event of dehydration. Monitor renal function and electrolytes in
`patients at risk of dehydration. (5.2)
`
`• Cases of hepatic failure and hepatorenal syndrome (including
`
`fatalities) have been reported. Monitor periodic liver function
`
`testing. Interrupt or discontinue TARCEVA if liver function
`changes are severe. (5.3)
`• Monitor patients with hepatic impairment closely. Interrupt or
`
`
`discontinue TARCEVA if changes in liver function are severe
`(5.4)
`• Gastrointestinal perforations, including fatalities, have been
`
`reported. Discontinue TARCEVA. (5.5)
`
`• Bullous and exfoliative skin disorders, including fatalities, have
`
`been reported. Interrupt or discontinue TARCEVA (5.6)
`
`
`• Myocardial infarction/ischemia has been reported, including
`
`
`fatalities, in patients with pancreatic cancer. (5.7)
`
`• Cerebrovascular accidents, including a fatality, have been reported
`in patients with pancreatic cancer. (5.8)
`• Microangiopathic Hemolytic Anemia with thrombocytopenia has
`been reported in patients with pancreatic cancer. (5.9)
`
`
`• Corneal perforation and ulceration have been reported. Interrupt or
`
`
`
`discontinue TARCEVA (5.10)
`
`• Women should be advised to avoid pregnancy while on
`
`TARCEVA. Treatment should only be continued if the potential
`
`
`benefit to the mother outweighs the risk to the fetus. (5.11)
`International Normalized Ratio (INR) elevations and bleeding
`events, some associated with concomitant warfarin administration
`have been reported. Monitor patients taking warfarin or other
`
`
`
`coumarin-derivative anticoagulants. (5.12)
`
`
`
`
`
`•
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions (>50%) in NSCLC are rash, diarrhea,
`
`
`anorexia and fatigue. (6.1)
`
`
`The most common adverse reactions (>50%) in pancreatic cancer are fatigue,
`
`
`rash, nausea and anorexia. (6.2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact OSI
`
`Pharmaceuticals Inc. at 1-800-572-1932 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`• 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)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`Revised: [04/2009]
`
`
`
` Nursing Mothers
`8.3
` Pediatric Use
`8.4
` Geriatric Use
`8.5
` Gender
`8.6
`
` Race
`8.7
`8.8 Patients with Hepatic Impairment
`8.9 Patients with Renal Impairment
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`14.1 Non-Small Cell Lung Cancer NSCLC – TARCEVA administered
`as a Single-agent
`14.2 NSCLC - TARCEVA Administered Concurrently with
`
`Chemotherapy
`
`
`14.3 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.
`
`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, oral
`
`Initial U.S. Approval: 2004
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions, Gastrointestinal Perforation (5.5)
`04/2009
`
`Warnings and Precautions, Bullous Skin Disorders (5.6)
`04/2009
`Warnings and Precautions, Ocular Disorders (5.10)
`04/2009
`Warning and Precautions, Renal Failure (5.2)
`09/2008
`Warnings and Precautions, Hepatotoxicity (5.3)
`09/2008
`
`Warnings and Precautions, Hepatic Impairment (5.4)
`09/2008
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`TARCEVA is a kinase inhibitor indicated for the treatment of:
`•
`
`Locally advanced or metastatic non-small cell lung cancer (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)
`
`•
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`•
`
`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 least one hour before or two
`
`hours after food. (2.1, 2.2)
`
`• Reduce in 50 mg decrements, when necessary. (2.3)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`•
`
`Tablets: 25 mg, 100 mg and 150 mg. (3)
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`• None. (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`•
`
`Interstitial Lung Disease (ILD)-like events, including fatalities
`have been infrequently reported. Interrupt TARCEVA if acute
`onset of new or progressive unexplained pulmonary symptoms,
`
`such as dyspnea, cough and fever occur. Discontinue TARCEVA
`if ILD is diagnosed. (5.1)
`
`• Cases of acute renal failure (including fatalities), and renal
`
`
`insufficiency have been reported. Interrupt TARCEVA in the
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`1
`INDICATIONS AND USAGE
`1.1 Non-Small Cell Lung Cancer (NSCLC)
`
`1.2
` Pancreatic Cancer
