Balversa
(erdafitinib)Dosage & Administration
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Balversa Prescribing Information
BALVERSA is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3genetic 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)] .
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)] .
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.
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 < 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 [see Pharmacodynamics (12.2)] .
Dose Modifications for Adverse Reactions
The recommended dose modifications for adverse reactions are listed in Table 1.
| Dose | 1 stdose reduction | 2 nddose reduction | 3 rddose reduction | 4 thdose reduction | 5 thdose reduction |
|---|---|---|---|---|---|
| 9 mg ➞ (three 3 mg tablets) | 8 mg (two 4 mg tablets) | 6 mg (two 3 mg tablets) | 5 mg (one 5 mg tablet) | 4 mg (one 4 mg tablet) | Stop |
| 8 mg ➞ (two 4 mg tablets) | 6 mg (two 3 mg tablets) | 5 mg (one 5 mg tablet) | 4 mg (one 4 mg tablet) | Stop | |
Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.
| Adverse Reaction | BALVERSA Dose Modification |
|---|---|
| |
| Hyperphosphatemia | |
| In all patients, restrict phosphate intake to 600–800 mg daily. | |
| <6.99 mg/dL | Continue BALVERSA at current dose. |
| 7–8.99 mg/dL |
|
| 9–10 mg/dL |
|
| >10 mg/dL |
|
| Serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis) |
|
| Central Serous Retinopathy (CSR) | |
| Any | Withhold BALVERSA and perform an ophthalmic evaluation within 2 weeks:
If recurs or has not improved after 4 weeks of withholding BALVERSA, consider permanent discontinuation. |
| Other Adverse Reactions * | |
| Grade 3 | Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower. |
| Grade 4 | Permanently discontinue. |
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.
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.
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.
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)] .
Pediatric Use
Safety and effectiveness of BALVERSA in pediatric patients have not been established.
In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats.
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 a 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)].
CYP2C9 Poor Metabolizers
CYP2C9*3/*3 Genotype:Erdafitinib plasma concentrations are predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype [see Pharmacogenomics (12.5)] .
None.
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 a 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 4 months of treatment and every 3 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)] .
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 a 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 2 [see Dosage and Administration (2.3)].
Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a 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)] .