erdafitinib (Rx)

Brand and Other Names:Balversa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 3mg
  • 4mg
  • 5mg

Urothelial Carcinoma

Indicated for locally advanced or metastatic urothelial carcinoma that has fibroblast growth factor receptor-2 (FGFR2) or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy

8 mg PO qDay initially; increase to 9 mg PO qDay based on serum phosphate (PO4) levels and tolerability at 14-21 days

Increase dose to 9 mg qDay if serum phosphate level <5.5 mg/dL and there are no ocular disorders or ≥Grade 2 adverse reactions

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction schedule

  • 9 mg/day reduction schedule
    • First: 8 mg/day
    • Second: 6 mg/day
    • Third: 5 mg/day
    • Fourth: 4 mg/day
    • Fifth: Stop drug if fifth reduction needed
  • 8 mg/day reduction schedule
    • First: 6 mg/day
    • Second: 5 mg/day
    • Third: 4 mg/day
    • Fourth: Stop drug if fourth reduction needed

Hyperphosphatemia

  • In all patients, restrict phosphate intake to 600-800 mg/day; if serum phosphate >7 mg/dL, consider adding oral phosphate binder until serum phosphate level returns to <5.5 mg/dL
  • Phosphate levels and dosage
    • 5.6-6.9 mg/dL (1.8-2.3 mmol/L): Continue at current dose
    • 7-9 mg/dL (2.3-2.9 mmol/L): Withhold drug; reassess weekly until phosphate <5.5 mg/dL (or baseline), then resume drug at same dose level; implement dose reduction if hyperphosphatemia lasts >1 week
    • >9 mg/dL (>2.9 mmol/L): Withhold drug; reassess weekly until phosphate <5.5 mg/dL (or baseline), then restart drug at 1 dose level lower
    • >10 mg/dL (>3.2 mmol/L) or significantly altered baseline renal function or Grade 3 hypercalcemia: Withhold drug; reassess weekly until phosphate <5.5 mg/dL (or baseline), then restart drug at 2 dose levels lower

Central serous retinopathy or retinal pigment epithelial detachment (CSR/RPED)

  • Grade 1
    • Asymptomatic; clinical or diagnostic observations only
    • Withhold drug until resolution
    • If resolves within 4 weeks, resume at the next lower dose level; then, if no recurrence for a month, consider reescalation
    • If stable for 2 consecutive eye examinations, but not resolved, resume at the next lower dose level
  • Grade 2
    • Visual acuity 20/40 or better or ≤3 lines of decreased vision from baseline
    • Withhold until resolution
    • If resolves within 4 weeks, may resume at the next lower dose level
  • Grade 3
    • Visual acuity worse than 20/40 or >3 lines of decreased vision from baseline
    • Withhold until resolution
    • If resolves within 4 weeks, may resume 2 dose levels lower
    • If recurs, consider permanent discontinuation
  • Grade 4
    • Visual acuity 20/200 or worse in affected eye
    • Permanently discontinue

Other adverse reactions

  • Grade 3: Withhold drug until resolves to Grade 1 or baseline, then may resume dose 1 level lower
  • Grade 4: Permanently discontinue

Renal impairment

  • Mild or moderate (eGFR 30-89 mL/min/1.73 m²): No clinically meaningful trends in the pharmacokinetics observed
  • Severe or dialysis: Unknown

Hepatic impairment

  • Mild (TB ≤ULN and AST >ULN or TB >1 to 1.5x ULN and any AST): No clinically meaningful trends in the pharmacokinetics observed
  • Moderate or severe: Unknown

Dosing Considerations

Patient selection

  • Select patients based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic
  • Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics

Monitoring

  • Assess serum phosphate levels 14-21 days after initiating
  • Monitor phosphate levels monthly for hyperphosphatemia

Safety and efficacy not established

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Interactions

Interaction Checker

and erdafitinib

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10% (All Grades)

            Phosphate increased (76%)

            Stomatitis (56%)

            Fatigue (54%)

            Creatinine increased (52%)

            Diarrhea (47%)

            Dry mouth (45%)

            ALT increased (41%)

            Alkaline phosphatase increased (41%)

            Onycholysis (41%)

            Sodium decreased (40%)

            Decreased appetite (38%)

            Albumin decreased (37%)

            Dysgeusia (37%)

            Hemoglobin decreased (35%)

            Dry skin (34%)

            AST increased (30%)

            Magnesium decreased (30%)

            Constipation (28%)

            Dry eye (28%)

            Palmar-plantar erythrodysesthesia (26%)

            Alopecia (26%)

            Phosphate decreased (24%)

            Abdominal pain (23%)

            Calcium increased (22%)

            Nausea (21%)

            Musculoskeletal pain (20%)

            Platelets decreased (19%)

            Leukocytes decreased (17%)

            Blurred vision (17%)

            Paronychia (17%)

            Urinary tract infection (17%)

            Potassium increased (16%)

            Weight decreased (16%)

            Pyrexia (14%)

            Vomiting (13%)

            Nail discoloration (11%)

            Conjunctivitis (11%)

            Oropharyngeal pain (11%)

            Hematuria (11%)

            Arthralgia (11%)

            >10% (Grades 3-4)

            Sodium decreased (16%)

            1-10% (All Grades)

            Neutrophils decreased (10%)

            Fasting glucose increased (10%)

            Lacrimation increased (10%)

            Dyspnea (10%)

            1-10% (Grades 3-4)

            Fatigue (10%)

            Onycholysis (10%)

            Phosphate decreased (9%)

            Stomatitis (9%)

            Palmar-plantar erythrodysesthesia (6%)

