BALVERSA

6 ADVERSE REACTIONS The following serious adverse reactions are also described elsewhere in the labeling: Ocular Disorders [see Warning and Precautions (5.1) ] . Hyperphosphatemia [see Warning and Precautions (5.2) ] . The most common adverse reactions including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, nail disorder, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP. at 1-800-526-7736 (1-800-JANSSEN and www.BALVERSA.com) 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 safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1) ] . Patients were treated with BALVERSA at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months). The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, nail disorder, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, and hyperphosphatemia. An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction. Serious adverse reactions occurred in 41% of patients including eye disorders (10%). Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%). Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysesthesia syndrome (8%). Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%). Table 3 presents ARs reported in ≥10% of patients treated with BALVERSA at 8 mg once daily. Table 3: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥5% (Grade 3–4) of Patients BALVERSA 8 mg daily (N=87) Adverse Reaction All Grades (%) Grade 3–4 (%) Any 100 67 Gastrointestinal disorders 92 24 Stomatitis 56 9 Diarrhea 47 2 Dry mouth 45 0 Constipation 28 1 Abdominal pain Includes abdominal pain, abdominal discomfort, abdominal pain upper, and abdominal pain lower 23 2 Nausea 21 1 Vomiting 13 2 Metabolism and nutrition disorders 90 16 Decreased appetite 38 0 General disorders and admin. site conditions 69 13 Fatigue Includes asthenia, fatigue, lethargy, and malaise 54 10 Pyrexia 14 1 Skin and subcutaneous disorders 75 16 Nail disorder Includes onycholysis, onychoclasis, nail disorder, nail dystrophy, nail ridging, and onychomadesis 45 10 Dry skin Includes dry skin and xerostomia 34 0 Palmar-plantar erythrodysesthesia 26 6 Alopecia 26 0 Nail discoloration 11 0 Eye disorders 62 11 Dry eye Includes dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion 28 6 Vision blurred 17 0 Lacrimation increased 10 0 Nervous system disorders 57 5 Dysgeusia 37 1 Infections and infestations 56 20 Paronychia 17 3 Urinary tract infection 17 6 Conjunctivitis 11 0 Respiratory, thoracic and mediastinal disorders 40 7 Oropharyngeal pain 11 1 Dyspnea Includes dyspnea and dyspnea exertional 10 2 Renal and urinary tract disorders 38 10 Hematuria 11 2 Musculoskeletal and connective tissue disorders 31 0 Musculoskeletal pain Includes back pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal chest pain, neck pain, pain in extremity 20 0 Arthralgia 11 0 Investigations 44 5 Weight decreased Includes weight decreased and cachexia 16 0 Table 4: Laboratory Abnormalities Reported in ≥ 10% (All Grade) or ≥ 5% (Grade 3–4) of Patients BALVERSA 8 mg daily (N=86 One of the 87 patients had no laboratory tests. ) Laboratory Abnormality All Grades (%) Grade 3–4 (%) Hematology Hemoglobin decreased 35 3 Platelets decreased 19 1 Leukocytes decreased 17 0 Neutrophils decreased 10 2 Chemistry Phosphate increased 76 1 Creatinine increased 52 5 Sodium decreased 40 16 Alanine aminotransferase increased 41 1 Alkaline phosphatase increased 41 1 Albumin decreased 37 0 Aspartate aminotransferase increased 30 0 Magnesium decreased 30 1 Phosphate decreased 24 9 Calcium increased 22 3 Potassium increased 16 0 Fasting glucose decreased 10 0

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Erdafitinib, the active ingredient in BALVERSA, is a kinase inhibitor. The chemical name is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine. Erdafitinib is a yellow powder. It is practically insoluble, or insoluble to freely soluble in organic solvents, and slightly soluble to practically insoluble, or insoluble in aqueous media over a wide range of pH values. The molecular formula is C 25 H 30 N 6 O 2 and molecular weight is 446.56. Chemical structure of erdafitinib is as follows: BALVERSA ® (erdafitinib) tablets are supplied as 3 mg, 4 mg or 5 mg film-coated tablets for oral administration and contains the following inactive ingredients: Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose. Film Coating: (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only). Chemical Structure

