Source: FDA, National Drug Code (US) Revision Year: 2020
None.
BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.
CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued BALVERSA.
Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of 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 BALVERSA when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].
Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8-116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA.
Monitor for hyperphosphatemia and follow the dose modification guidelines when required [see Dosage and Administration 2.2, 2.3].
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)].
The following serious adverse reactions are also described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients were treated with BALVERSA at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months).
The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia.
An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.
Serious adverse reactions occurred in 41% of patients including eye disorders (10%).
Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).
Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysaesthesia syndrome (8%).
Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysaesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%).
Table 3 presents ARs reported in ≥10% of patients treated with BALVERSA at 8 mg once daily.
Table 3. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3–4) of Patients:
| Adverse Reaction | BALVERSA 8 mg daily (N=87) | |
|---|---|---|
| All Grades (%) | Grade 3-4 (%) | |
| Any | 100 | 67 |
| Gastrointestinal disorders | 92 | 24 |
| Stomatitis | 56 | 9 |
| Diarrhea | 47 | 2 |
| Dry mouth | 45 | 0 |
| Constipation | 28 | 1 |
| Abdominal pain* | 23 | 2 |
| Nausea | 21 | 1 |
| Vomiting | 13 | 2 |
| Metabolism and nutrition disorders | 90 | 16 |
| Decreased appetite | 38 | 0 |
| General disorders and admin. site conditions | 69 | 13 |
| Fatigue† | 54 | 10 |
| Pyrexia | 14 | 1 |
| Skin and subcutaneous disorders | 75 | 16 |
| Onycholysis‡ | 41 | 10 |
| Dry skin§ | 34 | 0 |
| Palmar-plantar erythrodysaesthesia | 26 | 6 |
| Alopecia | 26 | 0 |
| Nail discoloration | 11 | 0 |
| Eye disorders | 62 | 11 |
| Dry eye¶ | 28 | 6 |
| Vision blurred | 17 | 0 |
| Lacrimation increased | 10 | 0 |
| Nervous system disorders | 57 | 5 |
| Dysgeusia | 37 | 1 |
| Infections and infestations | 56 | 20 |
| Paronychia | 17 | 3 |
| Urinary tract infection | 17 | 6 |
| Conjunctivitis | 11 | 0 |
| Respiratory, thoracic and mediastinal disorders | 40 | 7 |
| Oropharyngeal pain | 11 | 1 |
| Dyspnea# | 10 | 2 |
| Renal and urinary tract disorders | 38 | 10 |
| Hematuria | 11 | 2 |
| Musculoskeletal and connective tissue disorders | 31 | 0 |
| Musculoskeletal painÞ | 20 | 0 |
| Arthralgia | 11 | 0 |
| Investigations | 44 | 5 |
| Weight decreasedß | 16 | 0 |
* Includes abdominal pain, abdominal discomfort, abdominal pain upper, and abdominal pain lower
† Includes asthenia, fatigue, lethargy, and malaise
‡ Includes onycholysis, onychoclasis, nail disorder, nail dystrophy, and nail ridging
§ Includes dry skin and xerostomia
¶ Includes dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion
# Includes dyspnea and dyspnea exertional
Þ Includes back pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal chest pain, neck pain, pain in extremity
ß Includes weight decreased and cachexia
Table 4: Laboratory Abnormalities Reported in ≥10% (All Grade) or ≥5% (Grade 3–4) of Patients:
| Laboratory Abnormality | BALVERSA 8 mg daily (N=86*) | |
|---|---|---|
| All Grades (%) | Grade 3–4 (%) | |
| Hematology | ||
| Hemoglobin decreased | 35 | 3 |
| Platelets decreased | 19 | 1 |
| Leukocytes decreased | 17 | 0 |
| Neutrophils decreased | 10 | 2 |
| Chemistry | ||
| Phosphate increased | 76 | 1 |
| Creatinine increased | 52 | 5 |
| Sodium decreased | 40 | 16 |
| Alanine aminotransferase increased | 41 | 1 |
| Alkaline phosphatase increased | 41 | 1 |
| Albumin decreased | 37 | 0 |
| Aspartate aminotransferase increased | 30 | 0 |
| Magnesium decreased | 30 | 1 |
| Phosphate decreased | 24 | 9 |
| Calcium increased | 22 | 3 |
| Potassium increased | 16 | 0 |
| Fasting glucose increased | 10 | 0 |
* One of the 87 patients had no laboratory tests.