            Urinary tract infection (6%)

            Dry eye (6%)

            Creatinine increased (5%)

            Hemoglobin decreased (3%)

            Calcium increased (3%)

            Paronychia (3%)

            Neutrophils decreased (2%)

            Diarrhea (2%)

            Abdominal pain (2%)

            Vomiting (2%)

            Dyspnea (2%)

            Hematuria (2%)

            Platelets decreased (1%)

            Phosphate increased (1%)

            ALT increased (1%)

            Alkaline phosphatase increased (1%)

            Magnesium decreased (1%)

            Constipation (1%)

            Nausea (1%)

            Pyrexia (1%)

            Dysgeusia (1%)

            Oropharyngeal pain (1%)

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            Warnings

            Contraindications

            None

            Cautions

            Based on mechanism of action and animal studies, can cause fetal harm if administered to pregnant women

            Ocular disorders

            • Can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED), resulting in visual-field defect
            • Perform monthly ophthalmological examinations during first 4 months of treatment and then every 3 months afterwards, and urgently at any time for visual symptoms
            • Dry eye symptoms are common; all patients should receive dry eye prophylaxis with ocular demulcents as needed

            Hyperphosphatemia

            • Increases in serum phosphate levels are a pharmacodynamic effect as a consequence of FGFR inhibition
            • Median onset time for any grade event of hyperphosphatemia was 20 days
            • Monitor for hyperphosphatemia and follow dose modifications when required
            • Patients may require phosphate binders during treatment

            Drug interaction overview

            • CYP2C9 and CYP3A4 substrate; time-dependent CYP3A4 inhibitor and inducer; substrate and inhibitor of P-gp; OCT2 inhibitor
            • Strong CYP2C9 or CYP3A4 inhibitors
              • Coadministration increases erdafitinib plasma concentrations
              • If unable to avoid coadministration, consider lower erdafitinib dose
            • Strong CYP2C9 or CYP3A4 inducers
              • Coadministration may significantly decrease erdafitinib plasma concentrations and efficacy
              • Avoid coadministration
            • Moderate CYP2C9 or CYP3A4 inducers
              • Coadministration may significantly decrease erdafitinib plasma concentrations and efficacy
              • If moderate CYP2C9 or CYP3A4 inducer must be coadministered at start of treatment, administer 8-mg/day dose as recommended, with potential to increase to 9 mg/day based on serum phosphate levels on Days 14 to 21 and tolerability
              • If moderate CYP2C9 or CYP3A4 inducer must be coadministered after the initial dose increase period based on serum phosphate levels and tolerability, increase erdafitinib dose up to 9 mg
              • When a moderate inducer discontinued, continue erdafitinib at same dose, in absence of drug-related toxicity
            • Serum phosphate level-altering drugs
              • Coadministration with other serum phosphate level-altering agents may increase or decrease serum phosphate levels
              • Avoid coadministration before initial dose increase period (Days 14-21)
            • CYP3A4 substrates
              • Erdafitinib may altered plasma concentrations of CYP3A4 substrates, leading to either loss of activity or increased toxicity of the substrate
              • Avoid coadministration with sensitive CYP3A4 substrates with narrow therapeutic indices
            • OCT2 substrates
              • Erdafitinib may increase plasma concentrations of OCT2 substrates
              • Consider alternant therapies
            • P-gp substrates
              • Erdafitinib may increase plasma concentrations of P-gp substrates
              • If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index
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            Pregnancy

            Pregnancy

            Based on the mechanism of action and findings in animal reproduction studies, can cause fetal harm when administered to pregnant women

            Animal studies: Administration to pregnant rats during organogenesis caused malformations and embryofetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC

            Pregnancy testing recommended for females of reproductive potential before initiating erdafitinib

            Infertility: Based on findings in animal studies, may impair fertility in females of reproductive potential

            Contraception

            • Females: Advise females of reproductive potential to use effective contraception during treatment and for 1 month after last dose
            • Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 month after last dose

            Lactation

            No data are available on presence in human milk, effects on breastfed children, or on milk production

            Owing to potential serious adverse reactions in breastfed children, advise lactating women not to breastfeed during treatment and for 1 month following last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Fibroblast growth factor receptor (FGFR) inhibitor; FGFRs are a family of receptor tyrosine kinases

            In vitro, erdafitinib inhibits FGFR phosphorylation and signaling and decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions

            Absorption

            Peak plasma time: 2.5 hr

            Peak plasma concentration: 1399 ng/mL

            AUC: 29,268 ng·hr/mL

            Distribution

            Vd: 29 L

            Protein bound: 99.8%; primarily to alpha-1-acid glycoprotein

            Metabolism

            Primarily metabolized by CYP2C9 and CYP3A4

            Contribution of CYP2C9 and CYP3A4 in 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

            Elimination

            Half-life: 59 hr

            Total clearance: 0.362 L/hr

            Excretion: 69% feces (19% unchanged); 19% urine (19% unchanged)

            Pharmacogenomics

            CYP2C9 poor metabolizers

            • CYP2C9*3/*3 genotype: Erdafitinib systemic exposure predicted to be 50% higher
            • Estimated to be present in 0.4-3% of the population among various ethnic groups
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            Administration

            Oral Administration

            May take with or without food

            Swallow tablets whole; do not chew or crush

            Vomited dose: If vomiting occur any time after taking erdafitinib, the next dose should be taken the next day

            Missed dose

            • Take missed dose as soon as possible on the same day
            • Resume regular daily dose schedule the next day
            • Extra tablets should not be taken to make up for the missed dose

            Storage

            Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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