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 the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)] There are no available data on BALVERSA use in pregnant women to inform 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 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 DataIn 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 SummaryThere 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 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 pregnant woman [see Use in Specific Populations (8.1)] . Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating treatment with BALVERSA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose.. MalesAdvise 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. FemalesBased 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 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.Patients 65 years of age and older treated with BALVERSA experienced higher incidence of adverse reactions requiring treatment discontinuation than younger patients. In clinical trials, the incidence of treatment discontinuations of BALVERSA due to adverse reactions was 10% in patients younger than 65 years, 20% in patients ages 65-74 years, and 35% in patients 75 years or older.No overall difference in efficacy was observed between these patients and younger patients [see Clinical Studies (14.1)]. 8.6 CYP2C9 Poor Metabolizers. CYP2C93/3 Genotype:Erdafitinib plasma concentrations are predicted to be higher in patients with the CYP2C93/3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C93/3 genotype [see Pharmacogenomics (12.5)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Ocular disorders: BALVERSA can cause central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED). Perform monthly ophthalmological examinations during the first four months of treatment, every months afterwards, and at any time for visual symptoms. Withhold BALVERSA when CSR/RPED occurs and permanently discontinue if it does not resolve within weeks or if Grade in severity. 2.3, 5.1) Hyperphosphatemia: Increases in phosphate levels are pharmacodynamic effect of BALVERSA. Monitor for hyperphosphatemia and manage with dose modifications when required. 2.3, 5.2) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception 5.3, 8.1, 8.3) Ocular disorders: BALVERSA can cause central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED). Perform monthly ophthalmological examinations during the first four months of treatment, every months afterwards, and at any time for visual symptoms. Withhold BALVERSA when CSR/RPED occurs and permanently discontinue if it does not resolve within weeks or if Grade in severity. 2.3, 5.1) Hyperphosphatemia: Increases in phosphate levels are pharmacodynamic effect of BALVERSA. Monitor for hyperphosphatemia and manage with dose modifications when required. 2.3, 5.2) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception 5.3, 8.1, 8.3) 5.1 Ocular Disorders. BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.In the pooled safety population [see Adverse Reactions (6)] CSR/RPED occurred in 22% of patients treated with BALVERSA, with median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation. Dry eye symptoms occurred in 26% of BALVERSA-treated patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.Perform monthly ophthalmological examinations during the first months of treatment and every months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.Withhold or permanently discontinue BALVERSA based on severity and/or ophthalmology exam findings [see Dosage and Administration (2.3)] . 5.2 Hyperphosphatemia and Soft Tissue Mineralization. BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. In the pooled safety population [see Adverse Reactions (6)], increased phosphate occurred in 73% of BALVERSA-treated patients. The median onset time of increased phosphate was 16 days (range: 8-421) after initiating BALVERSA. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA. Monitor for hyperphosphatemia throughout treatment. Restrict dietary phosphate intake (600-800 mg daily) and avoid concomitant use of agents that may increase serum phosphate levels.If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia according to Table [see Dosage and Administration (2.3)]. 5.3 Embryo-Fetal Toxicity. Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. 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, 8.3)and Clinical Pharmacology (12.1)].

ADVERSE REACTIONS SECTION.

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)] . 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 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 single agent at the recommended dose (8 to mg orally daily) in 479 patients with advanced urothelial cancer and FGFRalterations 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. BLC3001The safety of BALVERSA was evaluated in Cohort of the BLC3001 study that included patients with locally advanced unresectable or metastatic urothelial carcinoma which had susceptible FGFR3genetic alterations and were previously treated with 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 mg) (n=135) or chemotherapy (docetaxel 75 mg/m 2once every weeks or vinflunine 320 mg/m 2once every 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%).Dose reductions of BALVERSA due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dose reductions in >4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysesthesia syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%).Table presents adverse reactions reported in >=15% of patients treated with BALVERSA at or mg once daily versus chemotherapy.Table 3: Adverse Reactions Reported in >=15% of Patients Who Received BALVERSA Versus Chemotherapy (Study BLC3001)Adverse ReactionBALVERSA (N=135)Chemotherapy (N=112)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Skin and subcutaneous tissue disorders Nail disorders Includes multiple terms 701250 Palmar-plantar erythrodysesthesia syndrome30100.90 