Dacomitinib

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 )

Tablets:

• 45 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB45" on the other side.
• 30 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB30" on the other side.
• 15 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB15" on the other side. Tablets: 15 mg, 30 mg, and 45 mg. ( 3 )

None. None. ( 4 )

• 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 )

5.1 Interstitial 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) ] .

5.2 Diarrhea Severe and fatal diarrhea occurred in patients treated with VIZIMPRO. Diarrhea occurred in 86% of the 394 VIZIMPRO-treated patients; Grade 3 or 4 diarrhea was reported in 11% of patients and 0.3% of cases were fatal. Withhold VIZIMPRO for Grade 2 or greater diarrhea until recovery to less than or equal to Grade 1 severity, then resume VIZIMPRO at the same or a 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.

5.3 Dermatologic Adverse Reactions Rash and exfoliative skin reactions occurred in patients treated with VIZIMPRO. Rash occurred in 78% of the 394 VIZIMPRO-treated patients; Grade 3 or 4 rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade 3 or 4 exfoliative skin reactions were reported in 1.8% of patients. Withhold VIZIMPRO for persistent Grade 2 or any Grade 3 or 4 dermatologic adverse reaction until recovery to less than or equal to Grade 1 severity, then resume VIZIMPRO at the same or a 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 1 rash, initiate treatment with topical antibiotics and topical steroids. Initiate oral antibiotics for Grade 2 or more severe dermatologic adverse reactions.

5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to a 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) ] .

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

• Proton Pump Inhibitors (PPIs): Avoid use with VIZIMPRO; use locally-acting antacids or H2-receptor antagonist; administer VIZIMPRO at least 6 hours before or 10 hours after H2-receptor antagonist. ( 2.4 , 7.1 )
• CYP2D6 Substrates: Avoid concomitant use with VIZIMPRO where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities. ( 7.2 )

7.1 Effect of Other Drugs on VIZIMPRO Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce VIZIMPRO efficacy. Avoid the concomitant use of PPIs with VIZIMPRO. As an alternative to PPIs, use locally-acting antacids or an H2-receptor antagonist. Administer VIZIMPRO at least 6 hours before or 10 hours after taking an H2-receptor antagonist [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

7.2 Effect of VIZIMPRO on CYP2D6 Substrates Concomitant use of VIZIMPRO increases the concentration of drugs that are CYP2D6 substrates [see Clinical Pharmacology (12.3) ] which may increase the risk of toxicities of these drugs. Avoid concomitant use of VIZIMPRO with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

• Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to a 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 a 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 Data Daily 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 5 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 Summary There 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 Testing Verify the pregnancy status of females of reproductive potential prior to initiating VIZIMPRO [ see Use in Specific Populations (8.1) ]. Contraception VIZIMPRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Females Advise 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 a 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 a higher incidence of Grade 3 and 4 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.

8.6 Renal 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) ] .

8.7 Hepatic Impairment No dosage modification is recommended in patients with mild, moderate or severe hepatic impairment (Child-Pugh A, B or C) [see Clinical Pharmacology (12.3) ] .

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.