How Much Does Afatinib Cost in Mexico vs the USA?

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.

• 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 ) ].

• Diarrhea : Diarrhea may result in dehydration and renal failure. Withhold afatinib for severe and prolonged diarrhea not responsive to anti-diarrheal agents. ( 2.3 , 5.1 ) • Bullous and exfoliative skin disorders : Severe bullous, blistering, and exfoliating lesions occurred in 0.2% of patients. Discontinue for life-threatening cutaneous reactions. Withhold afatinib for severe and prolonged cutaneous reactions. ( 2.3 , 5.2 ) • Interstitial lung disease (ILD) : Occurs in 1.6% of patients. Withhold afatinib for acute onset or worsening of pulmonary symptoms. Discontinue afatinib if ILD is diagnosed. ( 2.3 , 5.3 ) • Hepatic toxicity : Fatal hepatic impairment occurs in 0.2% of patients. Monitor with periodic liver testing. Withhold or discontinue afatinib for severe or worsening liver tests. ( 2.3 , 5.4 ) • Gastrointestinal perforation : Occurs in 0.2% of patients. Permanently discontinue afatinib in patients who develop gastrointestinal perforation. ( 2.3 , 5.5 ) • Keratitis : Occurs in 0.7% of patients. Withhold afatinib for keratitis evaluation. Withhold or discontinue afatinib for confirmed ulcerative keratitis. ( 2.3 , 5.6 ) • Embryo-fetal toxicit y: Can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.7 ) 5.1 Diarrhea Diarrhea has resulted in dehydration with or without renal impairment across the clinical experience; some cases were fatal. Grade 3 to 4 diarrhea occurred in 697 (16%) of the 4257 patients who received afatinib across 44 clinical trials. In LUX-Lung 3, diarrhea occurred in 96% of patients treated with afatinib (n=229), of which 15% were Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6% of patients treated with afatinib, of which 1.3% were Grade 3. In LUX-Lung 8, diarrhea occurred in 75% of patients treated with afatinib (n=392), of which 10% were Grade 3 in severity and 0.8% were Grade 4 in severity. Renal impairment as a consequence of diarrhea occurred in 7% of patients treated with afatinib, of which 2% were Grade 3 [ see Adverse Reactions ( 6.1 ) ]. For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold afatinib until diarrhea resolves to Grade 1 or less and resume afatinib with appropriate dose reduction [ see Dosage and Administration ( 2.3 ) ]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. 5.2 Bullous and Exfoliative Skin Disorders Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating skin lesions, occurred in 0.2% of the 4257 patients who received afatinib across clinical trials. In LUX-Lung 3, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1 to 3 palmar-plantar erythrodysesthesia syndrome was 7%. In LUX-Lung 8, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 70%, and the incidence of Grade 3 cutaneous reactions was 7%. In addition, the incidence of Grade 1 to 3 palmar-plantar erythrodysesthesia syndrome was 1.5% [see Adverse Reactions ( 6.1 )]. Discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2 cutaneous reactions, or Grade 3 cutaneous reactions, withhold afatinib until the adverse reaction resolves to Grade 1 or less and resume afatinib with appropriate dose reduction [see Dosage and Administration ( 2.3 )]. Postmarketing cases consistent with toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving afatinib. The cases of TEN and SJS bullous skin reactions result from a distinct and separate mechanism of toxicity than the bullous skin lesions secondary to the pharmacologic action of the drug on the epidermal growth factor receptor. Discontinue afatinib if TEN or SJS is suspected [see Dosage and Administration ( 2.3 )]. 