ADVERSE REACTIONS SECTION.

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)] 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 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 and summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate statistically significant difference in adverse reaction rates for VIZIMPRO or for gefitinib for any adverse reaction or laboratory value listed in Table or 4.Table 3. Adverse Reactions Occurring in >=10% of Patients Receiving VIZIMPRO in ARCHER 1050National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. Adverse ReactionVIZIMPRO(N=227)Gefitinib(N=224)All GradesGrades through are included in All Grades. %Grades and 4%All Grades%Grades and 4%Gastrointestinal DiarrheaOne Grade (fatal) event in the VIZIMPRO arm. 878560.9StomatitisStomatitis includes mucosal inflammation and stomatitis. 454.4190.4Nausea191.3220.4Constipation130140Mouth ulceration12060Skin and Subcutaneous TissueRashRash includes dermatitis acneiform, rash, and rash maculo-papular. 6923470.4ParonychiaParonychia includes nail infection, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. 648211.3Dry skinDry skin includes dry skin, xerosis. 301.8190.4Alopecia230.4130PruritusPruritus includes pruritus, pruritus generalized, rash pruritic. 210.9151.3Palmar-plantar erythrodysesthesia syndrome150.93.10Dermatitis111.840.4Metabolism and NutritionDecreased appetite313.1250.4Decreased weight262.2170.4RespiratoryCough210190.4Nasal mucosal disorderNasal mucosal disorder includes epistaxis, nasal inflammation, nasal mucosal disorder, nasal mucosal ulcer, rhinitis. 1904.90Dyspnea132.2131.8Upper respiratory tract infection121.3130Chest pain100140EyeConjunctivitis19040MusculoskeletalPain in extremity140120Musculoskeletal pain120.9130GeneralAsthenia132.2131.3PsychiatricInsomnia110.4150Additional 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 1050NCI CTCAE v4.03, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition. Laboratory Test AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test. VIZIMPROGefitinibChange from Baseline All Grades (%)Change from Baseline to Grade or Grade 4(%)Change from Baseline All Grades(%)Change from Baseline to Grade or Grade 4(%)ALT=alanine aminotransferase; AST=aspartate aminotransferase.Hematology Anemia440.9262.7 Lymphopenia426352.7Chemistry Hypoalbuminemia440340 Increased ALT401.46313 Hyperglycemia361.0382.5 Increased AST350.5578 Hypocalcemia331.4282.0 Hypokalemia297182.0 Hyponatremia262.9201.5 Increased creatinine240160.5 Increased alkaline phosphatase220.5212.0 Hypomagnesemia220.590 Hyperbilirubinemia160.5220.5.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations.Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of dacomitinib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC. Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with VIZIMPRO 45 mg orally once daily.. Exposure-Response RelationshipsHigher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade >=3 adverse events, specifically dermatologic toxicities and diarrhea.. 12.3 Pharmacokinetics. The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of VIZIMPRO mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] Cmax was 108 ng/mL (35%) and the AUC0-24h was 2213 ngh/mL (35%) at steady state in 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. AbsorptionThe mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after single oral dose of VIZIMPRO 45 mg in patients with cancer. Effect of FoodAdministration of VIZIMPRO with 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.. DistributionThe geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 (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.. EliminationFollowing 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%).. MetabolismHepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of single 45 mg dose of [14C] 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.. ExcretionFollowing single oral 45 mg dose of [14C] 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 ImpairmentBased 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 ImpairmentNo clinically significant differences in the pharmacokinetics of dacomitinib were observed in subjects with mild, moderate or severe hepatic impairment (Child-Pugh A, or C) [see Use in Specific Populations (8.7)]. Drug Interaction Studies. Clinical Studies. Effect of Acid-Reducing Agents on DacomitinibCoadministration of single 45 mg dose of VIZIMPRO with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0-96h by 39% [see Dosage and Administration (2.4) and Drug Interactions (7.1)]. Coadministration of VIZIMPRO with local antacid (Maalox(R) 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 DacomitinibCoadministration of single 45 mg dose of VIZIMPRO with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast 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 SubstratesCoadministration of single 45 mg oral dose of VIZIMPRO increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast 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 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 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.