Dry skin 271.560 Alopecia250.7240Gastrointestinal disorders Diarrhea 633172.7 Stomatitis 5610181.8 Dry Mouth3903.60 Constipation270281.8Nervous system disorders Dysgeusia 300.770General disorders Fatigue 291.5427Metabolism and nutrition disorders Decreased appetite273212.7Eye disorders Dry eye 250.73.60 Central serous retinopathy 182.200Investigations Decreased weight2222.70Clinically relevant adverse reactions in <15% of patients who received BALVERSA included nausea (15%), pyrexia (15%), epistaxis (13%), vomiting (10%), and arthralgia (10%).Table presents laboratory abnormalities reported in >=15% of patients treated with BALVERSA at or mg once daily versus chemotherapy.Table 4: Selected Laboratory Abnormalities Reported in >=15% of Patients Who Received BALVERSA Versus Chemotherapy; Cohort Safety Analysis Set (Study BLC3001)Laboratory AbnormalityBALVERSA (N=135 The denominator used to calculate the rate varied from 52 to 131 based on the number of patients with baseline value and at least one post-treatment value.) Chemotherapy (N=112 The denominator used to calculate the rate varied from 11 to 102 based on the number of patients with baseline value and at least one post-treatment value.) All Grades Severity graded per NCI CTCAE v4.03.(%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Increased phosphate76500 Increased alkaline phosphatase544.7291 Increased alanine aminotransferase463.8151 Increased aspartate aminotransferase443.1130 Decreased sodium4416256 Increased creatinine431.5170 Decreased phosphate348253.6 Increased calcium27890 Increased potassium240210Hematology Decreased hemoglobin50125712 Decreased platelet count171.5181 Decreased neutrophil count160.84026. BLC2001The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3and other FGFRalterations, 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 mg orally once daily; with dose increase to 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: to 17 months). Serious adverse reactions occurred in 41% of patients. The most frequent (>3%) serious adverse reactions were central serous retinopathy (4.6%), urinary tract infection (3.4%), and general physical health deterioration (3.4%).Fatal adverse reactions occurred in 8% of patients, including acute myocardial infarction (1.1%).Permanent discontinuation of BALVERSA due to an adverse reaction occurred in 21% of patients. The most frequent (>= 2%) reasons for permanent discontinuation included central serous retinopathy (4.6%), general physical health deterioration (3.4%), palmar-plantar erythrodysesthesia syndrome (2.3%), acute kidney injury (2.3%), and fatigue (2.3%).Dosage interruptions of BALVERSA occurred in 68% of patients. The most frequent (>= 5%) adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), nail disorders (16%), central serous retinopathy (9%), palmar-plantar erythro-dysesthesia syndrome (8%), and fatigue (8%).Dose reductions of BALVERSA occurred in 53% of patients. The most frequent (>= 5%) adverse reactions for dose reductions included nail disorders (21%), stomatitis (15%), central serous retinopathy (14%), hyperphosphatemia (7%), palmar-plantar erythro-dysesthesia syndrome (7%), fatigue (6%), and blurred vision (6%).Table presents adverse reactions reported in >=15% of patients treated with BALVERSA at mg or mg once daily.Table 5: Adverse Reactions Reported in >=15% of Patients (Study BLC2001)Adverse ReactionBALVERSA mg daily (N=87)All Grades (%)Grade 3-4 (%) Gastrointestinal disorders Stomatitis Includes multiple terms 6211 Diarrhea 484.6 Dry mouth450 Constipation281.1 Nausea211.1Skin and subcutaneous tissue disorders Nail disorders 6214 Dry skin 370 Alopecia260 Palmar-plantar erythrodysesthesia syndrome266General disorders and admin. site conditions Fatigue Includes fatal adverse reactions (n=2) 548 Decreased weight160Metabolism and nutrition disorders Decreased appetite380.0Nervous system disorders Dysgeusia 381.1Eye disorders Dry eye 291.1 Central serous retinopathy 284.6 Blurred vision170Infections and Infestations Urinary tract infection176Clinically relevant adverse reactions in <15% of patients who received BALVERSA included pyrexia (14%), extremity pain (13%), vomiting (13%), and peripheral edema (10%).Table presents laboratory abnormalities reported in >=15% of patients treated with BALVERSA at mg or mg once daily.Table 6: Selected Laboratory Abnormalities Reported in >= 15% of PatientsLaboratory AbnormalityBALVERSA mg daily (N=87 The denominator used to calculate the rate varied from 83 to 86 based on the number of patients with baseline value and at least one post-treatment value.) All Grades (%)Grade 3-4 (%)Chemistry Increased phosphate761.2 Increased creatinine524.7 Increased alanine aminotransferase411.2 Increased alkaline phosphatase411.2 Decreased sodium4016 Decreased magnesium311.2 Increased aspartate aminotransferase300 Decreased phosphate249 Increased calcium223.5Hematology Decreased hemoglobin353.5 Decreased platelets191.2 Decreased leukocytes170.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Erdafitinib is kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitrodata. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFRgenetic 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 ElectrophysiologyBased 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 PhosphateFGFR inhibition by BALVERSA increases serum phosphate level [see Dosage and Administration (2.3)and Drug Interactions (7.1)]. 