Erdafitinib (Monograph)

Brand name: Balversa
Drug class: Antineoplastic Agents
- Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitors
- FGFR Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: N'-(3,5-dimethoxyphenyl)-N'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine
Molecular formula: C₂₅H₃₀N₆O₂
CAS number: 1346242-81-6

Medically reviewed by Drugs.com on Jul 15, 2024. Written by ASHP.

Introduction

Antineoplastic agent; potent and reversible inhibitor of fibroblast growth factor receptor (FGFR)-1, FGFR-2, FGFR-3, and FGFR-4.

Uses for Erdafitinib

Urothelial Carcinoma

Treatment of locally advanced or metastatic urothelial carcinoma with susceptible FGFR-2 or FGFR-3 genomic aberration (e.g., gene mutation, gene fusion) that has progressed during or following ≥1 prior platinum-containing therapy, including within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.

Accelerated approval based on objective response rate of 32.2% in a cohort of adults with relapsed or refractory locally advanced or metastatic urothelial carcinoma; historical objective responses of approximately 10–20% with second-line, single-agent chemotherapy (e.g., taxanes, immune checkpoint inhibitors [e.g., pembrolizumab]) in such patients. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

FDA-approved companion diagnostic test (e.g., Qiagen therascreen FGFR RGQ RT-PCR Kit) required to confirm presence of FGFR genomic aberration prior to initiation of therapy.

Erdafitinib Dosage and Administration

General

Pretreatment Screening

Confirm presence of susceptible fibroblast growth factor receptor (FGFR) genomic aberration (e.g., gene mutation, gene fusion) prior to initiation of erdafitinib therapy.
Because elevated phosphate concentrations occur frequently in patients receiving erdafitinib, phosphate intake should not exceed 600–800 mg daily during therapy.
Assess concomitant therapy, including prescription drugs, OTC drugs, and dietary or herbal supplements, for agents that may alter plasma phosphate concentrations.
Verify pregnancy status in females of reproductive potential prior to initiating therapy.

Patient Monitoring

Monitor serum phosphate concentrations 14–21 days following initiation of erdafitinib therapy and then monthly thereafter or more frequently as clinically indicated.
Perform ophthalmologic examination, including visual acuity assessment, slit lamp examination, fundoscopy, and optical coherence tomography, monthly during the first 4 months of erdafitinib therapy; every 3 months thereafter; and as clinically indicated (e.g., if new or worsening visual disturbances occur).

Premedication and Prophylaxis

To minimize the risk of dry eye, the manufacturer recommends prophylaxis with ophthalmic demulcents (e.g., artificial tears substitutes, hydrating or lubricating ophthalmic gel or ointment) upon initiation of erdafitinib. Apply ophthalmic demulcents frequently (i.e., at least every 2 hours) during waking hours.

Administration

Oral Administration

Administer orally once daily without regard to meals. Swallow tablets whole.

If a dose of erdafitinib is missed, take the missed dose as soon as possible on the same day and resume the regular dosing schedule the next day.

If vomiting occurs at any time following administration of erdafitinib, do not administer a replacement dose; take the next dose at the regularly scheduled time.

Dosage

Adults

Urothelial Carcinoma

Oral

Initially, 8 mg once daily; if this initial dosage is tolerated (i.e., serum phosphate concentrations <5.5 mg/dL, absence of ocular disorders or grade 2 or greater adverse effects) for 14–21 days, increase dosage to a maximum dosage of 9 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance. If dosage modification is required, reduce dosage as described in Table 1.

Table 1. Dosage Modification for Erdafitinib Toxicity Following Therapy Interruption1
	Current Dosage	Current Dosage
Dose Reduction Level	8 mg daily	9 mg daily
First	Restart at 6 mg daily	Restart at 8 mg daily
Second	Restart at 5 mg daily	Restart at 6 mg daily
Third	Restart at 4 mg daily	Restart at 5 mg daily
Fourth	Discontinue erdafitinib	Restart at 4 mg daily
Fifth		Discontinue erdafitinib

Hyperphosphatemia

Oral

For serum phosphate concentrations ≥7 mg/dL, temporarily interrupt therapy. Upon resolution or improvement of hyperphosphatemia (i.e., return to baseline or improvement to less than 5.5 mg/dL), resume therapy at a reduced dosage as described in Table 2.

