Dacomitinib

1 INDICATIONS AND USAGE VIZIMPRO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . VIZIMPRO is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage: 45 mg orally once daily with or without food. ( 2.2 ) 2.1 Patient Selection Select patients for the first-line treatment of metastatic NSCLC with VIZIMPRO based on the presence of an EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. 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 VIZIMPRO is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs. VIZIMPRO can be taken with or without food [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Take VIZIMPRO the same time each day. If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose. 2.3 Dosage Modifications for Adverse Reactions Reduce the dose of VIZIMPRO for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2. Table 1. VIZIMPRO Recommended Dose Reductions for Adverse Reactions Dose Level Dose (Once Daily) First dose reduction 30 mg Second dose reduction 15 mg Table 2. VIZIMPRO Dosage Modifications for Adverse Reactions Adverse Reaction Severity National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. Dosage Modification Interstitial lung disease (ILD) [see Warnings and Precautions (5.1) ] Any Grade • Permanently discontinue VIZIMPRO. Diarrhea [see Warnings and Precautions (5.2) ] Grade 2 • Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at the same dose level. • For recurrent Grade 2 diarrhea, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose. Grade 3 or 4 • Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose. Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Grade 2 • Withhold VIZIMPRO for persistent dermatologic adverse reactions; upon recovery to less than or equal to Grade 1, resume VIZIMPRO at the same dose level. • For recurrent persistent Grade 2 dermatologic adverse reactions, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose. Grade 3 or 4 • Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose. Other Grade 3 or 4 • Withhold VIZIMPRO until recovery to less than or equal to Grade 2; then resume VIZIMPRO at a reduced dose. 2.4 Dosage Modifications for Acid-Reducing Agents Avoid the concomitant use of proton pump inhibitors (PPIs) while taking VIZIMPRO. As an alternative to PPIs, use locally-acting antacids or if using an histamine 2 (H2)-receptor antagonist, administer VIZIMPRO at least 6 hours before or 10 hours after taking an H2-receptor antagonist [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following adverse drug reactions are described elsewhere in the labeling: • Interstitial Lung Disease [see Warnings and Precautions (5.1) ] • Diarrhea [see Warnings and Precautions (5.2) ] • Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence >20%) are diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 VIZIMPRO in 394 patients with first-line or previously treated NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations who received VIZIMPRO at the recommended dose of 45 mg once daily in 4 randomized, active-controlled trials [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), and Study A7471028 (N=16)] and one single-arm trial [Study A7471017 (N=30)]. The median duration of exposure to VIZIMPRO was 10.8 months (range 0.07–68) [see Warnings and Precautions (5) ]. The data described below reflect exposure to VIZIMPRO in 227 patients with EGFR mutation-positive, metastatic NSCLC enrolled in a randomized, active-controlled trial (ARCHER 1050 ) ; 224 patients received gefitinib 250 mg orally once daily in the active control arm [see Clinical Studies (14) ] . Patients were excluded if they had a history of ILD, interstitial pneumonitis, or brain metastases. The median duration of exposure to VIZIMPRO was 15 months (range 0.07–37). The most common (>20%) adverse reactions in patients treated with VIZIMPRO were diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), dry skin (30%), decreased weight (26%), alopecia (23%), cough (21%), and pruritus (21%). Serious adverse reactions occurred in 27% of patients treated with VIZIMPRO. The most common (≥1%) serious adverse reactions were diarrhea (2.2%) and interstitial lung disease (1.3%). Dose interruptions occurred in 57% of patients treated with VIZIMPRO. The most frequent (>5%) adverse reactions leading to dose interruptions were rash (23%), paronychia (13%), and diarrhea (10%). Dose reductions occurred in 66% of patients treated with VIZIMPRO. The most frequent (>5%) adverse reactions leading to dose reductions were rash (29%), paronychia (17%), and diarrhea (8%). Adverse reactions leading to permanent discontinuation of VIZIMPRO occurred in 18% of patients. The most common (>0.5%) adverse reactions leading to permanent discontinuation of VIZIMPRO were: rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%), and diarrhea (0.9%). Tables 3 and 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate a statistically significant difference in adverse reaction rates for VIZIMPRO or for gefitinib for any adverse reaction or laboratory value listed in Table 3 or 4. Table 3. Adverse Reactions Occurring in ≥10% of Patients Receiving VIZIMPRO in ARCHER 1050 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. Adverse Reaction VIZIMPRO (N=227) Gefitinib (N=224) All Grades Grades 1 through 5 are included in All Grades. % Grades 3 and 4 % All Grades % Grades 3 and 4 % Gastrointestinal Diarrhea One Grade 5 (fatal) event in the VIZIMPRO arm. 87 8 56 0.9 Stomatitis Stomatitis includes mucosal inflammation and stomatitis. 45 4.4 19 0.4 Nausea 19 1.3 22 0.4 Constipation 13 0 14 0 Mouth ulceration 12 0 6 0 Skin and Subcutaneous Tissue Rash Rash includes dermatitis acneiform, rash, and rash maculo-papular. 