ERLOTINIB HYDROCHLORIDE 100 mg Tablet, Film Coated, 90-count

5 WARNINGS AND PRECAUTIONS Interstitial lung disease (ILD): Occurs in 1.1% of patients. Withhold erlotinib for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue erlotinib if ILD is diagnosed.

(5.1) Renal failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold erlotinib for severe renal toxicity. (5.2) Hepatotoxicity: Occurs with or without hepatic impairment, including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing.

Withhold or discontinue erlotinib for severe or worsening liver tests. (5.3) Gastrointestinal perforations: Discontinue erlotinib. (5.4) Bullous and exfoliative skin disorders: Discontinue erlotinib.

(5.5) Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.6) Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. (5.7) Ocular disorders: Discontinue erlotinib for corneal perforation, ulceration or persistent severe keratitis.

(5.8) Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. (5.9) 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)

5.1Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with erlotinib treatment. The overall incidence of ILD in approximately 32,000 erlotinib-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 erlotinib therapy.

Withhold erlotinib 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 erlotinib [see Dosage and Administration (2.4)].

5.2Renal Failure Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with erlotinib 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 erlotinib arms and 0.8% in the control arms.

The incidence of renal impairment in the pancreatic cancer study was 1.4% in the erlotinib plus gemcitabine arm and 0.4% in the control arm. Withhold erlotinib in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during erlotinib treatment [see Adverse Reactions (6.1) and Dosage and Administration (2.4)].

5.3Hepatotoxicity with or without Hepatic Impairment Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with erlotinib 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 erlotinibarms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the erlotinib 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 erlotinibdose. 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.

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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)] Renal Failure [see Warnings and Precautions (5.2)] Hepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3)] Gastrointestinal Perforation [see Warnings and Precautions (5.4)] Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5)] Cerebrovascular Accident [see Warnings and Precautions (5.6)] Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7)] Ocular Disorders [see Warnings and Precautions (5.8)] Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9)] The most common adverse reactions (≥ 20%) with erlotinib 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 FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch

6.1Clinical 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 erlotinib is based on more than 1200 cancer patients who received erlotinib as monotherapy, more than 300 patients who received erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib concurrently with other chemotherapies.

The most common adverse reactions with erlotinib are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib 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 (≥ 30%) adverse reactions in erlotinib-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite.

In erlotinib-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 to 4 adverse reactions in erlotinib-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of erlotinib-treated patients, and 14.3% of erlotinib-treated patients discontinued therapy due to adverse reactions.

In erlotinib-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 erlotinib or chemotherapy and an increase in ≥ 5% in the erlotinib-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 erlotinib treatment was 9.6 months in Study 1.

Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Erlotinib-Treated Group (Study 1) Adverse Reaction Erlotinib N = 84 Chemotherapy † N = 83 All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Rash ‡ 85 14 5 0 Diarrhea 62 5 21 1 Cough 48 1 40 0 Dyspnea 45 8 30 4 Dry skin 21 1 2 0 Back pain 19 2 5 0 Chest pain 18 1 12 0 Conjunctivitis 18 0 0 0 Mucosal inflammation 18 1 6 0 Pruritus 16 0 1 0 Paronychia 14 0 0 0 Arthralgia 13 1 6 1 Musculoskeletal pain 11 1 1 0 † 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 ra…

7 DRUG INTERACTIONS CYP3A4 Inhibitors Co-administration of erlotinib with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity [see Clinical Pharmacology (12.3)] .

Avoid co-administering erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin). Reduce the erlotinib dosage when co-administering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable [see Dosage and Administration (2.4)] .

CYP3A4 Inducers Pre-treatment with a CYP3A4 inducer prior to erlotinib decreased erlotinib exposure [see Clinical Pharmacology (12.3)]. Increase the erlotinib dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St. John's wort) is unavoidable [see Dosage and Administration (2.4)] .

CYP1A2 Inducers and Cigarette Smoking Cigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of erlotinib with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the erlotinib dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

Drugs the Increase Gastric pH Co-administration of erlotinib with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure [see Clinical Pharmacology (12.3)] . For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule [see Dosage and Administration (2.4)] .

Increasing the dose of erlotinib when co-administered with gastric PH elevating agents is not likely to compensate for the loss of exposure. Anticoagulants Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving erlotinib. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants.

Dose modification of erlotinib is not recommended [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)] . CYP3A4 inhibitors or a combined CYP3A4 and CYP1A2 inhibitor increase erlotinib plasma concentrations. Avoid concomitant use.

If not possible, reduce erlotinib dose. (2.4, 7) CYP3A4 inducers decrease erlotinib plasma concentrations. Avoid concomitant use.

If not possible, increase erlotinib dose. (2.4, 7) Cigarette smoking and CYP1A2 inducers decrease erlotinib plasma concentrations. Avoid concomitant use.

If not possible, increase erlotinib dose. (2.4, 7) Drugs that increase gastric pH decrease erlotinib plasma concentrations. For proton pump inhibitors avoid concomitant use if possible.

For H-2 receptor antagonists, take erlotinib 10 hours after H-2 receptor antagonist dosing. For use with antacids, separate dosing by several hours. (2.4, 7)