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. The efficacy of VIZIMPRO was demonstrated in randomized, multicenter, multinational, open-label study (ARCHER 1050; [NCT01774721]). Patients were required to have unresectable, metastatic NSCLC with no prior therapy for metastatic disease or recurrent disease with minimum of 12 months disease-free after completion of systemic therapy; an Eastern Cooperative Oncology Group (ECOG) performance status of or 1; EGFR exon 19 deletion or exon 21 L858R substitution mutations. EGFR mutation status was prospectively determined by local laboratory or commercially available tests (e.g., therascreen(R) EGFR RGQ PCR and cobas(R) EGFR Mutation Test).Patients were randomized (1:1) to receive VIZIMPRO 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by region (Japanese versus mainland Chinese versus other East Asian versus non-East Asian), and EGFR mutation status (exon 19 deletions versus exon 21 L858R substitution mutation). The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded Independent Radiologic Central (IRC) review per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR), duration of response (DoR), and overall survival (OS).A total of 452 patients were randomized to receive VIZIMPRO (N=227) or gefitinib (N=225). The demographic characteristics were 60% female; median age 62 years (range: 28 to 87), with 40% aged 65 years and older; and 23% White, 77% Asian, and less than 1% Black. Prognostic and tumor characteristics were ECOG performance status (30%) or (70%); 59% with exon 19 deletion and 41% with exon 21 L858R substitution; Stage IIIB (8%) and Stage IV (92%); 64% were never smokers; and 1% received prior adjuvant or neoadjuvant therapy.ARCHER 1050 demonstrated statistically significant improvement in PFS as determined by the IRC. Results are summarized in Table and Figures and 2. The hierarchical statistical testing order was PFS followed by ORR and then OS. No formal testing of OS was conducted since the formal comparison of ORR was not statistically significant.Table 5. Efficacy Results in ARCHER 1050VIZIMPRON=227GefitinibN=225CI=confidence interval; DoR=duration of response; HR=hazard ratio; IRC=Independent Radiologic Central; N/n=total number; PFS=progression-free survival.Progression-Free Survival (per IRC) Number of patients with event, (%)136 (59.9%)179 (79.6%) Median PFS in months (95% CI)14.7 (11.1, 16.6)9.2 (9.1, 11.0) HR (95% CI)From stratified Cox Regression. 0.59 (0.47, 0.74) p-valueBased on the stratified log-rank test. <0.0001Overall Response Rate (per IRC) Overall Response Rate (95% CI)75% (69, 80)72% (65, 77) p-valueBased on the stratified Cochran-Mantel-Haenszel test. 0.39Duration of Response in Responders (per IRC) Median DoR in months (95% CI)14.8 (12.0, 17.4)8.3 (7.4, 9.2)Figure 1. Kaplan-Meier Curve for PFS per IRC Review in ARCHER 1050 Figure 2. Kaplan-Meier Curve for OS in ARCHER 1050 Figure 1. Figure 2.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage: 45 mg orally once daily with or without food. (2.2). 2.1Patient 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.. 2.2Recommended 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 dose, do not take an additional dose or make up missed dose but continue with the next scheduled dose.. 2.3Dosage 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 LevelDose (Once Daily)First dose reduction30 mgSecond dose reduction15 mgTable 2. VIZIMPRO Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityNational Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. Dosage ModificationInterstitial lung disease (ILD) [see Warnings and Precautions (5.1)] Any GradePermanently discontinue VIZIMPRO.Diarrhea [see Warnings and Precautions (5.2)] Grade 2Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at the same dose level.For recurrent Grade diarrhea, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.Grade or 4Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)] Grade 2Withhold 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 dermatologic adverse reactions, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.Grade or 4Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.OtherGrade or 4Withhold VIZIMPRO until recovery to less than or equal to Grade 2; then resume VIZIMPRO at reduced dose.. Permanently discontinue VIZIMPRO.. Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at the same dose level.. For recurrent Grade diarrhea, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.. Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.. 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 dermatologic adverse reactions, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.. Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at reduced dose.. Withhold VIZIMPRO until recovery to less than or equal to Grade 2; then resume VIZIMPRO at reduced dose.. 2.4Dosage 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 (H2)-receptor antagonist, administer VIZIMPRO at least hours before or 10 hours after taking an H2-receptor antagonist [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Interstitial Lung Disease (ILD)Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].. Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].. DiarrheaAdvise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea [see Warnings and Precautions (5.2)].. Advise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea [see Warnings and Precautions (5.2)].. Dermatologic Adverse ReactionsAdvise patients to initiate use of moisturizers and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of VIZIMPRO. Advise patients to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative reactions [see Warning and Precautions (5.3)]. Advise patients to initiate use of moisturizers and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of VIZIMPRO. Advise patients to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative reactions [see Warning and Precautions (5.3)]. Drug InteractionsAdvise patients to avoid use of PPIs while taking VIZIMPRO. Short-acting antacids or H2 receptor antagonists may be used if needed. Advise patients to take VIZIMPRO at least hours before or 10 hours after taking an H2-receptor antagonist [see Drug Interactions (7.1)]. Advise patients to avoid use of PPIs while taking VIZIMPRO. Short-acting antacids or H2 receptor antagonists may be used if needed. Advise patients to take VIZIMPRO at least hours before or 10 hours after taking an H2-receptor antagonist [see Drug Interactions (7.1)]. Embryo-Fetal ToxicityAdvise females of reproductive potential that VIZIMPRO can result in fetal harm and to use effective contraception during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO. Advise females of reproductive potential to contact their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8.1 and 8.3)]. Advise females of reproductive potential that VIZIMPRO can result in fetal harm and to use effective contraception during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO. Advise females of reproductive potential to contact their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8.1 and 8.3)]. LactationAdvise women not to breastfeed during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO [see Use in Specific Populations (8.2)].. Advise women not to breastfeed during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO [see Use in Specific Populations (8.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of VIZIMPRO mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] Cmax was 108 ng/mL (35%) and the AUC0-24h was 2213 ngh/mL (35%) at steady state in 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. AbsorptionThe mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after single oral dose of VIZIMPRO 45 mg in patients with cancer. Effect of FoodAdministration of VIZIMPRO with 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.. DistributionThe geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 (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.. EliminationFollowing 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%).. MetabolismHepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of single 45 mg dose of [14C] 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.. ExcretionFollowing single oral 45 mg dose of [14C] 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 ImpairmentBased 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 ImpairmentNo clinically significant differences in the pharmacokinetics of dacomitinib were observed in subjects with mild, moderate or severe hepatic impairment (Child-Pugh A, or C) [see Use in Specific Populations (8.7)]. Drug Interaction Studies. Clinical Studies. Effect of Acid-Reducing Agents on DacomitinibCoadministration of single 45 mg dose of VIZIMPRO with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0-96h by 39% [see Dosage and Administration (2.4) and Drug Interactions (7.1)]. Coadministration of VIZIMPRO with local antacid (Maalox(R) 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 DacomitinibCoadministration of single 45 mg dose of VIZIMPRO with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast 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 SubstratesCoadministration of single 45 mg oral dose of VIZIMPRO increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast 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 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on VIZIMPRO use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose (see Data). The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals (see Data). Advise pregnant women of the potential risk to fetus [see Use in Special Populations (8.3)].