Table 5 summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management.
Table 5. Drug Interactions that Affect BALVERSA:
| Moderate CYP2C9 or Strong CYP3A4 Inhibitors | |
|---|---|
| Clinical Impact | • Co-administration of BALVERSA with moderate CYP2C9 or strong CYP3A4 inhibitors increased erdafitinib plasma concentrations [see Clinical Pharmacology (12.3)]. • Increased erdafitinib plasma concentrations may lead to increased drug-related toxicity [see Warnings and Precautions (5)]. |
| Clinical Management | • Consider alternative therapies that are not moderate CYP2C9 or strong CYP3A4 inhibitors during treatment with BALVERSA. • If co-administration of moderate CYP2C9 or strong CYP3A4 inhibitor is unavoidable, monitor closely for adverse reactions and consider dose modifications accordingly [see Dosage and Administration (2.3)]. If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, the BALVERSA dose may be increased in the absence of drug-related toxicity. |
| Strong CYP2C9 or CYP3A4 Inducers | |
| Clinical Impact | • Co-administration of BALVERSA with strong inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations significantly [see Clinical Pharmacology (12.3)]. • Decreased erdafitinib plasma concentrations may lead to decreased activity. |
| Clinical Management | • Avoid co-administration of strong inducers of CYP2C9 or CYP3A4 with BALVERSA. |
| Moderate CYP2C9 or CYP3A4 Inducers | |
| Clinical Impact | • Co-administration of BALVERSA with moderate inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations [see Clinical Pharmacology (12.3)]. • Decreased erdafitinib plasma concentrations may lead to decreased activity. |
| Clinical Management | • If a moderate CYP2C9 or CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA dose as recommended (8 mg once daily with potential to increase to 9 mg once daily based on serum phosphate levels on Days 14 to 21 and tolerability). • If a moderate CYP2C9 or CYP3A4 inducer must be co-administered after the initial dose increase period based on serum phosphate levels and tolerability, increase BALVERSA dose up to 9 mg. • When a moderate inducer of CYP2C9 or CYP3A4 is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity. |
| Serum Phosphate Level-Altering Agents | |
| Clinical Impact | • Co-administration of BALVERSA with other serum phosphate level-altering agents may increase or decrease serum phosphate levels [see Pharmacodynamics (12.2)]. • Changes in serum phosphate levels due to serum phosphate level-altering agents (other than erdafitinib) may interfere with serum phosphate levels needed for the determination of initial dose increased based on serum phosphate levels [see Dosage and Administration (2.3)]. |
| Clinical Management | • Avoid co-administration of serum phosphate level-altering agents with BALVERSA before initial dose increase period based on serum phosphate levels (Days 14 to 21) [see Dosage and Administration (2.3)]. |
Table 6 summarizes the effect of BALVERSA on other drugs and their clinical management.
Table 6. BALVERSA Drug Interactions that Affect Other Drugs:
| CYP3A4 Substrates | |
|---|---|
| Clinical Impact | • Co-administration of BALVERSA with CYP3A4 substrates may alter the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology (12.3)]. • Altered plasma concentrations of CYP3A4 substrates may lead to loss of activity or increased toxicity of the CYP3A4 substrates. |
| Clinical Management | • Avoid co-administration of BALVERSA with sensitive substrates of CYP3A4 with narrow therapeutic indices. |
| OCT2 Substrates | |
| Clinical Impact | • Co-administration of BALVERSA with OCT2 substrates may increase the plasma concentrations of OCT2 substrates [see Clinical Pharmacology (12.3)]. • Increased plasma concentrations of OCT2 substrates may lead to increased toxicity of the OCT2 substrates. |
| Clinical Management | • Consider alternative therapies that are not OCT2 substrates or consider reducing the dose of OCT2 substrates (e.g., metformin) based on tolerability. |
| P-glycoprotein (P-gp) Substrates | |
| Clinical Impact | • Co-administration of BALVERSA with P-gp substrates may increase the plasma concentrations of P-gp substrates [see Clinical Pharmacology (12.3)]. • Increased plasma concentrations of P-gp substrates may lead to increased toxicity of the P-gp substrates. |
| Clinical Management | • If co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic index. |
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.
In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4mg/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.
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.
Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with BALVERSA.
BALVERSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Population (8.1)].
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)].
Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
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.
Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14)].
CYP2C9*3/*3 Genotype: Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype [see Pharmacogenomics (12.5)].
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
