Afatinib

1 INDICATIONS AND USAGE Afatinib tablets are a kinase inhibitor indicated for: • First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test ( 1.1 ) Limitations of Use : Safety and efficacy of afatinib tablets were not established in patients whose tumors have resistant EGFR mutations ( 1.1 ) • Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy ( 1.2 ) 1.1 EGFR Mutation-Positive, Metastatic Non-Small Cell Lung Cancer Afatinib tablets are indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology (12.1), Clinical Studies (14.1)]. Limitations of Use : The safety and efficacy of afatinib tablets have not been established in patients whose tumors have resistant EGFR mutations [ see Clinical Studies (14.1)] . 1.2 Previously Treated, Metastatic Squamous NSCLC Afatinib tablets are indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

2 DOSAGE AND ADMINISTRATION • Recommended dosage : 40 mg orally once daily ( 2.2 ) • Renal impairment : 30 mg orally once daily in patients with severe renal impairment ( 2.4 , 8.6 , 12.3 ) • Instruct patients to take afatinib tablets at least 1 hour before or 2 hours after a meal ( 2.2 ) 2.1 Patient Selection for Non-Resistant EGFR Mutation-Positive Metastatic NSCLC Select patients for first-line treatment of metastatic NSCLC with afatinib tablets based on the presence of non-resistant EGFR mutations in tumor specimens [ see Clinical Pharmacology ( 12.1 ), 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 Dosage The recommended dosage of afatinib tablets is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take afatinib tablets at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. 2.3 Dosage Modifications for Adverse Reactions Withhold afatinib tablets for: • Grade* 3 or higher adverse reactions • Diarrhea of Grade 2 persisting for 2 or more consecutive days while taking anti-diarrheal medication [ see Warnings and Precautions ( 5.1 ) ] • Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [ see Warnings and Precautions ( 5.2 ) ] *National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 3.0 Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute afatinib tablets at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred. Permanently discontinue afatinib tablets for: • Life-threatening bullous, blistering, or exfoliating skin lesions [ see Warnings and Precautions ( 5.2 ) ] • Confirmed interstitial lung disease (ILD) [ see Warnings and Precautions ( 5.3 ) ] • Severe drug-induced hepatic impairment [ see Warnings and Precautions ( 5.4 ) ] • Gastrointestinal perforation [ see Warnings and Precautions ( 5.5 ) ] • Persistent ulcerative keratitis [ see Warnings and Precautions ( 5.6 ) ] • Symptomatic left ventricular dysfunction [ see Adverse Reactions ( 6.1 ) ] • Severe or intolerable adverse reaction occurring at a dose of 20 mg per day 2.4 Dosage Modification for Pre-Existing Severe Renal Impairment The recommended dosage of afatinib tablets in patients with pre-existing severe renal impairment (estimated glomerular filtration rate [eGFR*] 15 to 29 mL/min/1.73 m2) is 30 mg orally once daily [ see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 ) ]. *Use the Modification of Diet in Renal Disease [MDRD] formula to estimate eGFR. 2.5 Dosage Modifications for Drug Interactions P-glycoprotein Inhibitors Reduce afatinib tablets daily dose by 10 mg if not tolerated for patients who require therapy with a P-glycoprotein (P-gp) inhibitor. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [ see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 ) ]. P-glycoprotein Inducers Increase afatinib tablets daily dose by 10 mg as tolerated for patients who require chronic therapy with a P-gp inducer. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [ see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 ) ].

3 DOSAGE FORMS AND STRENGTHS • Afatinib tablets, 40 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A40” on one side and “H” on the other side. • Afatinib tablets, 30 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A30” on one side and “H” on the other side. • Afatinib tablets, 20 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A20” on one side and “H” on the other side. Tablets: 40 mg, 30 mg, and 20 mg ( 3 )

4 CONTRAINDICATIONS None. None .(4)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Diarrhea [see Warnings and Precautions ( 5.1 ) ] • Bullous and Exfoliative Skin Disorders [ see Warnings and Precautions ( 5.2 ) ] • Interstitial Lung Disease [ see Warnings and Precautions ( 5.3 ) ] • Hepatic Toxicity [ see Warnings and Precautions ( 5.4 ) ] • Gastrointestinal Perforation [ see Warnings and Precautions ( 5.5 ) ] • Keratitis [ see Warnings and Precautions ( 5.6 ) ] Most common adverse reactions (≥20%) were diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. The data in the Warnings and Precautions section reflect exposure to afatinib for clinically significant adverse reactions in 4257 patients enrolled in LUX-Lung 3 (n=229) and LUX-Lung 8 (n=392), and 3636 patients with cancer enrolled in 42 studies of afatinib administered alone or in combination with other anti-neoplastic drugs at afatinib doses ranging from 10 to 70 mg daily or at doses 10 to 160 mg in other regimens. The mean exposure was 5.5 months. The population included patients with various cancers, the most common of which were NSCLC, breast, colorectal, brain, and head and neck. The data described below reflect exposure to afatinib as a single agent in LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. EGFR Mutation-Positive Metastatic NSCLC The safety of afatinib was evaluated in 229 EGFR-tyrosine kinase inhibitor-naïve patients with EGFR mutation-positive, metastatic non-squamous NSCLC enrolled in a randomized (2:1), multicenter, open-label trial (LUX-Lung 3). Patients received either afatinib 40 mg daily until documented disease progression or intolerance to the therapy or pemetrexed 500 mg/m2 followed after 30 minutes by cisplatin 75 mg/m2 every three weeks for a maximum of six treatment courses. The median exposure was 11 months for patients treated with afatinib and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the afatinib arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on afatinib and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (afatinib 70%; pemetrexed/cisplatin 72%). Serious adverse reactions were reported in 29% of patients treated with afatinib. The most frequent serious adverse reactions reported in patients treated with afatinib were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in afatinib-treated patients in LUX-Lung 3 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). Dose reductions due to adverse reactions were required in 57% of afatinib-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with afatinib were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%). Discontinuation of therapy in afatinib-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in afatinib-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%). Clinical trials of afatin …