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose - NSCLC
`2.2 Recommended Dose – Pancreatic Cancer
`
`2.3
` Dose Modifications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
` Pulmonary Toxicity
`5.1
`
`
` Renal Failure
`5.2
`
` Hepatotoxicity
`5.3
`
`5.4 Patients with Hepatic Impairment
`5.5
` Gastrointestinal perforation
`5.6 Bullous and exfoliative skin disorders
`5.7
` Myocardial infarction/ischemia
` Cerebrovascular accident
`5.8
`
`5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia
`5.10 Ocular Disorders
`
`5.11 Use in Pregnancy
`
`
`
`5.12 Elevated International Normalized Ratio and Potential Bleeding
`6 ADVERSE REACTIONS
`6.1 Non-Small Cell Lung Cancer
`
`6.2
` Pancreatic Cancer
`6.3 NSCLC and Pancreatic Cancer Indications
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
`
`
`
`1 of 20
`
`AVENTIS EXHIBIT 2092
`Mylan v. Aventis, IPR2016-00712
`
`

`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`1.1
`
`Non-Small Cell Lung Cancer (NSCLC)
`
`TARCEVA monotherapy is indicated for 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 (14.1)].
`
`
`Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials 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 or gemcitabine and
`cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].
`
`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 (14.4)].
`
`DOSAGE AND ADMINISTRATION
`
`
`2
`
`
`2.1
`
`Recommended Dose - NSCLC
`
`The recommended daily dose of TARCEVA for non-small cell lung cancer is 150 mg taken at least one hour before or two hours after the ingestion of food.
`
`Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.
`
`
`2.2
`
`Recommended Dose – Pancreatic Cancer
`
`The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken at least one hour before or two hours after the ingestion of food, in
`combination with gemcitabine (see the gemcitabine package insert). Treatment should continue until disease progression or unacceptable toxicity occurs.
`
`2.3
`
`Dose Modifications
`
`In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with TARCEVA should be
`interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, TARCEVA should be discontinued and appropriate treatment
`
`instituted as necessary [see Warnings and Precautions (5.1)]. Discontinue TARCEVA for hepatic failure or gastrointestinal perforation. Interrupt or discontinue
`TARCEVA in patients with dehydration who are at risk for renal failure, in patients with severe bullous, blistering or exfoliative skin conditions, or in patients
`with acute /worsening ocular disorders [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.10)].
`
`Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require
`
`
`dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy.
`
`
`
`When dose reduction is necessary, the TARCEVA dose should be reduced in 50 mg decrements.
`
`
`In patients who are taking TARCEVA with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole,
`
`ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose
`reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking TARCEVA with an inhibitor of both CYP3A4 and
`
`CYP1A2 like ciprofloxacin, a dose reduction of TARCEVA should be considered if severe adverse reactions occur [see Drug Interactions (7)].
`
`
`
`
`
`2 of 20
`
`

`
`
`
`3
`
`Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3 to 4/5. Use of alternative treatments lacking CYP3A4 inducing
`activity is strongly recommended. If an alternative treatment is unavailable, an increase in the dose of TARCEVA should be considered as tolerated at two week
`
`
`intervals while monitoring the patient’s safety. The maximum dose of TARCEVA studied in combination with rifampicin is 450 mg. 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. John's Wort. These too should be
`
`
`avoided if possible [see Drug Interactions (7)].
`
`
`Cigarette smoking has been shown to reduce erlotinib exposure. Patients should be advised to stop smoking. If a patient continues to smoke, a cautious increase
`
`in the dose of TARCEVA, not exceeding 300 mg may be considered, while monitoring the patient’s safety. However, efficacy and long-term safety (> 14 days)
`
`of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes. If the TARCEVA dose is adjusted
`
`upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Clinical Pharmacology (12.3)].