2 DOSAGE AND ADMINISTRATION Confirm the presence of FGFR genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. ( 2.1 ) Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. ( 2.2 ) Swallow whole with or without food. ( 2.2 ) 2.1 Patient Selection Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic [see Clinical Studies (14.1) ] . Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage and Schedule The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO 4 ) levels and tolerability at 14 to 21 days [see Dosage and Administration (2.3) ]. Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs. If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose. Dose Increase based on Serum Phosphate Levels Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia [see Pharmacodynamics (12.2) ] . 2.3 Dose Modifications for Adverse Reactions The recommended dose modifications for adverse reactions are listed in Table 1. Table 1: BALVERSA Dose Reduction Schedule Dose 1 st dose reduction 2 nd dose reduction 3 rd dose reduction 4 th dose reduction 5 th dose reduction 9 mg ⭢ (three 3 mg tablets) 8 mg (two 4 mg tablets) 6 mg (two 3 mg tablets) 5 mg (one 5 mg tablet) 4 mg (one 4 mg tablet) Stop 8 mg ⭢ (two 4 mg tablets) 6 mg (two 3 mg tablets) 5 mg (one 5 mg tablet) 4 mg (one 4 mg tablet) Stop Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions. Table 2: Dose Modifications for Adverse Reactions Adverse Reaction BALVERSA Dose Modification Hyperphosphatemia In all patients, restrict phosphate intake to 600–800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to < 5.5 mg/dL. 5.6–6.9 mg/dL (1.8–2.3 mmol/L) Continue BALVERSA at current dose. 7.0–9.0 mg/dL (2.3–2.9 mmol/L) Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then restart BALVERSA at the same dose level. A dose reduction may be implemented for hyperphosphatemia lasting > 1 week. > 9.0 mg/dL (> 2.9 mmol/L) Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 1 dose level lower. > 10.0 mg/dL (> 3.2 mmol/L) or significant alteration in baseline renal function or Grade 3 hypercalcemia Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 2 dose levels lower. Central Serous Retinopathy/Retinal Pigment Epithelial Detachment (CSR/RPED) Grade 1: Asymptomatic; clinical or diagnostic observations only Withhold until resolution. If resolves within 4 weeks, resume at the next lower dose level. Then, if no recurrence for a month, consider re-escalation. If stable for 2 consecutive eye exams but not resolved, resume at the next lower dose level. Grade 2: Visual acuity 20/40 or better or ≤ 3 lines of decreased vision from baseline Withhold until resolution. If resolves within 4 weeks, may resume at the next lower dose level. Grade 3: Visual acuity worse than 20/40 or > 3 lines of decreased vision from baseline Withhold until resolution. If resolves within 4 weeks, may resume two dose levels lower. If recurs, consider permanent discontinuation. Grade 4: Visual acuity 20/200 or worse in affected eye Permanently discontinue. Other Adverse Reactions Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv4.03). Grade 3 Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower. Grade 4 Permanently discontinue.

1 INDICATIONS AND USAGE BALVERSA is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has: susceptible FGFR3 or FGFR2 genetic alterations, and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] . This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.1) ] . BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) that has susceptible FGFR3 or FGFR2 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA. ( 1 , 2.1 ) This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ( 1 , 14.1 )