For substantial change in baseline renal function or grade 3 hypercalcemia secondary to hyperphosphatemia, temporarily interrupt therapy. Upon resolution or improvement of hyperphosphatemia (i.e., return to baseline or improvement to less than 5.5 mg/dL), resume therapy at a dosage reduced by 2 dose levels (e.g., 9 mg to 6 mg daily; 8 mg to 5 mg daily). (See Table 1.)

Table 2. Dosage Modification for Hyperphosphatemia.1
Serum Phosphate Concentration (mg/dL)	Dosage Modification after Recovery from Toxicity
7–9	Resume therapy at the current dosage; however, if hyperphosphatemia persists for >1 week, consider dosage reduction (see Table 1)
>9 to 10	Reduce by 1 dose level (see Table 1)
>10	Reduce by 2 dose levels (see Table 1)

Ocular Effects

Oral

For central serous retinopathy or retinal pigment epithelial detachment, temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary (see Table 3).

Table 3. Dosage Modification for Central Serous Retinopathy or Retinal Pigment Epithelial Detachment.13
Severity	Findings	Dosage Modification Following Therapy Interruption
Grade 1	Asymptomatic	If resolution occurs within 4 weeks, reduce dosage by 1 dose level (see Table 1) and resume therapy If Grade 1 toxicity does not resolve but remains stable for 2 consecutive eye exams, reduce dosage by 1 dose level (see Table 1) and resume therapy If the toxicity does not recur within 1 month of dosage reduction, consider re-escalating dosage
Grade 2	Moderate decrease in visual acuity (20/40 or better or reduction by ≤3 lines from baseline)	If resolution occurs within 4 weeks, reduce dosage by 1 dose level (see Table 1) and resume therapy If the toxicity does not resolve within 4 weeks of withholding therapy, permanently discontinue drug
Grade 3	Marked decrease in visual acuity (worse than 20/40 or reduction >3 lines from baseline)	If resolution occurs within 4 weeks, reduce dosage by 2 dose levels (see Table 1) and resume therapy If Grade 3 toxicity recurs, consider permanent discontinuance of drug If the toxicity does not resolve within 4 weeks of withholding therapy, permanently discontinue drug
Grade 4	Blindness (20/200 or worse in affected eye)	Permanently discontinue drug

Other Adverse Effects

Oral

For other grade 3 adverse reaction, temporarily interrupt therapy; upon recovery to grade 1 or less or to baseline, resume therapy at a dosage reduced by 1 dose level.

For grade 4 adverse reaction, permanently discontinue drug.

Prescribing Limits

Adults

Urothelial Carcinoma

Oral

Maximum 9 mg once daily.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Limited data available.

Renal Impairment

Mild to moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No dosage adjustment necessary.

Severe renal impairment: No data available.

Geriatric Patients

No special dosage recommendations at this time.

Cautions for Erdafitinib

Contraindications

No known contraindications.

Warnings/Precautions

Ocular Effects

Central serous retinopathy and retinal pigment epithelial detachment resulting in visual field defect reported. Median time to initial onset is 50 days (range: 22–207 days); resolved in 50% of patients in principal efficacy study. Dry eye symptoms also reported.

Initiate dry eye prophylaxis with ophthalmic demulcents upon initiation of erdafitinib.

Perform ophthalmologic examinations, including visual acuity assessment, slit lamp examination, fundoscopy, and optical coherence tomography, monthly during the first 4 months of therapy, every 3 months thereafter, and as clinically indicated (e.g., if new or worsening visual disturbances occur); if visual disturbances occur, perform ophthalmologic examinations urgently. If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Hyperphosphatemia and Soft Tissue Mineralization

Elevated serum phosphate concentration occurs secondary to FGFR inhibition. Median time to onset is 20 days (range: 8–116 days) following initiation of therapy.

Erdafitinib can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, nonuremic calciphylaxis and vascular calcification.

