Balversa Drug Information

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. 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.

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. Information on FDA-approved tests for the detection of FGFR3 genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics.

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. 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 < 9.0 mg/dL and there are no ocular disorders or Grade 2 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.

Dose Modifications for Adverse Reactions

The recommended dose modifications for adverse reactions are listed in Table 1. Table 1: BALVERSA Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions. Table 2:

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 1. 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. 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.

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.

Dose reductions of BALVERSA due to an adverse reaction occurred in 69% of patients. Table 4: Selected Laboratory Abnormalities Reported in ≥15% of Patients Who Received BALVERSA Versus Chemotherapy; Cohort 1 Safety Analysis Set Study BLC BLC2001 The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 and other FGFR alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy. Median duration of treatment was 5.3 months (range: 0 to 17 months).

Fatal adverse reactions occurred in 8% of patients, including acute myocardial infarction (1.1%). Dosage interruptions of BALVERSA occurred in 68% of patients. Dose reductions of BALVERSA occurred in 53% of patients.

Table 6: Selected Laboratory Abnormalities Reported in ≥ 0

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. Increased erdafitinib plasma concentrations may lead to increased drug-related toxicity.

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. Strong CYP3A4 Inducers Clinical Impact Co-administration of BALVERSA with strong CYP3A4 inducers decreased erdafitinib plasma concentrations.

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. 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.

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. 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. 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).

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. 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.

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. 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.

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.