69 23 47 0.4 Paronychia Paronychia includes nail infection, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. 64 8 21 1.3 Dry skin Dry skin includes dry skin, xerosis. 30 1.8 19 0.4 Alopecia 23 0.4 13 0 Pruritus Pruritus includes pruritus, pruritus generalized, rash pruritic. 21 0.9 15 1.3 Palmar-plantar erythrodysesthesia syndrome 15 0.9 3.1 0 Dermatitis 11 1.8 4 0.4 Metabolism and Nutrition Decreased appetite 31 3.1 25 0.4 Decreased weight 26 2.2 17 0.4 Respiratory Cough 21 0 19 0.4 Nasal mucosal disorder Nasal mucosal disorder includes epistaxis, nasal inflammation, nasal mucosal disorder, nasal mucosal ulcer, rhinitis. 19 0 4.9 0 Dyspnea 13 2.2 13 1.8 Upper respiratory tract infection 12 1.3 13 0 Chest pain 10 0 14 0 Eye Conjunctivitis 19 0 4 0 Musculoskeletal Pain in extremity 14 0 12 0 Musculoskeletal pain 12 0.9 13 0 General Asthenia 13 2.2 13 1.3 Psychiatric Insomnia 11 0.4 15 0 Additional adverse reactions (All Grades) that were reported in <10% of patients who received VIZIMPRO in ARCHER 1050 include: General : fatigue 9% Skin and subcutaneous tissue : skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5% Gastrointestinal : vomiting 9% Nervous system : dysgeusia 7% Respiratory: interstitial lung disease 2.6% Ocular: keratitis 1.8% Metabolism and nutrition : dehydration 1.3% Table 4. Laboratory Abnormalities Worsening from Baseline in >20% of Patients in ARCHER 1050 NCI CTCAE v4.03, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition. Laboratory Test Abnormality Based on the number of patients with available baseline and at least one on-treatment laboratory test. VIZIMPRO Gefitinib Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) ALT=alanine aminotransferase; AST=aspartate aminotransferase. Hematology Anemia 44 0.9 26 2.7 Lymphopenia 42 6 35 2.7 Chemistry Hypoalbuminemia 44 0 34 0 Increased ALT 40 1.4 63 13 Hyperglycemia 36 1.0 38 2.5 Increased AST 35 0.5 57 8 Hypocalcemia 33 1.4 28 2.0 Hypokalemia 29 7 18 2.0 Hyponatremia 26 2.9 20 1.5 Increased creatinine 24 0 16 0.5 Increased alkaline phosphatase 22 0.5 21 2.0 Hypomagnesemia 22 0.5 9 0 Hyperbilirubinemia 16 0.5 22 0.5

12.3 Pharmacokinetics The maximum dacomitinib plasma concentration (C max ) and AUC at steady state increased proportionally over the dose range of VIZIMPRO 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At a dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] C max was 108 ng/mL (35%) and the AUC 0–24h was 2213 ng∙h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC. Absorption The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (T max ) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of VIZIMPRO 45 mg in patients with cancer. Effect of Food Administration of VIZIMPRO with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics. Distribution The geometric mean (CV%) volume of distribution of dacomitinib (V ss ) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL. Elimination Following a single 45 mg oral dose of VIZIMPRO in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%). Metabolism Hepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of a single 45 mg dose of [ 14 C] dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites. Excretion Following a single oral 45 mg dose of [ 14 C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib). Specific Populations Patients with Renal Impairment Based on population pharmacokinetic analyses, mild (60 mL/min ≤CLcr <90 mL/min; N=590) and moderate (30 mL/min ≤CLcr <60 mL/min; N=218) renal impairment did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal renal function (CLcr ≥90 mL/min; N=567). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring hemodialysis. Patients with Hepatic Impairment No clinically significant differences in the pharmacokinetics of dacomitinib were observed in subjects with mild, moderate or severe hepatic impairment (Child-Pugh A, B or C) [see Use in Specific Populations (8.7) ]. Drug Interaction Studies Clinical Studies Effect of Acid-Reducing Agents on Dacomitinib Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib C max by 51% and AUC 0–96h by 39% [see Dosage and Administration (2.4) and Drug Interactions (7.1) ]. Coadministration of VIZIMPRO with a local antacid (Maalox ® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations [see Dosage and Administration (2.4) and Drug Interactions (7.1) ] . The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied [see Dosage and Administration (2.4) and Drug Interactions (7.1) ] . Effect of Strong CYP2D6 Inhibitors on Dacomitinib Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUC last of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant. Effect of Dacomitinib on CYP2D6 Substrates Coadministration of a single 45 mg oral dose of VIZIMPRO increased dextromethorphan (a CYP2D6 substrate) C max by 9.7-fold and AUC last by 9.6-fold [see Drug Interactions (7.2) ] . In Vitro Studies Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes: Dacomitinib and its metabolite O-desmethyl dacomitinib do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Dacomitinib does not induce CYP1A2, CYP2B6, or CYP3A4. Effect of Dacomitinib on Uridine 5' diphospho-glucuronosyltransferase (UGT) Enzymes: Dacomitinib inhibits UGT1A1. Dacomitinib does not inhibit UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Effect of Dacomitinib on Transporter Systems: Dacomitinib is a substrate for the membrane transport protein P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT)1. Dacomitinib does not inhibit organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3.