Phosphate intake should not exceed 600–800 mg daily during therapy. Evaluate serum phosphate concentrations 14–21 days following initiation of therapy and monthly thereafter. If hyperphosphatemia (serum phosphate concentrations >7 mg/dL) occurs, consider initiation of an oral phosphate binder until serum phosphate concentrations improve to <5.5 mg/dL or baseline. If hyperphosphatemia occurs or if substantial changes in baseline renal function or grade 3 hypercalcemia occur secondary to hyperphosphatemia, monitor serum phosphate concentrations more frequently (i.e., weekly) until they improve to <5.5 mg/dL or to baseline. Treatment interruption and subsequent dosage reduction also may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Confirmation of pregnancy status is recommended prior to initiating therapy. Avoid pregnancy during therapy. (See Females and Males of Reproductive Potential under Cautions.) If used during pregnancy, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether erdafitinib is distributed into milk, affects milk production, or affects nursing infants.

Females should not breast-feed during therapy and for 1 month following the last dose.

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraceptive methods while receiving erdafitinib and for 1 month after discontinuance of the drug.

Advise males with female partners of reproductive potential to use effective methods of contraception while receiving erdafitinib and for 1 month after discontinuance of the drug.

Results of animal studies suggest erdafitinib may impair female fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Chondroid dysplasia or metaplasia in multiple bones and tooth abnormalities (i.e., abnormal or irregular dentin, odontoblast discoloration and degeneration) observed in animals.

Geriatric Use

In clinical trials, 45% of patients were ≥65 years of age and 12% were ≥75 years of age; no overall differences in safety or efficacy relative to younger adults.

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially affect pharmacokinetics of erdafitinib.

Pharmacokinetics of erdafitinib have not been established in patients with severe hepatic impairment.

Renal Impairment

Mild or moderate renal impairment do not substantially affect pharmacokinetics of erdafitinib.

Pharmacokinetics of erdafitinib have not been established in patients with severe renal impairment or those with renal impairment requiring dialysis.

Pharmacogenomic Considerations

Closely monitor patients who are known or suspected poor CYP2C9 metabolizers carrying the CYP2C9*3/*3 genotype; systemic exposure of erdafitinib may be increased.

Common Adverse Effects

Adverse effects and laboratory abnormalities reported in ≥20% of patients: Increased serum phosphate concentrations, stomatitis, fatigue, increased S_cr concentrations, diarrhea, dry mouth, onycholysis, increased ALT and/or AST concentrations, increased alkaline phosphatase concentrations, decreased serum sodium concentrations, decreased appetite, decreased albumin concentrations, dysgeusia, decreased hemoglobin concentrations, dry skin, decreased serum magnesium concentrations, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), constipation, decreased serum phosphate concentrations, abdominal pain, elevated serum calcium concentrations, nausea, musculoskeletal pain.

Drug Interactions

Principally metabolized by CYP2C9 and 3A4.

Time-dependent inhibitor and inducer of CYP3A4, but is not an inhibitor of other major CYP isoenzymes.

In vitro, substrate of P-glycoprotein (P-gp). Inhibitor of P-gp and organic cation transporter (OCT) 2, but is not an inhibitor of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B or 1B3, organic anion transporter (OAT) 1 or 3, OCT1, and multidrug and toxin extrusion (MATE) 1 or 2K transporters.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate CYP2C9 and/or potent CYP3A4 inhibitors: Possible increased erdafitinib plasma concentrations and increased risk of erdafitinib toxicity. Avoid concomitant use; consider alternative agent with less CYP2C9 and/or 3A4 inhibition potential. If concomitant use cannot be avoided, monitor closely for signs of toxicity; dosage modification may be necessary if serious or life-threatening adverse effects occur. When the moderate CYP2C9 or potent CYP3A4 inhibitor is discontinued and erdafitinib-related toxicity has resolved, may increase dosage of erdafitinib (up to a maximum of 9 mg once daily) based on tolerance.

Potent CYP2C9 and/or 3A4 inducers: Possible decreased erdafitinib plasma concentrations and reduced erdafitinib efficacy. Avoid concomitant use.

