Erlotinib

1 INDICATIONS AND USAGE Erlotinib tablets are a kinase inhibitor indicated for: 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 ) First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. ( 1.2 ) Limitations of Use: Safety and efficacy of erlotinib have not been established in patients with NSCLC whose tumors have other EGFR mutations. ( 1.1 ) Erlotinib is not recommended for use in combination with platinum-based chemotherapy. ( 1.1 ) 1.1 Non-Small Cell Lung Cancer (NSCLC) Erlotinib tablets are indicated for: 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 [see Clinical Studies ( 14.1 , 14.3 )]. Limitations of use: Safety and efficacy of erlotinib tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations [see Clinical Studies ( 14.1 , 14.2 )] . Erlotinib tablets are not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies ( 14.4 )] . 1.2 Pancreatic Cancer Erlotinib tablets in combination with gemcitabine are indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies ( 14.5 )] .

2 DOSAGE AND ADMINISTRATION NSCLC: 150 mg orally, on an empty stomach, once daily. ( 2.2 ) Pancreatic cancer: 100 mg orally, on an empty stomach, once daily. ( 2.3 ) 2.1 Selection of Patients with Metastatic NSCLC Select patients for the treatment of metastatic NSCLC with erlotinib 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 erlotinib 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 erlotinib for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take erlotinib 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 † For additional information see Warnings and Precautions ( 5 ) . * Reduce erlotinib by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1. ‡ For additional information see Drug Interactions ( 7 ) . § For additional information see Clinical Pharmacology ( 12.3 ) . Adverse Reactions Pulmonary † Interstitial Lung Disease (ILD) Discontinue erlotinib During diagnostic evaluation for possible ILD Withhold erlotinib * Hepatic † Severe hepatic toxicity that does not improve significantly or resolve within three weeks Discontinue erlotinib In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline Withhold erlotinib * 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 Withhold erlotinib * and consider discontinuation Renal † For severe (CTCAE grade 3 to 4) renal toxicity Withhold erlotinib * and consider discontinuation Gastrointestinal † Gastrointestinal perforation Discontinue erlotinib For persistent severe diarrhea not responsive to medical management (e.g., loperamide) Withhold erlotinib * Skin † Severe bullous, blistering or exfoliating skin conditions Discontinue erlotinib * For severe rash not responsive to medical management Withhold erlotinib Ocular † Corneal perforation or severe ulceration Discontinue erlotinib For keratitis of (NCI-CTC version 4.0) grade 3 to 4 or for grade 2 lasting more than 2 weeks Withhold erlotinib * For acute/worsening ocular disorders such as eye pain Withhold erlotinib * and consider discontinuation Drug Interactions CYP3A4 inhibitors ‡ 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) Reduce erlotinib by 50 mg decrements; avoid concomitant use if possible CYP3A4 inducers ‡ Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John's Wort Increase erlotinib by 50 mg increments at 2 week intervals to a maximum of 450 mg as tolerated. Avoid concomitant use if possible Concurrent Cigarette Smoking ‡§ Concurrent cigarette smoking Inc …

3 DOSAGE FORMS AND STRENGTHS Erlotinib Tablets equivalent to 25 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '913' on one side and plain on other side. Erlotinib Tablets equivalent to 100 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '914' on one side and plain on other side. Erlotinib Tablets equivalent to 150 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '915' on one side and plain on other side. Tablets: 25 mg, 100 mg, and 150 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 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 erlotinib is based on more than 1,200 cancer patients who received erlotinib as monotherapy, more than 300 patients who received erlotinib 100 mg or 150 mg plus gemcitabine, and 1,228 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) † 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. Erlotinib N = 84 Chemotherapy † N = 83 Adverse Reaction 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 …

7 DRUG INTERACTIONS CYP3A4 Inhibitors Coadministration 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 coadministering 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 coadministering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if coadministration 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 coadministration 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 coadministration with moderate CYP1A2 inducers is unavoidable [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] . Drugs That Increase Gastric pH Coadministration 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 coadministered with gastric PH elevating agents is not likely to compensate for the loss of exposure. A n ticoagulants 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 modifications of erlotinib are 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 )