7 DRUG INTERACTIONS Moderate CYP2C9 or strong CYP3A4 inhibitors: Consider alternative agents or monitor closely for adverse reactions. ( 7.1 ) Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. ( 7.1 ) Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. ( 7.1 ) Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. ( 2.3 , 7.1 ) CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. ( 7.2 ) OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. ( 7.2 ) P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. ( 7.2 ) 7.1 Effect of Other Drugs on BALVERSA Table 5 summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management. Table 5: Drug Interactions that Affect BALVERSA Moderate CYP2C9 or Strong CYP3A4 Inhibitors Clinical Impact Co-administration of BALVERSA with moderate CYP2C9 or strong CYP3A4 inhibitors increased erdafitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Increased erdafitinib plasma concentrations may lead to increased drug-related toxicity [see Warnings and Precautions (5) ]. Clinical Management Consider alternative therapies that are not moderate CYP2C9 or strong CYP3A4 inhibitors during treatment with BALVERSA. If co-administration of a moderate CYP2C9 or strong CYP3A4 inhibitor is unavoidable, monitor closely for adverse reactions and consider dose modifications accordingly [see Dosage and Administration (2.3) ]. If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, the BALVERSA dose may be increased in the absence of drug-related toxicity. Strong CYP2C9 or CYP3A4 Inducers Clinical Impact Co-administration of BALVERSA with strong inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations significantly [see Clinical Pharmacology (12.3) ]. Decreased erdafitinib plasma concentrations may lead to decreased activity. Clinical Management Avoid co-administration of strong inducers of CYP2C9 or CYP3A4 with BALVERSA. Moderate CYP2C9 or CYP3A4 Inducers Clinical Impact Co-administration of BALVERSA with moderate inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Decreased erdafitinib plasma concentrations may lead to decreased activity. Clinical Management If a moderate CYP2C9 or CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA dose as recommended (8 mg once daily with potential to increase to 9 mg once daily based on serum phosphate levels on Days 14 to 21 and tolerability). If a moderate CYP2C9 or CYP3A4 inducer must be co-administered after the initial dose increase period based on serum phosphate levels and tolerability, increase BALVERSA dose up to 9 mg. When a moderate inducer of CYP2C9 or CYP3A4 is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity. Serum Phosphate Level-Altering Agents Clinical Impact Co-administration of BALVERSA with other serum phosphate level-altering agents may increase or decrease serum phosphate levels [see Pharmacodynamics (12.2) ]. Changes in serum phosphate levels due to serum phosphate level-altering agents (other than erdafitinib) may interfere with serum phosphate levels needed for the determination of initial dose increased based on serum phosphate levels [see Dosage and Administration (2.3) ]. Clinical Management Avoid co-administration of serum phosphate level-altering agents with BALVERSA before initial dose increase period based on serum phosphate levels (Days 14 to 21) [see Dosage and Administration (2.3) ]. 7.2 Effect of BALVERSA on Other Drugs Table 6 summarizes the effect of BALVERSA on other drugs and their clinical management. Table 6: BALVERSA Drug Interactions that Affect Other Drugs CYP3A4 Substrates Clinical Impact Co-administration of BALVERSA with CYP3A4 substrates may alter the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology (12.3) ]. Altered plasma concentrations of CYP3A4 substrates may lead to loss of activity or increased toxicity of the CYP3A4 substrates. Clinical Management Avoid co-administration of BALVERSA with sensitive substrates of CYP3A4 with narrow therapeutic indices. OCT2 Substrates Clinical Impact Co-administration of BALVERSA with OCT2 substrates may increase the plasma concentrations of OCT2 substrates [see Clinical Pharmacology (12.3) ]. Increased plasma concentrations of OCT2 substrates may lead to increased toxicity of the OCT2 substrates. Clinical Management Consider alternative therapies that are not OCT2 substrates or consider reducing the dose of OCT2 substrates (e.g., metformin) based on tolerability. P-glycoprotein (P-gp) Substrates Clinical Impact Co-administration of BALVERSA with P-gp substrates may increase the plasma concentrations of P-gp substrates [see Clinical Pharmacology (12.3) ]. Increased plasma concentrations of P-gp substrates may lead to increased toxicity of the P-gp substrates. Clinical Management If co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic index.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. 12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing [see Dosage and Administration (2.3) ]. In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels [see Drug Interactions (7.1) ]. 12.3 Pharmacokinetics Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (C max ), area under the curve (AUC tau ), and minimum observed plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [C max ] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold. Absorption Median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). Effect of Food No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects. Distribution The mean apparent volume of distribution of erdafitinib was 29 L in patients. Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein. Elimination The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. The mean effective half-life of erdafitinib was 59 hours in patients. Metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20%, respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21–88 years), sex, race, body weight (36–132 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m 2 ). Limited data are available in patients with severe (Child-Pugh C) hepatic impairment. The pharmacokinetics of erdafitinib in patients with severe renal impairment and renal impairment requiring dialysis is unknown. Drug Interaction Studies Clinical Studies and Model-Based Approaches Moderate CYP2C9 Inhibitors: Erdafitinib mean ratios (90% CI) for C max and AUC inf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone. Strong CYP3A4 Inhibitors: Erdafitinib mean ratios (90% CI) for C max and AUC inf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. Strong CYP3A4/2C9 Inducers: Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib C max and AUC. In Vitro Studies CYP Substrates: Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. Transporters: Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. Acid-Lowering Agents: Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H 2 -antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib. 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic variants, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C9*1/*2 and *1/*3 genotypes relative to subjects with CYP2C9*1/*1 genotype (wild type). No data are available in subjects characterized by other genotypes (e.g., *2/*2, *2/*3, *3/*3). Simulation suggested no clinically meaningful differences in erdafitinib exposure in subjects with CYP2C9*2/*2 and *2/*3 genotypes. The exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype, estimated to be present in 0.4% to 3% of the population among various ethnic groups.