`
`
`Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic
`function (Child-Pugh B), patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with
`
`
`TARCEVA [see Warnings and Precautions (5.4)]. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN.
`TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of
`transaminases in the setting of pretreatment values outside normal range. In the setting of worsening liver function tests, before they become severe, dose
`interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if
`
`total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.3, 5.4), Adverse
`
`
`Reactions (6.3) and Use in Specific Populations (8.6)].
`
`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 Pulmonary Toxicity
`
`
`There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of
`NSCLC, pancreatic cancer or other advanced 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 the placebo and TARCEVA groups. In the pancreatic cancer study - in combination with gemcitabine – [see Clinical Studies
`
`
`
`(14.3)], the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group.
`
`
`
`The overall incidence of ILD-like events in approximately 4900 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with
`concurrent chemotherapy) was approximately 0.7%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation
`
`pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory
`
`Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating TARCEVA therapy. In the lung
`
`cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre­
`
`
`existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.
`
`
`
`
`
`
`
`3 of 20
`
`

`
`
`
`In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be
`interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed [see Dosage
`
`
`and Administration (2.3)].
`
`5.2
`
` Renal Failure
`
`
`Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic
`
`impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of
`
`
`
`dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may
`
`lead to renal disease, or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be
`taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see
`
`Adverse Reactions (6.3) and Dosage and Administration (2.3)].
`
`
` Hepatotoxicity
`
`Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of TARCEVA, particularly in patients with baseline
`hepatic impairment. Therefore, periodic liver function 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 function test monitoring should be considered. TARCEVA dosing should be
`interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions
`(6.3) and Dosage and Administration (2.3)].
`
`
`
`Patients with Hepatic Impairment
`
`In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients
`
`
`died on treatment or 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 suggesting severe
`hepatic impairment. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment
`
`
`(total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or
`discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values
`outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)].
` Gastrointestinal Perforation
`
`Gastrointestinal perforation (including fatalities) has been reported in patients receiving TARCEVA. Patients receiving concomitant anti-angiogenic agents,
`corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. [see
`Adverse Reactions (6.3]. Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation.
`
`
`5.3
`
`
`5.4
`
`5.5
`
`5.6
`
`Bullous and Exfoliative Skin Disorders
`
`Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis,
`which in some cases were fatal [see Adverse Reactions (6.3)]. Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or
`
`exfoliating conditions.
`
`5.7
`
` Myocardial infarction/ischemia
`
`
`In the pancreatic carcinoma trial, six patients (incidence of 2.3%) 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 1.2%) and
`
`one died due to myocardial infarction.
`
`
`5.8 Cerebrovascular accident
`
`In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%) One of these was
`
`hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.
`
`
`
`
`
`4 of 20
`
`

`
`
`
`
`5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia
`
`In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia
`
`(incidence: 0.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of
`
`microangiopathic hemolytic anemia with thrombocytopenia.
`
`
`5.10 Ocular Disorders
`
`Corneal perforation and ulceration have been reported during use of TARCEVA. 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 (6.3)].
`
`Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular disorders such as eye pain.
`
`
`5.11 Use in Pregnancy
`
`Pregnancy Category D
`
`
`Women of childbearing potential should avoid becoming pregnant while being treated with TARCEVA. Erlotinib administered to rabbits during organogenesis
`
`
`at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose) was associated with embryo/fetal
`lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the
`clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses [see Use in Specific
`
`
`
`
`Populations (8.1)].
`
`
`
`5.12 Elevated International Normalized Ratio and Potential Bleeding
`
`International Normalized Ratio (INR) elevations and infrequent reports of bleeding events including gastrointestinal and non-gastrointestinal bleedings have
`
`been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants
`
`should be monitored regularly for changes in prothrombin time or INR [see Adverse Reactions (6.3)].