5.3 Interstitial Lung Disease Interstitial lung disease or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.6% of the 4257 patients who received afatinib across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in Asian patients (2.3%; 38/1657) as compared to Whites (1.0%; 23/2241). In LUX-Lung 3, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of afatinib-treated patients. In LUX-Lung 8, the incidence of Grade ≥3 ILD was 0.9% and resulted in death in 0.8% of afatinib-treated patients. Withhold afatinib during evaluation of patients with suspected ILD and discontinue afatinib in patients with confirmed ILD [see Dosage and Administration ( 2.3 )]. 5.4 Hepatic Toxicity In 4257 patients who received afatinib across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal. In LUX-Lung 3, liver test abnormalities of any grade occurred in 17.5% of the patients treated with afatinib, of which 3.5% had Grade 3 to 4 liver test abnormalities. In LUX-Lung 8, liver test abnormalities of any grade occurred in 6% of the patients treated with afatinib , of which 0.2% had Grade 3 to 4 liver test abnormalities. Obtain periodic liver testing in patients during treatment with afatinib. Withhold afatinib in patients who develop worsening of liver function [see Dosage and Administration ( 2.3 )] . In patients who develop severe hepatic impairment while taking afatinib, discontinue treatment. 5.5 Gastrointestinal Perforation Gastrointestinal perforation, including fatal cases, has occurred with afatinib. Gastrointestinal perforation has been reported in 0.2% of patients treated with afatinib among 3213 patients across 17 randomized controlled clinical trials. Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) or anti-angiogenic agents, or patients with increasing age or who have an underlying history of gastrointestinal ulceration, underlying diverticular disease or bowel metastases may be at increased risk of perforation. Permanently discontinue afatinib in patients who develop gastrointestinal perforation [see Dosage and Administration ( 2.3 )]. 5.6 Keratitis Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.7% of patients treated with afatinib among 4257 patients across clinical trials, of which 0.05% of patients experienced Grade 3 keratitis. Keratitis was reported in 2.2% patients in LUX-Lung 3, with Grade 3 in 0.4%. In LUX-Lung 8, keratitis was reported in 0.3% patients; there were no patients with ≥Grade 3 keratitis. Withhold afatinib during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue afatinib [see Dosage and Administration ( 2.3 )] . If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions ( 6.1 )] . Contact lens use is also a risk factor for keratitis and ulceration. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, afatinib can cause fetal harm when administered to a pregnant woman. 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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of afatinib [see Use in Specific Populations ( 8.1 , 8.3 )].