12.1 Mechanism of Action Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

12.2 Pharmacodynamics Cardiac Electrophysiology Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. Serum Phosphate Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing [see Dosage and Administration (2.3) ]. In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels [see Drug Interactions (7.1) ].

12.3 Pharmacokinetics Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (C max ), area under the curve (AUC tau ), and minimum observed plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng∙h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [C max ] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold. Absorption Median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). Effect of Food No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects. Distribution The mean apparent volume of distribution of erdafitinib was 29 L in patients. Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein. Elimination The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. The mean effective half-life of erdafitinib was 59 hours in patients. Metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20%, respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites. Excretion Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). Specific Populations No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21–88 years), sex, race, body weight (36–132 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m 2 ). Limited data are available in patients with severe (Child-Pugh C) hepatic impairment. The pharmacokinetics of erdafitinib in patients with severe renal impairment and renal impairment requiring dialysis is unknown. Drug Interaction Studies Clinical Studies and Model-Based Approaches Moderate CYP2C9 Inhibitors: Erdafitinib mean ratios (90% CI) for C max and AUC inf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone. Strong CYP3A4 Inhibitors: Erdafitinib mean ratios (90% CI) for C max and AUC inf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone. Strong CYP3A4/2C9 Inducers: Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib C max and AUC. In Vitro Studies CYP Substrates: Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations. Transporters: Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2. Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. Acid-Lowering Agents: Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H 2 -antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

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3 DOSAGE FORMS AND STRENGTHS Tablets: 3 mg, 4 mg, and 5 mg. ( 3 ) Tablets: 3 mg: Yellow, round biconvex, film-coated, debossed with "3" on one side; and "EF" on the other side. 4 mg: Orange, round biconvex, film-coated, debossed with "4" on one side; and "EF" on the other side. 5 mg: Brown, round biconvex, film-coated, debossed with "5" on one side; and "EF" on the other side.

BALVERSA Erdafitinib CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MANNITOL MEGLUMINE MICROCRYSTALLINE CELLULOSE GLYCERYL MONOCAPRYLOCAPRATE POLYVINYL ALCOHOL, UNSPECIFIED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW ERDAFITINIB ERDAFITINIB biconvex shaped 3;EF BALVERSA Erdafitinib CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MANNITOL MEGLUMINE MICROCRYSTALLINE CELLULOSE GLYCERYL MONOCAPRYLOCAPRATE POLYVINYL ALCOHOL, UNSPECIFIED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED ERDAFITINIB ERDAFITINIB biconvex shaped 4;EF BALVERSA Erdafitinib CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MANNITOL MEGLUMINE MICROCRYSTALLINE CELLULOSE GLYCERYL MONOCAPRYLOCAPRATE POLYVINYL ALCOHOL, UNSPECIFIED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED FERROSOFERRIC OXIDE ERDAFITINIB ERDAFITINIB biconvex shaped 5;EF

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity studies have not been conducted with erdafitinib. Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity studies have not been conducted with erdafitinib. Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.