7 DRUG INTERACTIONS Effect of P-glycoprotein (P-gp) Inhibitors and Inducers Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with afatinib can increase exposure to afatinib [ see Clinical Pharmacology ( 12.3 ) ]. Reduce afatinib daily dose as recommended [ see Dosage and Administration ( 2.5 ) ]. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with afatinib can decrease exposure to afatinib [see Clinical Pharmacology ( 12.3 ) ]. Increase afatinib daily dose as recommended [s ee Dosage and Administration ( 2.5 ) ]. • P-glycoprotein (P-gp) Inhibitors : Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce afatinib by 10 mg per day if not tolerated. ( 2.5 , 7 ) • P-gp Inducers : Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase afatinib by 10 mg per day as tolerated. ( 2.5 , 7 )

8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [ see Clinical Pharmacology ( 12.1 ) ], afatinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of afatinib in pregnant women. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times the exposure in humans at the recommended dose of 40 mg daily resulted in embryotoxicity and, in rabbits showing maternal toxicity, increased abortions at late gestational stages ( see Data ). Advise a pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 In an embryo-fetal development study in rabbits, administration of afatinib to pregnant animals at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post-implantation loss, and in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily), there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryo-fetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure based on AUC at the recommended human dose of 40 mg daily). 8.2 Lactation Risk Summary There are no data on the presence of afatinib in human milk or its effects on the breastfed infant or on milk production. Afatinib was present in the milk of lactating rats ( see Data ). Because of the potential for serious adverse reactions in breastfed infants from afatinib, advise women not to breastfeed during treatment with afatinib and for 2 weeks after the final dose. Data Afatinib was present in the milk of lactating rats at concentrations 80 and 150 times higher than those found in plasma at 1 and 6 hours after administration. 8.3 Females and Males of Reproductive Potential Contraception Females Afatinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with afatinib and for at least 2 weeks after the last dose of afatinib [ see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.3 ) ]. Infertility Based on results from an animal fertility study, afatinib may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible [ see Nonclinical Toxicology ( 13.1 ) ]. 8.4 Pediatric Use Safety and effectiveness of afatinib in pediatric patients have not been established. The safety and efficacy of afatinib were assessed, but not established, in a single-arm, open-label, multicentre trial [NCT02372006] which included 37 pediatric patients 2 to <17 years of age with recurrent/refractory solid tumors with known ErbB pathway deregulation who received 80% of the adult dose per body surface area. No new safety signals were observed in pediatric patients in this trial. In these 37 patients, the pharmacokinetic parameters were within range of values in adults. 8.6 Renal Impairment Patients with severe renal impairment have a higher exposure to afatinib than patients with normal renal function. Administer afatinib at a starting dose of 30 mg once daily in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 as determined by Modification of Diet in R …

12.1 Mechanism of Action Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2. Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

11 DESCRIPTION Afatinib tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2-butenedioate(1:2). Its structural formula is: Afatinib dimaleate is an off-white to yellow color, hygroscopic powder, slightly soluble in dimethyl sulfoxide, dimethylformamide and very slightly soluble in water, with an empirical formula of C 24 H 25 ClFN 5 O 3 .2C 4 H 4 O 4 (1:2), and a relative molecular mass of 718.09. Afatinib tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of afatinib tablets are the following: Tablet Core: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose and Coating: hypromellose, polyethylene glycol, polysorbate 80, talc and titanium dioxide. afatinibstructure

10 OVERDOSAGE Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of afatinib (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase [<1.5 times upper limit of normal (ULN)]. Both subjects recovered.

16 HOW SUPPLIED/STORAGE AND HANDLING Afatinib tablets, 40 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A40” on one side and “H” on the other side. They are supplied as follows: Bottle of 30 tablets NDC 31722-783-30 Afatinib tablets, 30 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A30” on one side and “H” on the other side. They are supplied as follows: Bottle of 30 tablets NDC 31722-782-30 Afatinib tablets, 20 mg are white to off white, round, biconvex, bevel-edged, film-coated tablets debossed with “A20” on one side and “H” on the other side. They are supplied as follows: Bottle of 30 tablets NDC 31722-781-30 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense medication in the original container to protect from exposure to high humidity and light.