8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, erlotinib can cause fetal harm when administered to a pregnant woman. Limited available data on use of erlotinib in pregnant women are not sufficient to inform a risk of major birth defects or miscarriage. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m 2 /day or 60 mg/m 2 /day (0.3 or 0.7 times the recommended daily dose, on a mg/m 2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses. No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m 2 /day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m 2 /day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m 2 basis). 8.2 Lactation Risk Summary There are no data on the presence of erlotinib in human milk, or the effects of erlotinib on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from erlotinib, including interstitial lung disease, hepatotoxicity, bullous and exfoliative skin disorders, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, and diarrhea. Advise a lactating woman not to breastfeed during treatment with erlotinib and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Erlotinib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) ]. Advise females of reproductive potential to use effective contraception during treatment with erlotinib and for one month after the last dose of erlotinib. 8.4 Pediatric Use The safety and effectiveness of erlotinib in pediatric patients have not been established. In an open-label, multi-center trial, 25 pediatric patients (median age 14 years, range 3 years to 20 years) with recurrent or refractory ependymoma were randomized (1:1) to erlotinib or etoposide. Thirteen patients received erlotinib at a dose of 85 mg/m 2 /day orally until disease progression, death, patient request, investigator decision to discontinue study drug, or intolerable toxicity. Four patients randomized to etoposide also received erlotinib following disease progression. The trial was terminated prematurely for lack of efficacy; there were no objective responses observed in these 17 erlotinib-treated patients. No new adverse events were identified in the pediatric population. Based on the population pharmacokinetics analysis conducted in 105 pediatric patients (2 years to 21 years old) with cancer, the geometric mean estimates of CL/F/BSA (apparent clearance normalized to body surface area) were comparable across the three age groups: 2 years to 6 years (n = 29), 7 years to 16 years (n = 59), and 17 years to 21 years (n = 17). 8.5 Geriatric Use Of t …

12.1 Mechanism of Action Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized.

11 DESCRIPTION Erlotinib tablet, a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) -4-quinazolinamine hydrochloride. Erlotinib tablet contains erlotinib as the hydrochloride salt that has the following structural formula: Erlotinib hydrochloride has the molecular formula C 22 H 23 N 3 O 4 •HCl and a molecular weight of 429.90. The molecule has a pKa of 5.35 at 25°C. Erlotinib hydrochloride is off white to pale yellow powder. It is slightly soluble in methanol and practically insoluble in acetonitrile and acetone. Aqueous solubility of erlotinib hydrochloride at 25 ̊C is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.2 to 9.5, maximal solubility of approximately 0.15 mg/mL occurs at a pH of approximately 2. Erlotinib tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, talc and titanium dioxide. Image

10 OVERDOSAGE Withhold erlotinib in patients with an overdose or suspected overdose and institute symptomatic treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING Erlotinib Tablets equivalent to 25 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '913' on one side and plain on other side and are supplied as follows: NDC 68382-913-06 in bottles of 30 tablets with child-resistant closure NDC 68382-913-16 in bottles of 90 tablets with child-resistant closure NDC 68382-913-84 in unit-dose blister cartons of 30 tablets (3 x 10 unit-dose) Erlotinib Tablets equivalent to 100 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '914' on one side and plain on other side and are supplied as follows: NDC 68382-914-06 in bottles of 30 tablets with child-resistant closure NDC 68382-914-16 in bottles of 90 tablets with child-resistant closure NDC 68382-914-84 in unit-dose blister cartons of 30 tablets (3 x 10 unit-dose) Erlotinib Tablets equivalent to 150 mg of erlotinib are white to off-white, round, film-coated tablets, debossed with '915' on one side and plain on other side and are supplied as follows: NDC 68382-915-06 in bottles of 30 tablets with child-resistant closure NDC 68382-915-16 in bottles of 90 tablets with child-resistant closure NDC 68382-915-84 in unit-dose blister cartons of 30 tablets (3 x 10 unit-dose) Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].