`
`
`
`6
`
` ADVERSE REACTIONS
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reactions 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 856 cancer patients who received TARCEVA as monotherapy, 308 patients who received TARCEVA 100 or 150
`mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies.
`
`There have been reports of serious events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced
`
`solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3)].
`
`
`6.1
`
`Non-Small Cell Lung Cancer
`
`
`Adverse reactions, 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 8 days, and the median time to onset of
`
`diarrhea was 12 days.
`
`
`
`
`
`5 of 20
`
`

`
`
`
`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 mg
`
`N = 485
`
`Placebo
`N = 242
`
`NCI-CTC Grade
`
`
`MedDRA Preferred Term
`
`
`Rash
`
`Diarrhea
`
`Anorexia
`
`Fatigue
`
`Dyspnea
`
`Cough
`
`Any
`Grade
`
`Grade 3 Grade 4
`
`Any
`Grade
`
`Grade 3 Grade 4
`
`%
`
`75
`
`54
`
`52
`
`52
`
`41
`
`33
`
`%
`
`8
`
`6
`
`8
`
`14
`
`17
`
`4
`
`3
`
`%
`
`<1
`
`<1
`
`1
`
`4
`
`11
`
`0
`
`0
`
`%
`
`17
`
`18
`
`38
`
`45
`
`35
`
`29
`
`24
`
`%
`
`0
`
`<1
`
`5
`
`16
`
`15
`
`2
`
`2
`
`%
`
`0
`
`0
`
`<1
`
`4
`
`11
`
`0
`
`0
`
`Nausea
`
`Infection
`
`Vomiting
`
`Stomatitis
`
`Pruritus
`
`Dry skin
`
`Conjunctivitis
`
`Keratoconjunctivitis sicca
`
`Abdominal pain
`
`33
`
`24
`
`23
`
`17
`
`13
`
`12
`
`12
`
`12
`
`11
`
`4
`
`2
`
`<1
`
`<1
`
`0
`
`<1
`
`0
`
`2
`
`0
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`15
`
`19
`
`3
`
`5
`
`4
`
`2
`
`3
`
`7
`
`2
`
`2
`
`0
`
`0
`
`0
`
`<1
`
`0
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`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 (2.3)].
`
`
`6.2
`
`Pancreatic Cancer
`
`
`Adverse reactions, 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 a higher rate of
`certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.
`
`
`
`
`
`
`6 of 20
`
`

`
`
`
`Table 2:
`
`
`
`Adverse Reactions Occurring in ≥ 10% of TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort
`
`
`
`TARCEVA + Gemcitabine
`1000 mg/m2 IV
`N=259
`
`Placebo + Gemcitabine
`1000 mg/m2 IV
`N=256
`
`NCI-CTC Grade
`
`
`Any Grade Grade 3 Grade 4
`
`Any
`Grade
`
`Grade 3 Grade 4
`
`MedDRA Preferred Term
`
`
`Fatigue
`
`Rash
`
`Nausea
`
`Anorexia
`
`Diarrhea
`
`%
`
`73
`
`69
`
`60
`
`52
`
`48
`
`%
`
`14
`
`5
`
`7
`
`6
`
`5
`
`%
`
`2
`
`0
`
`0
`
`<1
`
`<1
`
`%
`
`70
`
`30
`
`58
`
`52
`
`36
`
`%
`
`13
`
`1
`
`7
`
`5
`
`2
`
`%
`
`2
`
`0
`
`0
`
`<1
`
`0
`
`Abdominal pain
`
`Vomiting
`
`Weight decreased
`
`Infection*
`
`Edema
`
`Pyrexia
`
`Constipation
`
`46
`
`42
`
`39
`
`39
`
`37
`
`36
`
`31
`
`9
`
`7
`
`2
`
`13
`
`3
`
`3
`
`3
`
`<1
`
`<1
`
`0
`
`3
`
`<1
`
`0
`
`1
`
`45
`
`41
`
`29
`
`30
`
`36
`
`30
`
`34
`
`23
`
`12
`
`4
`
`<1
`
`9
`
`2
`
`4
`
`5
`
`2
`
`<1
`
`<1
`
`0
`
`2
`
`<1
`
`0
`
`1
`
`0
`
`Bone pain
`
`Dyspnea
`
`Stomatitis
`
`Myalgia
`
`Depression
`
`Dyspepsia
`
`Cough
`
`25
`
`24
`
`22
`
`21
`
`19
`
`17
`
`16
`
`15
`
`4
`
`5
`
`<1
`
`1
`
`2
`
`<1
`
`0
`
`<1
`
`<1
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`23
`
`12
`
`20
`
`14
`
`13
`
`11
`
`13
`
`5
`
`0
`
`<1
`
`<1
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`Dizziness
`
`Headache
`
`Insomnia
`
`Alopecia
`
`Anxiety
`
`
`Neuropathy
`
`
`Flatulence
`
`Rigors
`
`15
`
