomitant use of TARCEVA with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction
`since proton pump inhibitors affect the pH of the upper GI tract for an extended period.
`If treatment with an H2-receptor antagonist such as ranitidine is required, 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.
`(cid:120) Although 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.
`
`(cid:120)
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`25 mg tablets
`White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange
`with a “T” and “25” on one side and plain on the other side.
`
`100 mg tablets
`White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with
`“T” and “100” on one side and plain on the other side.
`
`150 mg tablets
`White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon
`with “T” and “150” on one side and plain on the other side.
`
`4
`
`CONTRAINDICATIONS
`None
`
`5 WARNINGS AND PRECAUTIONS
`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 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
`
`Reference ID: 3308430
`
`3
`
`

`

`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)].
`
`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 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)].
`
`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 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)].
`
`5.6 Myocardial Infarction/Ischemia
`In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the TARCEVA/gemcitabine group developed myocardial
`infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group
`developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial
`infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the TARCEVA arms and 0.4% in the control arms.
`
`5.7 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 0.9% in the control arms.
`
`5.8 Microangiopathic Hemolytic Anemia with Thrombocytopenia
`The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung 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.
`
`5.9 Ocular Disorders
`Corneal perforation or ulceration can occur with TARCEVA treatment. Other ocular disorders including abnormal eyelash growth,
`keratoconjunctivitis sicca or keratitis have been observed with TARCEVA treatment and are known risk factors for corneal
`ulceration/perforation [see Adverse Reactions (6.1)]. 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/worsening ocular disorders such as eye pain [see Dosage and Administration (2.4)].
`
`5.10 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)].
`
`5.11 Embryo-Fetal Toxicity
`Based on 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 doses approximately 3 times the
`recommended human daily dose of 150 mg. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking
`this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
`
`Reference ID: 3308430
`
`4
`
`

`

`Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose
`of TARCEVA. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking
`TARCEVA [see Use in Specific Populations (8.1) and (8.6)].
`
`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) Myocardial Infarction/Ischemia [see Warnings and Precautions (5.6)]
`(cid:120) Cerebrovascular Accident [see Warnings and Precautions (5.7)]
`(cid:120) Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.8)]
`(cid:120) Ocular Disorders [see Warnings and Precautions (5.9)]
`(cid:120) Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.10)]
`
`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:149) 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%).
`
`Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an
`increase in (cid:149) 5% in the TARCEVA treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of
`TARCEVA treatment was 9.6 months in Study 4.
`
`Reference ID: 3308430
`
`5
`
`

`

`Table 1: Selected Adverse Reactions with an Incidence Rate (cid:149) 10% and an Increase of (cid:149) 5% in the TARCEVA-treated Group
`(Study 4)
`
`TARCEVA
`N = 84
`
`Chemotherapy †
`N = 83
`All Grades
`%
`2
`21
`40
`30
`2
`5
`12
`0
`6
`1
`0
`6
`1
`
`Grades 3-4
`All Grades
`%
`%
`MedDRA Preferred Term
`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 doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel)
`‡ Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia
`syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.
`
`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 4 [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-CTC (version 3.0)
`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: Selected Adverse Reactions Occurring with an Incidence Rate (cid:149) 10% and an Increase of
`(cid:149) 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 3)
`TARCEVA
`PLACEBO
`N = 433
`N = 445
`Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
`NCI-CTC Grade
`%
`%
`%
`%
`%
`%
`MedDRA Preferred Term
`Rash †
`60
`9
`0
`9
`0
`0
`20
`2
`0
`4
`0
`0
`Diarrhea
`† Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin
`exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, skin hyperpigmentation,
`skin reaction, skin ulcer.
`
`Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% 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 Precaution (5.3)].
`
`Reference ID: 3308430
`
`6
`
`

`

`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 (version
`2.0) 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.
`
`Table 3: NSCLC 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence Rate (cid:149) 10% and an Increase of
`(cid:149) 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 1)
`TARCEVA 150 mg
`Placebo
`N=485
`N=242
`Any Grade Grade 3 Grade 4
`Any Grade Grade 3 Grade 4
`NCI-CTC Grade
`%
`%
`%
`%
`%
`%
`MedDRA Preferred Term
`Rash †
`75
`8
`<1
`17
`0
`0
`54
`6
`<1
`18
`<1
`0
`Diarrhea
`52
`8
`1
`38
`5
`<1
`Anorexia
`52
`14
`4
`45
`16
`4
`Fatigue
`41
`17
`11
`35
`15
`11
`Dyspnea
`33
`3
`0
`24
`2
`0
`Nausea
`24
`4
`0
`15
`2
`0
`Infection
`17
`<1
`0
`3
`0
`0
`Stomatitis
`13
`<1
`0
`5
`0
`0
`Pruritus
`12
`0
`0
`4
`0
`0
`Dry skin
`12
`<1
`0
`2
`<1
`0
`Conjunctivitis
`12
`0
`0
`3
`0
`0
`Keratoconjunctivitis sicca
`† Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema,
`skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.
`
`Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin)
`were 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 ULN) ALT elevations occurred in 4% and < 1% of TARCEVA and placebo 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 IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population
`comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo
`group (256 in the 100 mg cohort and 24 in the 150 mg cohort).
`
`Adverse reactions that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial of
`patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4.
`
`The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine 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 ((cid:149) Grade 3 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 a higher rate of certain class-specific adverse reactions including rash and required more
`frequent dose reduction or interruption.
`
`Reference ID: 3308430
`
`7
`
`

`

`Table 4: Selected Adverse Reactions Occurring with an Incidence Rate (cid:149) 10