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 DataDaily oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at mg/kg/day (approximately 1.2 times the exposure based on area under the curve [AUC] at the 45 mg human dose). Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: September 2018PATIENT INFORMATIONVIZIMPRO(R) (vih-ZIM-pro)(dacomitinib)tabletsWhat is VIZIMPROVIZIMPRO is prescription medicine used to treat non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic):As your first treatment if your tumor has certain types of abnormal epidermal growth factor receptor (EGFR) gene(s). Your healthcare provider will perform test to make sure that VIZIMPRO is right for you. It is not known if VIZIMPRO is safe and effective in children.Before taking VIZIMPRO, tell your healthcare provider about all your medical conditions, including if you:have frequent diarrhea.have history of lung or breathing problems other than lung cancer.are pregnant, or plan to become pregnant. VIZIMPRO can harm your unborn baby.Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with VIZIMPRO.You should use effective birth control (contraception) during treatment and for at least 17 days after your last dose of VIZIMPRO. Talk to your healthcare provider about birth control methods that may be right for you during this time.Tell your healthcare provider right away if you become pregnant during your treatment with VIZIMPRO.are breastfeeding or plan to breastfeed. It is not known if VIZIMPRO passes into your breast milk. Do not breastfeed during treatment and for at least 17 days after your last dose of VIZIMPRO. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VIZIMPRO and other medicines or supplements may affect each other causing side effects.How should take VIZIMPROTake VIZIMPRO exactly as your healthcare provider tells you.Take your dose at approximately the same time each day.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with VIZIMPRO if you have side effects.Take VIZIMPRO time each day with or without food.If you take an antacid or H2 blocker medicine during treatment with VIZIMPRO, take your dose of VIZIMPRO at least hours before or 10 hours after taking the antacid or H2 blocker medicine. Do not change your dose or stop taking VIZIMPRO unless your healthcare provider tells you.If you vomit or miss dose of VIZIMPRO, do not take another dose or make up for the missed dose. Take your next dose at your regular time.What should avoid during treatment with VIZIMPROMinimize exposure to sunlight. VIZIMPRO can cause skin reactions. See What are the possible side effects of VIZIMPRO What are the possible side effects of VIZIMPROVIZIMPRO may cause serious side effects, including:Lung or breathing problems. VIZIMPRO may cause severe inflammation of the lung that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you have any new or worsening lung symptoms, including trouble breathing or shortness of breath, cough, or fever.Diarrhea. Diarrhea is common during treatment with VIZIMPRO, and can be severe and lead to death. Diarrhea can cause you to lose too much body fluid (dehydration). Your healthcare provider may tell you to start drinking more fluids or start taking your anti-diarrheal medicines. Tell your healthcare provider right away, if you have any loose stools or have stools more often than is normal for you.Skin reactions. Skin reactions are common with VIZIMPRO and can be severe. These skin reactions may include: dry skin, redness, rash, acne, itching, and peeling or blistering of your skin. Use moisturizers every day when taking VIZIMPRO. Use sunscreen and wear protective clothing that covers your skin, while exposed to sunlight, while you are taking VIZIMPRO. Your healthcare provider may prescribe other medicines to help skin reactions. Tell your healthcare provider right away about any worsening skin reactions.The most common side effects of VIZIMPRO include:rashdiarrheamouth pain and soresnail inflammationcommon colddry skindecreased appetitedecreased weightdry, red, itchy eyeshair lossitchingCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VIZIMPRO Store VIZIMPRO at 20 to 25 (68 to 77 F).Keep VIZIMPRO and all medicines out of