12.3 Pharmacokinetics. Following administration of BALVERSA mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum plasma concentration (C max), area under the curve (AUC tau), and minimum plasma concentration (C min) were 1,399 ng/mL (51%), 29,268 ngh/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing of BALVERSA, erdafitinib exposure (C maxand 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 weeks with once daily dosing with mean accumulation ratio was 4-fold. AbsorptionMedian time to achieve peak plasma concentration (t max) was 2.5 hours (range: to hours). Effect of FoodNo clinically meaningful differences in erdafitinib exposure was observed following administration of BALVERSA with high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat).. DistributionThe mean apparent volume of distribution of erdafitinib was 29 L.Erdafitinib protein binding was 99.7% in patients, primarily to alpha-1-acid glycoprotein.. EliminationThe mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h.The mean effective half-life of erdafitinib was 59 hours.. MetabolismErdafitinib 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.. ExcretionFollowing 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 PopulationsNo clinically meaningful effects on erdafitinib exposure were observed based on age (21-92 years), sex, race (White, Hispanic or Asian), body weight (36-166 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 m2). Limited data are available in patients with severe (Child-Pugh C) hepatic impairment and in patients with severe renal impairment. The pharmacokinetics of erdafitinib in patients with renal impairment requiring dialysis is unknown.. Drug Interaction Studies. Clinical Studies. Effect of Other Drugs on Erdafitinib. Moderate CYP2C9 InhibitorsErdafitinib mean ratios for maxand AUC infwere 121% and 148%, respectively, when BALVERSA was co-administered with fluconazole, moderate CYP2C9 and CYP3A4 inhibitor, relative to BALVERSA administered alone. Strong CYP3A4 InhibitorsErdafitinib mean ratios for maxand AUC infwere 105% and 134%, respectively, when BALVERSA was co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to BALVERSA alone. CYP3A4/2C9 InducersErdafitinib mean ratios for maxand AUC infwere 78% and 45%, respectively, when BALVERSA was co-administered with carbamazepine (a strong CYP3A4 and weak CYP2C9 inducer) relative to BALVERSA alone. Effect of Erdafitinib on Other Drugs. CYP3A4 Substrates:No clinically meaningful effect on the exposure of midazolam (a CYP3A4 substrate) was observed following coadministration with BALVERSA.. OCT2 Substrates:No clinically meaningful effect on the exposure of metformin (an OCT2 substrate) was observed following coadministration with BALVERSA.. In Vitro Studies. CYP SubstratesErdafitinib is time dependent inhibitor and inducer of CYP3A4. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.. TransportersErdafitinib is substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to 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 AgentsErdafitinib has adequate solubility across the pH range of to 7.4. Acid-lowering agents (including antacids, 2-antagonists and 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 CYP2C92 and CYP2C93 polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C91/2 and 1/3 genotypes relative to subjects with CYP2C91/1 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 CYP2C92/2 and 2/3 genotypes. The exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C93/3 genotype, estimated to be present in 0.4% to 3% of the population among various ethnic groups.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Urothelial Carcinoma with Susceptible FGFR3Genetic Alterations. The efficacy of BALVERSA was evaluated in Study BLC3001 (NCT03390504) Cohort 1, randomized, open-label, multicenter study in which 266 patients with advanced urothelial cancer harboring selected FGFR3alterations were randomized 1:1 to receive BALVERSA (8 mg with titration up to mg) versus chemotherapy (docetaxel 75 mg/m 2once every weeks or vinflunine 320 mg/m 2once every weeks) until unacceptable toxicity or progression. Randomization was stratified by region (North America vs. Europe vs. rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or vs. 2) and visceral or bone metastases (yes vs. no). All patients needed to have had disease progression after or prior treatments, at least of which included PD-1 or PD-L1 inhibitor. FGFR3genetic alterations were identified from tumor tissue in central laboratory by the QIAGEN therascreen (R) FGFRRGQ RT-Polymerase Chain Reaction (PCR) kit in 75% of patients while the remainder (25%) were identified by local next generation sequencing (NGS) assays. The major efficacy outcome measures were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) assessed by investigator using RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1.The median age was 67 years (range: 32 to 86 years) and 71% were male; 54% were White, 29% Asian, 0.4% Black, 0.4% multiple races, 16% not reported; 2% were Hispanic/Latino; and baseline ECOG performance status was (43%), (48%), or (9%). Eighty-one percent of patients had FGFR3mutations, 17% had fusions, and 2% had both mutations and fusions. Ninety-five percent of patients had pure transitional cell carcinoma (TCC) and 5% had TCC with other histologic variants. The primary tumor location was the upper tract for 33% of subjects and lower tract for 67%; 74% of patients had visceral or bone metastases. Eighty-eight percent of patients received platinum-containing chemotherapy previously. PD-1 or PD-L1 inhibitor therapy was received only in the neoadjuvant or adjuvant setting in 7% of patients. Statistically significant improvements in OS, PFS, and ORR were demonstrated for BALVERSA compared with chemotherapy.Table and Figures and summarize the efficacy results for BLC3001 Cohort 1.Table 9: Efficacy Results for Study BLC3001 Cohort 1BALVERSA N=136 Chemotherapy N=130 All p-values reported are 2-sided and compared with 0.019 of the allocated alpha for the interim analysis. ORR confirmed objective response (CR PR) CI Confidence Interval Overall Survival (OS) Number of events (%)77 (56.6%)78 (60.0%) Median Based on Kaplan-Meier estimates, months (95% CI) 12.1 (10.3, 16.4)7.8 (6.5, 11.1) Hazard ratio Based on an unstratified Cox proportional hazard model(95% CI) 0.64 (0.47, 0.88) p-value Based on an unstratified log-rank test 0.0050Progression-free survival (PFS) Number of events (%)101 (74.3%)90 (69.2%) Median months (95% CI) 