NDA212018

BALVERSA

Erdafitinib

59676-030

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 3 mg Tablet Bottle Carton NDC 59676-030-56 Balversa ® (erdafitinib) tablets 3 mg Each film-coated tablet contains 3 mg of erdafitinib. Rx only 56 film-coated tablets 3 mg Tablet Bottle Carton

Warnings and Precautions ( 5.2 ) 04/2022

Product of Switzerland Manufactured for: Janssen Products, LP Horsham, PA 19044 Under license from Astex Therapeutics Limited. ©2019 Janssen Pharmaceutical Companies

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). FGFR Genetic Alterations Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated [see Dosage and Administration (2.1) ] . Ocular Disorders Advise patients to contact their healthcare provider if they experience any visual changes [see Warnings and Precautions (5.1) ]. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours [see Dosage and Administration (2.3) ]. Skin, Mucous or Nail Disorders Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders [see Adverse Reactions (6.1) ] . Hyperphosphatemia and Soft Tissue Mineralization Inform patients that BALVERSA may cause hyperphosphatemia and soft tissue mineralization. Advise patients to immediately inform their healthcare provider of painful skin lesions or any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth [see Warnings and Precautions (5.2) ] . Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed [see Warnings and Precautions (5.2) ] . Advise patients to restrict phosphate intake to 600–800 mg daily. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with BALVERSA [see Drug Interactions (7.1) ]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [see Drug Interactions (7.1 , 7.2) ] . Dosing Instructions Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking BALVERSA, advise patients to take the next dose the next day. [see Dosage and Administration (2.1) ] . Missed Dose If a dose is missed, advise patients to take the missed dose as soon as possible. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose [see Dosage and Administration (2.3) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy [see Warning and Precautions (5.3) and Use in Specific Population (8.1) ] . Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA [see Use in Specific Populations (8.3) ]. Lactation Advise females not to breastfeed during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.2) ].

14 CLINICAL STUDIES 14.1 Urothelial Carcinoma with Susceptible FGFR Genetic Alterations Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty-seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen ® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA. Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1. The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy. Efficacy results are summarized in Table 7 and Table 8. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy. Table 7: Efficacy Results BIRC BIRC: Blinded Independent Review Committee Assessment Endpoint N=87 ORR = CR + PR CI = Confidence Interval ORR (95% CI) 32.2% (22.4, 42.0) Complete response (CR) 2.3% Partial response (PR) 29.9% Median DoR in months (95% CI) 5.4 (4.2, 6.9) Table 8: Efficacy Results by FGFR Genetic Alteration BIRC BIRC: Blinded Independent Review Committee Assessment ORR = CR + PR CI = Confidence Interval FGFR3 Point Mutation N=64 ORR (95% CI) 40.6% (28.6, 52.7) FGFR3 Fusion Both responders had FGFR3-TACC3_V1 fusion , One patient with a FGFR2-CASP7/FGFR3-TACC3_V3 fusion is reported in both FGFR2 fusion and FGFR3 fusion above N=18 ORR (95% CI) 11.1% (0, 25.6) FGFR2 Fusion N=6 ORR 0

8.5 Geriatric Use Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14.1) ].

8.4 Pediatric Use Safety and effectiveness of BALVERSA in pediatric patients have not been established. In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats.

8.1 Pregnancy Risk Summary Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on BALVERSA use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC (see Data ). Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4 mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on BALVERSA use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC (see Data ). Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4 mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight. 8.2 Lactation Risk Summary There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with BALVERSA. Contraception Females BALVERSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Population (8.1) ] . Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1) ] . Infertility Females Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness of BALVERSA in pediatric patients have not been established. In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats. 8.5 Geriatric Use Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14.1) ]. 8.6 Renal Impairment No dose adjustment is recommended for patients with mild to moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m 2 ]. No data are available in patients with severe renal impairment [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Limited data are available in patients with severe (Child-Pugh C) hepatic impairment. [see Clinical Pharmacology (12.3) ] . 8.8 CYP2C9 Poor Metabolizers CYP2C9*3/*3 Genotype: Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype [see Pharmacogenomics (12.5) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING BALVERSA ® (erdafitinib) tablets are available in the strengths and packages listed below: 3 mg tablets: Yellow, round biconvex, film-coated, debossed with "3" on one side and "EF" on the other side. Bottle of 56-tablets with child resistant closure (NDC 59676-030-56). Bottle of 84-tablets with child resistant closure (NDC 59676-030-84). 4 mg tablets: Orange, round biconvex, film-coated, debossed with "4" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure (NDC 59676-040-28). Bottle of 56-tablets with child resistant closure (NDC 59676-040-56). 5 mg tablets: Brown, round biconvex, film-coated, debossed with "5" on one side and "EF" on the other side. Bottle of 28-tablets with child resistant closure (NDC 59676-050-28). Store at 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] .

Store at 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] .