`15
`
`14
`
`13
`
`13
`
`13
`
`12
`
`<1
`
`<1
`
`0
`
`1
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`0
`
`0
`
`10
`
`16
`
`11
`
`11
`
`10
`
`9
`
`9
`
`0
`
`<1
`
`0
`
`<1
`
`<1
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`
`
`
`7 of 20
`
`

`
`
`
`
`
`*Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class
`
`
`In the pancreatic carcinoma trial, 10 patients in the TARCEVA/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3
`
`patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 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 3 or Grade 4 hematologic laboratory toxicities were detected between the TARCEVA plus gemcitabine group compared to the
`
`placebo plus gemcitabine group.
`
`Severe adverse reactions (≥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)].
`
`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 3 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 Cohort
`
`
`
`
`NCI-CTC
`Grade
`
`Bilirubin
`
`ALT
`
`
`AST
`
`
`TARCEVA + Gemcitabine 1000 mg/m2 IV
`N = 259
`
`Placebo + Gemcitabine 1000 mg/m2 IV
`N = 256
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`17 %
`
`31%
`
`
`24%
`
`10%
`
`13%
`
`10%
`
`<1%
`
`<1%
`
`<1%
`
`11%
`
`22%
`
`19%
`
`10%
`
`9%
`
`9%
`
`3%
`
`0%
`
`0%
`
`6.3 NSCLC and Pancreatic Cancer Indications
`
`Gastrointestinal Disorders
`
`Gastrointestinal perforations have been reported in patients in clinical studies and during post-marketing use of TARCEVA [see Warnings and Precautions
`(5.5)].
`
`
`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 (5.12)]. These adverse reactions were reported as peptic ulcer bleeding
`
`(gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.
`
`
`Renal Disorders
`
`
`Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported [see Warnings and Precautions (5.2)].
`
`Hepatic Disorders
`
`
`
`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 a causal relationship to
`TARCEVA treatment.
`
`
`
`
`
`8 of 20
`
`

`
`
`
`Ocular Disorders
`
`
`Corneal ulcerations or perforations have been reported in patients receiving TARCEVA treatment. Abnormal eyelash growth including in-growing eyelashes,
`
`excessive growth and thickening of the eyelashes have been reported [see Warnings and Precautions (5.10)] and are risk factors for corneal
`
`ulceration/perforation.
`
`
`NCI-CTC Grade 3 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)].
`
`
`
`Skin, Hair and Nail Disorders
`
`Bullous, blistering and exfoliative skin conditions have been reported, including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis [see
`Warnings and Precautions (5.6)].
`
`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
`3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas; therefore, the use of sunscreen or avoidance of sun exposure is
`
`recommended. Associated symptoms may include itching, tenderness and/or burning. Also, hyperpigmentation or dry skin with or without digital skin fissures
`
`
`may occur.
`
`
`Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow (see above) changes, paronychia and brittle and loose nails have been reported in clinical
`trials and during post-marketing use of TARCEVA.
`
`
` Other Disorders
`
`
`Epistaxis has been reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.
`
`In general, no notable d