5.6 (4.4, 5.7)2.7 (1.8, 3.7) Hazard ratio (95% CI) 0.58 (0.44, 0.78) p-value 0.0002Objective response rate (ORR) ORR (95% CI)35.3% (27.3, 43.9)8.5% (4.3, 14.6) p-value p-value is estimated using Cochran-Haenszel (CMH) test with ECOG performance status (0 or vs 2) as stratification factor. <0.001 Complete response, CR (%)5.1%0.8% Partial response, PR (%)30.1%7.7%Figure 1: Kaplan-Meier Plot of Overall Survival (Study BLC3001 Cohort 1)Figure 2: Kaplan-Meier Plot of Progression-free Survival (Study BLC3001 Cohort 1). Figure 1. Figure 2. Study BLC3001 Cohort 2Study BLC3001 (NCT03390504) Cohort was multicenter, open-label, randomized study in 351 patients with locally advanced or metastatic urothelial carcinoma with selected FGFR3alterations who received prior line of systemic therapy and no prior PD-1 or PD-L1 inhibitor. Patients were randomized 1:1 to receive BALVERSA (8 mg with titration up to mg) or pembrolizumab 200 mg every weeks. The study did not meet its major efficacy outcome measure for superiority of OS at the pre-specified final analysis. The OS hazard ratio (HR) was 1.18 (95% CI: 0.92, 1.51; p=0.18), median 10.9 (95% CI: 9.2, 12.6) months for BALVERSA versus 11.1 (95% CI: 9.7, 13.6) months for pembrolizumab [see Indications and Usage (1)] . Study BLC2001Study BLC2001 (NCT02365597) was multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC). FGFRmutation status for screening and enrollment of patients was determined by clinical trial assay (CTA). The efficacy population consists of 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 of the following genetic alterations: FGFR3gene mutations R248C, S249C, G370C, Y373C) or FGFRgene fusions FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by the CTA performed at central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen (R) FGFRRGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA. Patients received starting dose of BALVERSA at mg once daily with dose increase to mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were 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 baseline Eastern Cooperative Oncology Group (ECOG) performance status of 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 10 and Table 11. ORR was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy.Table 10: Efficacy ResultsEndpointBIRC BIRC: Blinded Independent Review Committee Assessment N=87ORR 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 11: Efficacy Results by FGFR Genetic AlterationBIRC BIRC: Blinded Independent Review CommitteeAssessment ORR CR PR CI Confidence Interval FGFR3Point Mutation N=64 ORR (95% CI)40.6% (28.6, 52.7)FGFR3Fusion Both responders had FGFR3-TACC3V1 fusion,One patient with FGFR2-CASP7/FGFR3-TACC3V3 fusion is reported in both FGFR2 fusion and FGFR3 fusion aboveN=18 ORR (95% CI)11.1% (0, 25.6)FGFR2Fusion N=6 ORR0.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to BALVERSA as single agent at the recommended dose (8 to mg orally daily) in 479 patients with advanced urothelial cancer and FGFRalterations 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. BLC3001The safety of BALVERSA was evaluated in Cohort of the BLC3001 study that included patients with locally advanced unresectable or metastatic urothelial carcinoma which had susceptible FGFR3genetic alterations and were previously treated with 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 mg) (n=135) or chemotherapy (docetaxel 75 mg/m 2once every weeks or vinflunine 320 mg/m 2once every 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%).Dose reductions of BALVERSA due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dose reductions in >4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysesthesia syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%).Table presents adverse reactions reported in >=15% of patients treated with BALVERSA at or mg once daily versus chemotherapy.Table 3: Adverse Reactions Reported in >=15% of Patients Who Received BALVERSA Versus Chemotherapy (Study BLC3001)Adverse ReactionBALVERSA (N=135)Chemotherapy (N=112)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Skin and subcutaneous tissue disorders Nail disorders Includes multiple terms 701250 Palmar-plantar erythrodysesthesia syndrome30100.90 Dry skin 271.560 Alopecia250.7240Gastrointestinal disorders Diarrhea 633172.7 Stomatitis 5610181.8 Dry Mouth3903.60 Constipation270281.8Nervous system disorders Dysgeusia 300.770General disorders Fatigue 291.5427Metabolism and nutrition disorders Decreased appetite273212.7Eye disorders Dry eye 250.73.60 Central serous retinopathy 182.200Investigations Decreased weight2222.70Clinically relevant adverse reactions in <15% of patients who received BALVERSA included nausea (15%), pyrexia (15%), epistaxis (13%), vomiting (10%), and arthralgia (10%).Table presents laboratory abnormalities reported in >=15% of patients treated with BALVERSA at or mg once daily versus chemotherapy.Table 4: Selected Laboratory Abnormalities Reported in >=15% of Patients Who Received BALVERSA Versus Chemotherapy; Cohort Safety Analysis Set (Study BLC3001)Laboratory AbnormalityBALVERSA (N=135 The denominator used to calculate the rate varied from 52 to 131 based on the number of patients with baseline value and at least one post-treatment value.) Chemotherapy (N=112 The denominator used to calculate the rate varied from 11 to 102 based on the number of patients with baseline value and at least one post-treatment value.) All Grades Severity graded per NCI CTCAE v4.03.