the reach of children.General information about the safe and effective use of VIZIMPRO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VIZIMPRO for condition for which it was not prescribed. Do not give VIZIMPRO to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or healthcare provider for more information about VIZIMPRO that is written for health professionals.What are the ingredients in VIZIMPROActive ingredient: dacomitinib Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.Film coating contains: Opadry II(R) Blue 85F30716 containing: Polyvinyl alcohol partially hydrolyzed, Talc, Titanium dioxide, Macrogol/PEG 3350, and FD&C Blue 2/Indigo Carmine Aluminum Lake. LAB-1238-1.0For more information, go to www.VIZIMPRO.com or call 1-800-438-1985.. As your first treatment if your tumor has certain types of abnormal epidermal growth factor receptor (EGFR) gene(s). have frequent diarrhea.. have history of lung or breathing problems other than lung cancer.. are pregnant, or plan to become pregnant. VIZIMPRO can harm your unborn baby.. Your healthcare provider should do pregnancy test before you start treatment with VIZIMPRO.You should use effective birth control (contraception) during treatment and for at least 17 days after your last dose of VIZIMPRO. Talk to your healthcare provider about birth control methods that may be right for you during this time.Tell your healthcare provider right away if you become pregnant during your treatment with VIZIMPRO.. Your healthcare provider should do pregnancy test before you start treatment with VIZIMPRO.. You should use effective birth control (contraception) during treatment and for at least 17 days after your last dose of VIZIMPRO. Talk to your healthcare provider about birth control methods that may be right for you during this time.. Tell your healthcare provider right away if you become pregnant during your treatment with VIZIMPRO.. are breastfeeding or plan to breastfeed. It is not known if VIZIMPRO passes into your breast milk. Do not breastfeed during treatment and for at least 17 days after your last dose of VIZIMPRO. Talk to your healthcare provider about the best way to feed your baby during this time. Take VIZIMPRO exactly as your healthcare provider tells you.. Take your dose at approximately the same time each day.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with VIZIMPRO if you have side effects.. Take VIZIMPRO time each day with or without food.. If you take an antacid or H2 blocker medicine during treatment with VIZIMPRO, take your dose of VIZIMPRO at least hours before or 10 hours after taking the antacid or H2 blocker medicine. Do not change your dose or stop taking VIZIMPRO unless your healthcare provider tells you.. If you vomit or miss dose of VIZIMPRO, do not take another dose or make up for the missed dose. Take your next dose at your regular time.. Minimize exposure to sunlight. VIZIMPRO can cause skin reactions. See What are the possible side effects of VIZIMPRO Lung or breathing problems. VIZIMPRO may cause severe inflammation of the lung that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you have any new or worsening lung symptoms, including trouble breathing or shortness of breath, cough, or fever.. Diarrhea. Diarrhea is common during treatment with VIZIMPRO, and can be severe and lead to death. Diarrhea can cause you to lose too much body fluid (dehydration). Your healthcare provider may tell you to start drinking more fluids or start taking your anti-diarrheal medicines. Tell your healthcare provider right away, if you have any loose stools or have stools more often than is normal for you.. Skin reactions. Skin reactions are common with VIZIMPRO and can be severe. These skin reactions may include: dry skin, redness, rash, acne, itching, and peeling or blistering of your skin. Use moisturizers every day when taking VIZIMPRO. Use sunscreen and wear protective clothing that covers your skin, while exposed to sunlight, while you are taking VIZIMPRO. Your healthcare provider may prescribe other medicines to help skin reactions. Tell your healthcare provider right away about any worsening skin reactions.. rash. diarrhea. mouth pain and sores. nail inflammation. common cold. dry skin. decreased appetite. decreased weight. dry, red, itchy eyes. hair loss. itching. Store VIZIMPRO at 20 to 25 (68 to 77 F).. Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on VIZIMPRO use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose (see Data). The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals (see Data). Advise pregnant women of the potential risk to fetus [see Use in Special Populations (8.3)].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 DataDaily oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at mg/kg/day (approximately 1.2 times the exposure based on area under the curve [AUC] at the 45 mg human dose). Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VIZIMPRO, advise women not to breastfeed during treatment with VIZIMPRO and for at least 17 days after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating VIZIMPRO [see Use in Specific Populations (8.1)]. ContraceptionVIZIMPRO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. FemalesAdvise females of reproductive potential to use effective contraception during treatment with VIZIMPRO and for at least 17 days after the final dose.. 8.4 Pediatric Use. The safety and effectiveness of VIZIMPRO in pediatrics have not been established.. 8.5 Geriatric Use. Of the total number of patients (N=394) in five clinical studies with EGFR mutation-positive NSCLC who received VIZIMPRO at dose of 45 mg orally once daily [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), Study A7471028 (N=16), and Study A7471017 (N=30)] 40% were 65 years of age and older. Exploratory analyses across this population suggest higher incidence of Grade and adverse reactions (67% versus 56%, respectively), more frequent dose interruptions (53% versus 45%, respectively), and more frequent discontinuations (24% versus 10%, respectively) for adverse reactions in patients 65 years or older as compared to those younger than 65 years.. 8.6Renal Impairment. No dosage modification is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of VIZIMPRO has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. No dosage modification is recommended in patients with mild, moderate or severe hepatic impairment (Child-Pugh A, or C) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Interstitial Lung Disease (ILD): Permanently discontinue VIZIMPRO if ILD is confirmed. (5.1)Diarrhea: Withhold and reduce the dose of VIZIMPRO based on the severity. (2.3, 5.2)Dermatologic Adverse Reactions: Withhold and reduce the dose of VIZIMPRO based on the severity. (2.3, 5.3)Embryo-Fetal Toxicity: VIZIMPRO can cause fetal harm. Advise females of reproductive potential to use effective contraception. (5.4, 8.1, 8.3). Interstitial Lung Disease (ILD): Permanently discontinue VIZIMPRO if ILD is confirmed. (5.1). Diarrhea: Withhold and reduce the dose of VIZIMPRO based on the severity. (2.3, 5.2). Dermatologic Adverse Reactions: Withhold and reduce the dose of VIZIMPRO based on the severity. (2.3, 5.3). Embryo-Fetal Toxicity: VIZIMPRO can cause fetal harm. Advise females of reproductive potential to use effective contraception. (5.4, 8.1, 8.3). 5.1Interstitial Lung Disease (ILD). Severe and fatal ILD/pneumonitis occurred in patients treated with VIZIMPRO and occurred in 0.5% of the 394 VIZIMPRO-treated patients; 0.3% of cases were fatal.Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold VIZIMPRO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue VIZIMPRO if ILD is confirmed [see Adverse Reactions (6.1)].. 5.2Diarrhea. Severe and fatal diarrhea occurred in patients treated with VIZIMPRO. Diarrhea occurred in 86% of the 394 VIZIMPRO-treated patients; Grade or diarrhea was reported in 11% of patients and 0.3% of cases were fatal.Withhold VIZIMPRO for Grade or greater diarrhea until recovery to less than or equal to Grade severity, then resume VIZIMPRO at the same or reduced dose depending on the severity of diarrhea [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Promptly initiate anti-diarrheal treatment (loperamide or diphenoxylate hydrochloride with atropine sulfate) for diarrhea.. 5.3Dermatologic Adverse Reactions. Rash and exfoliative skin reactions occurred in patients treated with VIZIMPRO. Rash occurred in 78% of the 394 VIZIMPRO-treated patients; Grade or rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade or exfoliative skin reactions were reported in 1.8% of patients. Withhold VIZIMPRO for persistent Grade or any Grade or dermatologic adverse reaction until recovery to less than or equal to Grade severity, then resume VIZIMPRO at the same or reduced dose depending on the severity of the dermatologic adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. The incidence and severity of rash and exfoliative skin reactions may increase with sun exposure. At the time of initiation of VIZIMPRO, initiate use of moisturizers and appropriate measures to limit sun exposure. Upon development of Grade rash, initiate treatment with topical antibiotics and topical steroids. Initiate oral antibiotics for Grade or more severe dermatologic adverse reactions.. 5.4Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to pregnant woman. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VIZIMPRO and for at least 17 days after the final dose [see Use in Specific Populations (8.1 and 8.3)].