BALVERSA

1 INDICATIONS AND USAGE BALVERSA is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] . BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA. ( 1 , 2.1 ) Limitations of Use BALVERSA is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy. ( 1 , 14.1 ) Limitations of Use BALVERSA is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy [see Clinical Studies (14.1) ] .

2 DOSAGE AND ADMINISTRATION Confirm the presence of FGFR3 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 FGFR3 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 FGFR3 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 tolerability, including hyperphosphatemia, 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 10 mg/dL Withhold BALVERSA with weekly reassessments until level returns to 2 weeks, discontinue BALVERSA permanently. Medical management of symptoms as clinically relevant. Serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis) Discontinue BALVERSA permanently. Central Serous Retinopathy (CSR) Any Withhold BALVERSA and perform an ophthalmic evaluation within 2 weeks: If improving within 14 days, restart BALVERSA at the current dose. If not improving within 14 days, withhold BALVERSA until improving; once improving, may resume at the next lower dose level. Upon restarting BALVERSA, monitor for recurrence every 1 to 2 weeks for a month. If recurs or has not improved after 4 weeks of withholding BALVERSA, consider permanent discontinuation. Other Adverse Reactions Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv5.0). Grade 3 Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower. Grade 4 Permanently discontinue.

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.

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are also described elsewhere in the labeling: Ocular Disorders [see Warnings and Precautions (5.1) ] . Hyperphosphatemia [see Warnings and Precautions (5.2) ] . The most common (>20%) adverse reactions, including laboratory abnormalities, were increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy. ( 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to BALVERSA as a single agent at the recommended dose (8 to 9 mg orally daily) in 479 patients with advanced urothelial cancer and FGFR alterations in 42756493BLC3001 (NCT03390504), 42756493BLC2001 (NCT02365597), 42756493BLC2002 (NCT 03473743), and 42756493EDI1001 (NCT01703481). Among 479 patients who received BALVERSA, the median duration of treatment was 4.8 months (range: 0.1 to 43 months). In this pooled safety population, the most common (>20%) adverse reactions, including laboratory abnormalities, were increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy. BLC3001 The safety of BALVERSA was evaluated in Cohort 1 of the BLC3001 study that included patients with locally advanced unresectable or metastatic urothelial carcinoma which had susceptible FGFR3 genetic alterations and were previously treated with a PD-1 or PD-L1 inhibitor [see Clinical Studies (14.1) ] . Patients received either BALVERSA (8 mg orally once daily with individualized up-titration to 9 mg) (n=135) or chemotherapy (docetaxel 75 mg/m 2 once every 3 weeks or vinflunine 320 mg/m 2 once every 3 weeks) (n=112). Among patients who received BALVERSA, median duration of treatment was 4.8 months (range: 0.2 to 38 months). Serious adverse reactions occurred in 41% of patients who received BALVERSA. Serious reactions in >2% of patients included urinary tract infection (4.4%), hematuria (3.7%), hyponatremia (2.2%), and acute kidney injury (2.2%). Fatal adverse reactions occurred in 4.4% of patients who received BALVERSA, including sudden death (1.5%), pneumonia (1.5%), renal failure (0.7%), and cardiorespiratory arrest (0.7%). Permanent discontinuation of BALVERSA due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BALVERSA in >2% of patients included nail disorders (3%) and eye disorders (2.2%). Dosage interruptions of BALVERSA due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in >4% of patients included nail disorders (22%), stomatitis (19%), eye disorders (16%), palmar-plantar erythrodysesthesia syndrome (15%), diarrhea (10%), hyperphosphatemia (7%), increased aspartate aminotransferase (6%), and increased alanine aminotransferase (5%). …

7 DRUG INTERACTIONS Moderate CYP2C9 or strong CYP3A4 inhibitors: Consider alternative agents or monitor closely for adverse reactions. ( 7.1 ) Strong CYP3A4 inducers: Avoid concomitant use with BALVERSA. ( 7.1 ) Moderate CYP3A4 inducers: Administer BALVERSA at a dose of 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 ) 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 7 summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management. Table 7: 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, resume the BALVERSA dose before dose modifications in the absence of drug-related toxicity. Strong CYP3A4 Inducers Clinical Impact Co-administration of BALVERSA with strong CYP3A4 inducers decreased erdafitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Decreased erdafitinib plasma concentrations may lead to decreased activity. Clinical Management Avoid co-administration of strong CYP3A4 inducers with BALVERSA. Moderate CYP3A4 Inducers Clinical Impact Co-administration of BALVERSA with moderate CYP3A4 inducers may decrease erdafitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Decreased erdafitinib plasma concentrations may lead to decreased activity. Clinical Management If a moderate CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA at a dose of 9 mg daily. When a moderate CYP3A4 inducer 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 8 summarizes the effect of BALVERSA on other drugs and their clinical management. Table 8: BALVERSA Drug Interactions that Affect Other Drugs 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.

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 BALVERSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with BALVERSA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. 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. 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. Skeletal adverse reactions have occurred in pediatric patients treated with BALVERSA. In a study of BALVERSA that included pediatric patients ages 6 to <18 years with FGFR-positive advanced solid tumors, epiphysiolysis and bone fractures occurred. In the postmarket setting and in literature reports, cases of slipped capital femoral epiphysis and accelerated linear growth in patients treated with BALVERSA have been reported. Juvenile Animal Toxicity Data 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 479 patients treated with BALVERSA in clinical studies, 40% of patients were less than 65 years old, 40% of patients were 65 years to 74 years old, and 20% were 75 years old and over. Pati …

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 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.

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

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