(%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Increased phosphate76500 Increased alkaline phosphatase544.7291 Increased alanine aminotransferase463.8151 Increased aspartate aminotransferase443.1130 Decreased sodium4416256 Increased creatinine431.5170 Decreased phosphate348253.6 Increased calcium27890 Increased potassium240210Hematology Decreased hemoglobin50125712 Decreased platelet count171.5181 Decreased neutrophil count160.84026. BLC2001The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3and other FGFRalterations, 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 mg orally once daily; with dose increase to 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: to 17 months). Serious adverse reactions occurred in 41% of patients. The most frequent (>3%) serious adverse reactions were central serous retinopathy (4.6%), urinary tract infection (3.4%), and general physical health deterioration (3.4%).Fatal adverse reactions occurred in 8% of patients, including acute myocardial infarction (1.1%).Permanent discontinuation of BALVERSA due to an adverse reaction occurred in 21% of patients. The most frequent (>= 2%) reasons for permanent discontinuation included central serous retinopathy (4.6%), general physical health deterioration (3.4%), palmar-plantar erythrodysesthesia syndrome (2.3%), acute kidney injury (2.3%), and fatigue (2.3%).Dosage interruptions of BALVERSA occurred in 68% of patients. The most frequent (>= 5%) adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), nail disorders (16%), central serous retinopathy (9%), palmar-plantar erythro-dysesthesia syndrome (8%), and fatigue (8%).Dose reductions of BALVERSA occurred in 53% of patients. The most frequent (>= 5%) adverse reactions for dose reductions included nail disorders (21%), stomatitis (15%), central serous retinopathy (14%), hyperphosphatemia (7%), palmar-plantar erythro-dysesthesia syndrome (7%), fatigue (6%), and blurred vision (6%).Table presents adverse reactions reported in >=15% of patients treated with BALVERSA at mg or mg once daily.Table 5: Adverse Reactions Reported in >=15% of Patients (Study BLC2001)Adverse ReactionBALVERSA mg daily (N=87)All Grades (%)Grade 3-4 (%) Gastrointestinal disorders Stomatitis Includes multiple terms 6211 Diarrhea 484.6 Dry mouth450 Constipation281.1 Nausea211.1Skin and subcutaneous tissue disorders Nail disorders 6214 Dry skin 370 Alopecia260 Palmar-plantar erythrodysesthesia syndrome266General disorders and admin. site conditions Fatigue Includes fatal adverse reactions (n=2) 548 Decreased weight160Metabolism and nutrition disorders Decreased appetite380.0Nervous system disorders Dysgeusia 381.1Eye disorders Dry eye 291.1 Central serous retinopathy 284.6 Blurred vision170Infections and Infestations Urinary tract infection176Clinically relevant adverse reactions in <15% of patients who received BALVERSA included pyrexia (14%), extremity pain (13%), vomiting (13%), and peripheral edema (10%).Table presents laboratory abnormalities reported in >=15% of patients treated with BALVERSA at mg or mg once daily.Table 6: Selected Laboratory Abnormalities Reported in >= 15% of PatientsLaboratory AbnormalityBALVERSA mg daily (N=87 The denominator used to calculate the rate varied from 83 to 86 based on the number of patients with baseline value and at least one post-treatment value.) All Grades (%)Grade 3-4 (%)Chemistry Increased phosphate761.2 Increased creatinine524.7 Increased alanine aminotransferase411.2 Increased alkaline phosphatase411.2 Decreased sodium4016 Decreased magnesium311.2 Increased aspartate aminotransferase300 Decreased phosphate249 Increased calcium223.5Hematology Decreased hemoglobin353.5 Decreased platelets191.2 Decreased leukocytes170.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Confirm the presence of FGFR3genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. 2.1) Recommended initial dosage: mg orally once daily with dose increase to mg daily if criteria are met. 2.2) Swallow whole with or without food. 2.2) Confirm the presence of FGFR3genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. 2.1) Recommended initial dosage: mg orally once daily with dose increase to 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 FGFR3genetic 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 FGFR3genetic 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 mg (two mg tablets) orally once daily, with dose increase to mg (three 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 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 LevelsAssess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to mg once daily if serum phosphate level is 9.0 mg/dL and there are no ocular disorders or Grade or greater adverse reactions. If the phosphate level is 9.0 mg/dL or higher follow the relevant dose modifications in Table 2. 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 ScheduleDose1 stdose reduction nddose reduction rddose reduction thdose reduction thdose reduction mg (three mg tablets) mg (two mg tablets) mg (two mg tablets) mg (one mg tablet) mg (one mg tablet) Stop mg (two mg tablets) mg (two mg tablets) mg (one mg tablet) mg (one mg tablet) StopTable summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.Table 2: Dose Modifications for Adverse ReactionsAdverse ReactionBALVERSA Dose ModificationHyperphosphatemiaIn all patients, restrict phosphate intake to 600-800 mg daily.<6.99 mg/dLContinue BALVERSA at current dose.7-8.99 mg/dLContinue BALVERSA at current dose.Start phosphate binder with food until phosphate level is <7 mg/dL.Reduce the dose if serum phosphate remains >=7 mg/dL for period of months or if clinically necessary.9-10 mg/dLWithhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then restart BALVERSA at the same dose level.Start phosphate binder with food until serum phosphate level returns to <7 mg/dL.Reduce the dose if serum phosphate remains >=9 mg/dL for period of month or if clinically necessary.>10 mg/dLWithhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then may restart BALVERSA at the first reduced dose level.If hyperphosphatemia (>=10 mg/dL) for >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)AnyWithhold BALVERSA and perform an ophthalmic evaluation within 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 to weeks for month. If recurs or has not improved after weeks of withholding BALVERSA, consider permanent discontinuation. Other Adverse ReactionsDose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv5.0).Grade 3Withhold BALVERSA until resolves to Grade or baseline, then may resume dose level lower.Grade 4Permanently discontinue.. Continue BALVERSA at current dose.. Start phosphate binder with food until phosphate level is <7 mg/dL.. Reduce the dose if serum phosphate remains >=7 mg/dL for period of months or if clinically necessary.. Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then restart BALVERSA at the same dose level.. Start phosphate binder with food until serum phosphate level returns to <7 mg/dL.. Reduce the dose if serum phosphate remains >=9 mg/dL for period of month or if clinically necessary.. Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then may restart BALVERSA at the first reduced dose level.. If hyperphosphatemia (>=10 mg/dL) for >2 weeks, discontinue BALVERSA permanently.. Medical management of symptoms as clinically relevant.. Discontinue BALVERSA permanently.. 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.

DRUG INTERACTIONS SECTION.

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 dose of 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 hours before or after administration of P-gp substrates with narrow therapeutic indices. 7.2) 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 dose of 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 hours before or after administration of P-gp substrates with narrow therapeutic indices. 7.2) 7.1 Effect of Other Drugs on BALVERSA. Table summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management.Table 7: Drug Interactions that Affect BALVERSAModerate CYP2C9 or Strong CYP3A4 InhibitorsClinical ImpactCo-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 ManagementConsider alternative therapies that are not moderate CYP2C9 or strong CYP3A4 inhibitors during treatment with BALVERSA.If co-administration of 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 InducersClinical ImpactCo-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 ManagementAvoid co-administration of strong CYP3A4 inducers with BALVERSA.Moderate CYP3A4 InducersClinical ImpactCo-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 ManagementIf moderate CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA at dose of mg daily.When moderate CYP3A4 inducer is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity.Serum Phosphate Level-Altering AgentsClinical ImpactCo-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 ManagementAvoid 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)]. 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)]. Consider alternative therapies that are not moderate CYP2C9 or strong CYP3A4 inhibitors during treatment with BALVERSA.. If co-administration of 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. 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.. Avoid co-administration of strong CYP3A4 inducers with BALVERSA.. 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.. If moderate CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA at dose of mg daily.. When moderate CYP3A4 inducer is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity.. 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)]. 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 summarizes the effect of BALVERSA on other drugs and their clinical management.Table 8: BALVERSA Drug Interactions that Affect Other DrugsP-glycoprotein (P-gp) SubstratesClinical ImpactCo-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 ManagementIf co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least hours before or after administration of P-gp substrates with narrow therapeutic index.. 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.. If co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least hours before or after administration of P-gp substrates with narrow therapeutic index.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. FGFRGenetic Alterations Advise patients that evidence of susceptible FGFR3mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated [see Dosage and Administration (2.1)] . Ocular DisordersAdvise 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 hours during waking hours [see Dosage and Administration (2.3)]. Skin, Mucous or Nail DisordersAdvise 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 MineralizationInform 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 InteractionsAdvise 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 InstructionsInstruct 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 (2.2)] . Missed DoseIf 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 ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of known or suspected pregnancy [see Warnings and Precautions (5.3)and Use in Specific Populations (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)]. LactationAdvise females not to breastfeed during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.2)]. InfertilityAdvise females of reproductive potential that BALVERSA may impair fertility [see Use in Specific Populations (8.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following administration of BALVERSA mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum plasma concentration (C max), area under the curve (AUC tau), and minimum plasma concentration (C min) were 1,399 ng/mL (51%), 29,268 ngh/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeat once daily dosing of BALVERSA, erdafitinib exposure (C maxand 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 weeks with once daily dosing with mean accumulation ratio was 4-fold. AbsorptionMedian time to achieve peak plasma concentration (t max) was 2.5 hours (range: to hours). Effect of FoodNo clinically meaningful differences in erdafitinib exposure was observed following administration of BALVERSA with high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat).. DistributionThe mean apparent volume of distribution of erdafitinib was 29 L.Erdafitinib protein binding was 99.7% in