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 )

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 afatinib excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the afatinib-treated group and as needed in the pemetrexed/cisplatin group. More afatinib-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). Tables 1 and 2 summarize common adverse reactions and laboratory abnormalities in LUX-Lung 3. Table 1 Adverse Reactions Reported in ≥10% of Afatinib-Treated Patients in LUX-Lung 3* Adverse Reaction Afatinib n=229 Pemetrexed/Cisplatin n=111 All Grades (%) Grade 3† (%) All Grades (%) Grade 3† (%) Gastrointestinal disorders Diarrhea 96 15 23 2 Stomatitis 1 71 9 15 1 Cheilitis 12 0 1 0 Skin and subcutaneous tissue disorders Rash/acneiform dermatitis 2 90 16 11 0 Pruritus 21 0 1 0 Dry skin 31 0 2 0 Infections Paronychia 3 58 11 0 0 Cystitis 13 1 5 0 Respiratory, thoracic and mediastinal disorders Epistaxis 17 0 2 1 Rhinorrhea 11 0 6 0 Investigations Weight decreased 17 1 14 1 General disorders and administration site conditions Pyrexia 12 0 6 0 Eye disorders Conjunctivitis 11 0 3 0 *NCI CTCAE v 3.0 †None of the adverse reactions in this table except stomatitis (one patient on afatinib [0.4%]) were Grade 4 in severity. 1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2Includes acne, acne pustular, dermatitis, acneiform dermatitis, dermatosis, drug eruption, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin disorder, skin erosion, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer 3Includes paronychia, nail infection, nail bed infection Other clinically important adverse reactions observed in patients treated with afatinib but that occurred at a higher incidence in pemetrexed/cisplatin-treated patients and not listed elsewhere in section 6 include: decreased appetite (29% Grades 1 to 4, 4% Grade 3), nausea (25% Grades 1 to 4, 4% Grade 3), and vomiting (23% Grades 1 to 4, 4% Grade 3). Table 2 Laboratory Abnormalities Occurring in ≥10% of Afatinib Arm and at ≥2% Higher Incidence than in Chemotherapy Arm in LUX-Lung 3* Laboratory Abnormality Afatinib n=229 Pemetrexed/Cisplatin n=111 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Increased alanine aminotransferase (ALT) 54 2 27 1 Increased alkaline phosphate 51 3 46 1 Decreased creatinine clearance 49 2 47 1 Increased aspartate aminotransferase (AST) 46 3 22 1 Decreased lymphocytes 38 9 32 14 Decreased potassium 30 8 11 3 Increased bilirubin 16 1 8 0 *NCI CTCAE v 3.0 Previously Treated, Metastatic Squamous NSCLC The safety of afatinib was evaluated in 392 afatinib-treated patients with metastatic squamous NSCLC enrolled in a randomized, multicenter, open-label trial (LUX-Lung 8). Patients were required to have received at least four cycles of platinum-based chemotherapy, ECOG Performance Status (PS) 0 or 1, and normal left ventricular ejection fraction (LVEF). Patients received afatinib 40 mg once daily (n=392) or erlotinib 150 mg once daily (n=395). Treatment continued until documented disease progression or intolerance to the therapy. The median exposure was 2.1 months for patients treated with afatinib, 15% were exposed for at least 6 months, and 5% were exposed for at least 12 months. Among the 392 afatinib -treated patients, the median age was 65 years, 53% were 65 years of age or older, 84% were male, 72% were White, 25% were Asian, ECOG PS 0 (32%) or 1 (68%). Serious adverse reactions occurred in 44% of patients treated with afatinib. The most frequent serious adverse reactions in patients treated with afatinib were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in afatinib-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%). The most frequent adverse reactions that led to discontinuation in afatinib-treated patients were diarrhea (4.1%) and rash/acne (2.6%). Dose reductions due to adverse reactions were required in 27% of afatinib-treated patients and discontinuation of afatinib for adverse reactions was required for 20%. The most frequent adverse reactions that led to dose reduction in the patients treated with afatinib were diarrhea (15%), rash/acne (5.9%), and stomatitis (3.1%). Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in LUX-Lung 8. Table 3 Adverse Reactions Reported in ≥10% of Afatinib -Treated Patients in LUX-Lung 8* Adverse Reaction Afatinib n=392 Erlotinib n=395 All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) Gastrointestinal disorders Diarrhea 75 11 41 3 Stomatitis 1 30 4 11 1 Nausea 21 2 16 1 Vomiting 13 1 10 1 Skin and subcutaneous tissue disorders Rash/acneiform dermatitis2 70 7 70 11 Pruritus 10 0 13 0 Metabolism and nutrition disorders Decreased appetite 25 3 26 2 Infections Paronychia 3 11 1 5 0 *NCI CTCAE v 3.0 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2 Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer 3 Includes paronychia, nail infection, nail bed infection Table 4 Laboratory Abnormalities Occurring in ≥10% of Afatinib Arm and at ≥2% Higher Incidence than in Erlotinib Arm in LUX-Lung 8* Laboratory Abnormality Afatinib n=392 Erlotinib n=395 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Increased alkaline phosphate 34 2 31 0 Decreased white blood cell count 12 1 8 1 Decreased potassium 11 1 8 1 *NCI CTCAE v 3.0 Other clinically important laboratory abnormalities observed in patients treated with afatinib that are not listed in Table 4 are: increased alanine aminotransferase (10% Grade 1 to 4; 1% Grade 3 to 4), increased aspartate aminotransferase (7% Grade 1 to 4; 1% Grade 3 to 4), and increased bilirubin (3% Grade 1 to 4; 0 Grade 3 to 4). Less Common Adverse Reactions Other adverse reactions reported in patients treated with afatinib in LUX-Lung 3 and LUX-Lung 8 include: Skin and subcutaneous disorders: nail disorders occurred in 9.2% and 2.8% of patients, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of afatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Pancreatitis • Toxic epidermal necrolysis/Stevens Johnson syndrome

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).