Moderate CYP2C9 and/or 3A4 inducers: Possible decreased erdafitinib plasma concentrations and reduced erdafitinib efficacy. Avoid concomitant use. If concomitant use cannot be avoided upon initiation of erdafitinib, initiate erdafitinib at recommended initial dosage (8 mg once daily followed by a potential increase up to a maximum of 9 mg once daily). If concomitant use is necessary following initial erdafitinib dosage titration, increase dosage of erdafitinib up to a maximum of 9 mg once daily. When the moderate CYP2C9 or CYP3A4 inducer is discontinued, continue erdafitinib at the same dosage, if tolerated.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Possible altered plasma concentrations of CYP3A4 substrate and either reduced efficacy or increased toxicity of CYP3A4 substrate; effect on sensitive CYP3A4 substrate not established. Avoid concomitant use with sensitive CYP3A4 substrates that have a narrow therapeutic index.

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inhibitors: Pharmacokinetic interactions unlikely.

P-gp substrates: Possible increased plasma concentrations of P-gp substrate and increased risk of toxicity of P-gp substrate. If concomitant use is necessary, administer erdafitinib ≥6 hours before or after administration of P-gp substrates that have a narrow therapeutic index.

Drugs Affected by Organic Cation Transporter

OCT2 substrates: Possible increased plasma concentrations of OCT2 substrate and increased risk of OCT2 substrate toxicity. Consider selection of an alternative drug that is not an OCT2 substrate or reduce dosage of OCT2 substrate based on tolerance.

Drugs Affecting Serum Phosphate Concentrations

Concomitant use with drugs affecting serum phosphate concentrations may result in increased or decreased serum phosphate concentrations. Avoid concomitant use prior to initial dosage titration period (i.e., initial 14–21 days of erdafitinib therapy).

Specific Drugs

Drug	Interaction	Comments
Antacids	No clinically meaningful effect on erdafitinib bioavailability	Avoid concomitant use prior to initial serum phosphate concentration-based dosage titration
Antifungals, azoles (e.g., fluconazole, itraconazole)	Potent CYP2C9 and/or CYP3A4 inhibitors: Possible increased erdafitinib plasma concentrations and increased risk of toxicity Fluconazole: Increased peak plasma concentrations and AUC of erdafitinib by 21 and 48%, respectively Itraconazole: Increased peak plasma concentrations and AUC of erdafitinib by 5 and 34%, respectively	Consider alternative antifungal with less CYP2C9 or CYP3A4 inhibition potential; if concomitant use cannot be avoided, monitor closely for toxicity If serious or life-threatening toxicity occurs, interrupt therapy and reduce erdafitinib dosage
Digoxin	Possible increased plasma concentrations of digoxin and increased risk of toxicity	If concomitant use is necessary, administer erdafitinib ≥6 hours before or after administration of digoxin
Histamine H₂-receptor antagonists	No clinically meaningful effect on erdafitinib bioavailability
Metformin	Possible increased metformin concentrations; potential metformin toxicity	Consider an alternative drug that is not an OCT2 substrate or reduce dosage of metformin based on tolerance
Midazolam	Possible increased or decreased plasma concentrations of midazolam and reduced efficacy or increased toxicity
Phosphate-containing products (e.g., laxative, enema)	Possible altered serum phosphate concentrations	Avoid concomitant use prior to initial serum phosphate concentration-based dosage titration
Proton-pump inhibitors	No clinically meaningful effect on erdafitinib bioavailability
Potassium phosphate supplements	Possible altered serum phosphate concentrations	Avoid concomitant use prior to initial serum phosphate concentration-based dosage titration
Rifampin	Potent CYP2C9 and CYP3A inducer: Possible decreased erdafitinib concentrations and reduced efficacy	Avoid concomitant use
Vitamin D supplements	Possible altered serum phosphate concentrations	Avoid concomitant use prior to initial serum phosphate concentration-based dosage titration

Erdafitinib Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are dose proportional over dose range of 0.5–12 mg following single or repeated once-daily dosing.