patients, primarily to alpha-1-acid glycoprotein.. EliminationThe mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h.The mean effective half-life of erdafitinib was 59 hours.. MetabolismErdafitinib 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.. ExcretionFollowing 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 PopulationsNo clinically meaningful effects on erdafitinib exposure were observed based on age (21-92 years), sex, race (White, Hispanic or Asian), body weight (36-166 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 m2). Limited data are available in patients with severe (Child-Pugh C) hepatic impairment and in patients with severe renal impairment. The pharmacokinetics of erdafitinib in patients with renal impairment requiring dialysis is unknown.. Drug Interaction Studies. Clinical Studies. Effect of Other Drugs on Erdafitinib. Moderate CYP2C9 InhibitorsErdafitinib mean ratios for maxand AUC infwere 121% and 148%, respectively, when BALVERSA was co-administered with fluconazole, moderate CYP2C9 and CYP3A4 inhibitor, relative to BALVERSA administered alone. Strong CYP3A4 InhibitorsErdafitinib mean ratios for maxand AUC infwere 105% and 134%, respectively, when BALVERSA was co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to BALVERSA alone. CYP3A4/2C9 InducersErdafitinib mean ratios for maxand AUC infwere 78% and 45%, respectively, when BALVERSA was co-administered with carbamazepine (a strong CYP3A4 and weak CYP2C9 inducer) relative to BALVERSA alone. Effect of Erdafitinib on Other Drugs. CYP3A4 Substrates:No clinically meaningful effect on the exposure of midazolam (a CYP3A4 substrate) was observed following coadministration with BALVERSA.. OCT2 Substrates:No clinically meaningful effect on the exposure of metformin (an OCT2 substrate) was observed following coadministration with BALVERSA.. In Vitro Studies. CYP SubstratesErdafitinib is time dependent inhibitor and inducer of CYP3A4. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.. TransportersErdafitinib is substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to 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 AgentsErdafitinib has adequate solubility across the pH range of to 7.4. Acid-lowering agents (including antacids, 2-antagonists and proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION BALVERSA (R)(bal-VER-sah) (erdafitinib) tablets This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 10/2024What is BALVERSA BALVERSA is prescription medicine used to treat adults with bladder cancer (urothelial cancer) that has spread or cannot be removed by surgery: which has certain type of abnormal FGFR gene, and who have tried at least one other medicine by mouth or injection (systemic therapy) that did not work or is no longer working.Your healthcare provider will test your cancer for certain types of abnormal FGFR genes and make sure that BALVERSA is right for you. BALVERSA is not recommended for the treatment of people who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy. It is not known if BALVERSA is safe and effective in children. Before taking BALVERSA tell your healthcare provider about all of your medical conditions, including if you:have vision or eye problems.are pregnant or plan to become pregnant. BALVERSA can harm your unborn baby. You should not become pregnant during treatment with BALVERSA. Females who can become pregnant: Your healthcare provider may do pregnancy test before you start treatment with BALVERSA.You should use effective birth control during treatment and for month after the last dose of BALVERSA. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you may be pregnant. Males with female partners who can become pregnant: You should use effective birth control when sexually active during treatment with BALVERSA and for month after the last dose. are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for month after the last dose of BALVERSA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take BALVERSATake BALVERSA exactly as your healthcare provider tells you.Take BALVERSA time each day.Swallow BALVERSA tablets whole with or without food.Your healthcare provider may change your dose of BALVERSA, temporarily stop or completely stop treatment if you get certain side effects.If you miss dose of BALVERSA, take the missed dose as soon as possible on the same day. Take your regular dose of BALVERSA the next day. Do not take more BALVERSA than prescribed to make up for the missed dose.If you vomit after taking BALVERSA, do not take another BALVERSA tablet. Take your regular dose of BALVERSA the next day.What are the possible side effects of BALVERSA BALVERSA may cause serious side effects, including: Eye problems.Eye problems are common with BALVERSA but can also be serious. Eye problems include dry or inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Tell your healthcare provider right away if you develop blurred vision, loss of vision or other visual changes. You should use artificial tear substitutes, hydrating or lubricating eye gels or ointments at least every hours during waking hours to help prevent dry eyes. During treatment with BALVERSA, your healthcare provider will send you to see an eye specialist. High phosphate levels in the blood (hyperphosphatemia).Hyperphosphatemia is common with BALVERSA but can also be serious. High levels of phosphate in your blood may lead to build-up of minerals such as calcium in different tissues in your body. Your healthcare provider will check your blood phosphate level between 14 and 21 days after starting treatment with BALVERSA, and then monthly. Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change or stop treatment with BALVERSA if needed.Tell your healthcare provider right away if you develop painful skin lesions, any muscle cramps, or numbness or tingling around your mouth.The most common side effects of BALVERSA include:nails separate from the bed or poor formation of the nailmouth soresdiarrheaincreased level of creatinine in the bloodincreased level of the enzyme alkaline phosphatase in the bloodchange in liver functiondecreased red blood cells (anemia)decreased salt (sodium) levels in the bloodtirednessdry mouthdry skindecreased phosphate in the blooddecreased appetitechange in sense of tasteconstipationincreased level of calcium in the blooddry eyeredness, swelling, peeling or tenderness, mainly on the hands or feet (hand-foot syndrome)increased level of potassium in the bloodhair lossfluid buildup behind the retina in your eyeTell your healthcare provider right away if you develop any nail or skin problems including nails separating from the nail bed, nail pain, nail bleeding, breaking of the nails, color or texture changes in your nails, infected skin around the nail, an itchy skin rash, dry skin, or cracks in the skin. BALVERSA may affect fertility in females who are able to become pregnant. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of BALVERSA. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store BALVERSAStore BALVERSA tablets at room temperature between 68F to 77F (20C to 25C).Keep BALVERSA and all medicines out of the reach of children.General information about the safe and effective use of BALVERSA. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use BALVERSA for condition for which it was not prescribed. Do not give BALVERSA to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BALVERSA that is written for healthcare professionals. What are the ingredients in BALVERSAActive ingredient:erdafitinib 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). Manufactured for:Janssen Products, LP, Horsham, PA 19044, USA For patent information: www.janssenpatents.com (C) 2019 Janssen Pharmaceutical Companies For more information call Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN) or go to www.BALVERSA.com. which has certain type of abnormal FGFR gene, and who have tried at least one other medicine by mouth or injection (systemic therapy) that did not work or is no longer working.. have vision or eye problems.. are pregnant or plan to become pregnant. BALVERSA can harm your unborn baby. You should not become pregnant during treatment with BALVERSA. Females who can become pregnant: Your healthcare provider may do pregnancy test before you start treatment with BALVERSA.You should use effective birth control during treatment and for month after the last dose of BALVERSA. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you may be pregnant. Males with female partners who can become pregnant: You should use effective birth control when sexually active during treatment with BALVERSA and for month after the last dose. Your healthcare provider may do pregnancy test before you start treatment with BALVERSA.. You should use effective birth control during treatment and for month after the last dose of BALVERSA. Talk to your healthcare provider about birth control methods that may be right for you.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.. You should use effective birth control when sexually active during treatment with BALVERSA and for month after the last dose.. are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for month after the last dose of BALVERSA.. Take BALVERSA exactly as your healthcare provider tells you.. Take BALVERSA time each day.. Swallow BALVERSA tablets whole with or without food.. Your healthcare provider may change your dose of BALVERSA, temporarily stop or completely stop treatment if you get certain side effects.. If you miss dose of BALVERSA, take the missed dose as soon as possible on the same day. Take your regular dose of BALVERSA the next day. Do not take more BALVERSA than prescribed to make up for the missed dose.. If you vomit after taking BALVERSA, do not take another BALVERSA tablet. Take your regular dose of BALVERSA the next day.. Eye problems.Eye problems are common with BALVERSA but can also be serious. Eye problems include dry or inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Tell your healthcare provider right away if you develop blurred vision, loss of vision or other visual changes. You should use artificial tear substitutes, hydrating or lubricating eye gels or ointments at least every hours during waking hours to help prevent dry eyes. During treatment with BALVERSA, your healthcare provider will send you to see an eye specialist. High phosphate levels in the blood (hyperphosphatemia).Hyperphosphatemia is common with BALVERSA but can also be serious. High levels of phosphate in your blood may lead to build-up of minerals such as calcium in different tissues in your body. Your healthcare provider will check your blood phosphate level between 14 and 21 days after starting treatment with BALVERSA, and then monthly. Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change or stop treatment with BALVERSA if needed.Tell your healthcare provider right away if you develop painful skin lesions, any muscle cramps, or numbness or tingling around your mouth.. Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change or stop treatment with BALVERSA if needed.. Tell your healthcare provider right away if you develop painful skin lesions, any muscle cramps, or numbness or tingling around your mouth.. nails separate from the bed or poor formation of the nail. mouth sores. diarrhea. increased level of creatinine in the blood. increased level of the enzyme alkaline phosphatase in the blood. change in liver function. decreased red blood cells (anemia). decreased salt (sodium) levels in the blood. tiredness. dry mouth. dry skin. decreased phosphate in the blood. decreased appetite. change in sense of taste. constipation. increased level of calcium in the blood. dry eye. redness, swelling, peeling or tenderness, mainly on the hands or feet (hand-foot syndrome). increased level of potassium in the blood. hair loss. fluid buildup behind the retina in your eye. Store BALVERSA tablets at room temperature between 68F to 77F (20C to 25C).