Peak plasma concentrations attained in a median of 2.5 hours.

Steady-state concentrations achieved after 2 weeks of once-daily dosing with approximately fourfold accumulation.

Food

Administration of single 9-mg dose of erdafitinib with a high-fat, high-calorie meal (800–1000 calories with approximately 50% of calories from fat) did not affect erdafitinib pharmacokinetics in healthy individuals.

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration above normal but not >1.5 times the ULN with any AST concentration) does not affect pharmacokinetics. Pharmacokinetics not established in patients with moderate or severe hepatic impairment.

Mild or moderate renal impairment (eGFR 30–89 mL/min per 1.73 m²) does not affect pharmacokinetics. Pharmacokinetics not established in patients with severe renal impairment or those with renal impairment requiring dialysis.

Poor CYP2C9 metabolizers (those with CYP2C9*3/*3 genotype): Systemic exposure increased by 50% compared with individuals with the CYP2C9*1/*1 wild-type genotype.

Distribution

Extent

Not known whether erdafitinib is distributed into milk.

Plasma Protein Binding

99.8% (mainly α₁-acid glycoprotein).

Elimination

Metabolism

Principally metabolized by CYP2C9 and 3A4.

Elimination Route

Eliminated in feces (69% of the recovered dose [19% as unchanged drug]) and urine (19% [13% as unchanged drug]).

Half-life

59 hours.

Special Populations

Age, sex, race, or body weight does not have meaningful effects on clearance of erdafitinib.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

A potent and reversible inhibitor of FGFR-1, FGFR-2, FGFR-3, and FGFR-4.
FGFR signaling pathway involved in proliferation and processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis); aberrant expression of FGFR signaling implicated in pathogenesis of various solid tumors. Inhibition of FGFR reduces cell viability in cell lines with aberrant FGFR expression.
Serum phosphate concentration is a marker of FGFR inhibition. (See Urothelial Carcinoma under Dosage and Administration.)
Demonstrates antitumor activity in FGFR-expressing cell lines and xenograft models of tumor types such as bladder cancer.
Also binds to ret proto-oncogene (RET), colony stimulating factor receptor type 1 (CSF-1R), platelet-derived growth factor receptors (PDGFR)-α and PDGFR-β, fms-like tyrosine kinase-4 (Flt-4), stem cell factor receptor (c-Kit), and vascular endothelial growth factor receptor (VEGFR)-2.

Advice to Patients

Importance of instructing patients to read the manufacturer’s patient information.
Importance of advising patients to take erdafitinib tablets once daily without regard to meals. Importance of advising patients to swallow erdafitinib tablets whole. If a dose is vomited, importance of taking the next dose at the regularly scheduled time; an additional dose should not be administered to make up for the vomited dose.
If a dose is missed, importance of taking the missed dose as soon as possible on the same day and taking the next dose at the regularly scheduled time on the following day. An additional dose should not be taken to make up for a missed dose.
Risk of ocular disorders. Importance of patients immediately informing their clinician if any visual changes (e.g., blurry or loss of vision) occur. Importance of preventing or treating dry eyes with artificial tears substitutes or hydrating or lubricating eye gels or ointments at least every 2 hours while awake.
Risk of dermatologic effects. Importance of informing clinician if progressive or intolerable skin, mucous, or nail disorders occur.
Risk of hyperphosphatemia and soft tissue mineralization. Importance of advising patients that phosphate intake should not exceed 600–800 mg daily during therapy. Importance of advising patients to avoid drugs that may alter serum phosphate concentrations during the first 14–21 days of erdafitinib therapy. Importance of patients immediately informing their clinician if painful skin lesions or any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth occur.
Risk of fetal harm. Necessity of advising females of reproductive potential and males who are partners of such females that they should use effective methods of contraception while receiving the drug and for 1 month after discontinuance of therapy. Importance of females informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant females of potential risk to the fetus.
Importance of advising females to avoid breast-feeding while receiving the drug and for 1 month after discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing medications), as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Erdafitinib is available only from a designated specialty pharmacy. Contact the manufacturer for additional information.