erdafitinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications: Genetic Implications

Pronunciation:
er-da-fi-ti-nib


Trade Name(s)

  • Balversa

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

fibroblast growth factor receptor inhibitor

Indications

Genetic implication Locally advanced or metastatic urothelial carcinoma that has susceptible fibroblast growth factor receptor (FGFR) 3 genetic alterations and has progressed during or following ≥1 line of prior systemic therapy.

Action

FGFR kinase inhibitor that binds to and inhibits FGFR1, FGFR2, FGFR3, and FGFR4 enzyme activity, which results in decreased FGFR-related signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions.

Therapeutic Effect(s):

Decreased spread of urothelial carcinoma.

Pharmacokinetics

Absorption: Unknown.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized in liver by the CYP2C9 and CYP3A4 isoenzymes; Genetic implication the CYP2C9 isoenzyme exhibits genetic polymorphism (intermediate or poor metabolizers may have significantly ↑ erdafitinib concentrations and an ↑ risk of adverse reactions).69% excreted in feces (19% as unchanged drug), 19% in urine (13% as unchanged drug).

Half-life: 59 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown2–6 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • OB:   Pregnancy;
  • Lactation:  Lactation.

Use Cautiously in:

  • Genetic implication  CYP2C9 poor metabolizers (↑ risk of adverse reactions);
  • Severe hepatic impairment;
  • Severe renal impairment;
  • Rep:   Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: vascular calcification

Derm: alopecia, dry skin, nail detachment, nail discoloration, cutaneous calcinosis, palmar-plantar erythrodysesthesia syndrome

EENT: blurred vision, central serous retinopathy/retinal pigment epithelial detachment, conjunctivitis, dry eyes, lacrimation

Endo: hypoglycemia

F and E: hypercalcemia, hyperkalemia, hyperphosphatemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: abdominal pain, ↓ albumin, constipation, diarrhea, dry mouth, ↑ liver enzymes, metallic taste, nausea, stomatitis, vomiting

GU: hematuria, ↑ serum creatinine, ↓ fertility (females)

Hemat: anemia, leukopenia, neutropenia, thrombocytopenia

MS: arthralgia, pain

Metabolic: ↓ appetite, ↓ weight

Neuro: fatigue

Resp: dyspnea

Misc: fever, nonuremic calciphylaxis

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Moderate CYP2C9 inhibitors, including  fluconazole, and  strong CYP3A4 inhibitors, including  itraconazole, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use unavoidable, ↓ erdafitinib dose.
  •  Strong CYP3A4 inducers, including  rifampin, may ↓ levels and effectiveness; avoid concurrent use.

  •  Moderate CYP3A4 inducers  may ↓ levels and effectiveness; avoid concurrent use; if concurrent use unavoidable, ↑ erdafitinib dose.

     Serum-phosphate level altering drugs  may ↑ or ↓ phosphate levels, which can have impact on ability to adjust erdafitinib doses; avoid concurrent use before initial erdafitinib dose increase period.
  • May ↑ or ↓ levels of  CYP3A4 substrates ; avoid concurrent use with CYP3A4 substrates that have a narrow therapeutic index.
  • May ↑ levels of  P-glycoprotein substrates ; avoid concurrent use; if concurrent use unavoidable, separate by ≥6 hr.

Route/Dosage

PO (Adults): 8 mg once daily; may ↑ to 9 mg once daily at 14–21 days if serum phosphate level <9 mg/dL, no ocular disorders, and no Grade 2 or higher adverse reactions. Continue until disease progression or unacceptable toxicity.  Concurrent use of moderate CYP3A4 inducers– 9 mg once daily; continue until disease progression or unacceptable toxicity.

Availability

Tablets: 3 mg, 4 mg, 5 mg

Assessment

  • Perform monthly ophthalmological exams including assessment of visual acuity, slit lamp exam, fundoscopy, and optical coherence tomography during first 4 months of therapy and every 3 months afterward, and urgently for visual symptoms. Monitor for central serous retinopathy (CSR)/retinal pigment epithelial detachment. If any CSR occurs, hold erdafitinib and perform an ophthalmic evaluation within 2 wk: If improving within 14 days, restart at current dose. If not improving within 14 days, hold erdafitinib until improving; once improving, may resume at next lower dose level. On restarting erdafitinib, monitor for recurrence every 1 to 2 wk for a month. If recurs or has not improved after 4 wk of holding erdafitinib, consider permanent discontinuation. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Genetic implication Patient selection is based on 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 FGFR3 genetic alterations in urothelial cancer is available at http://www.fda.gov/CompanionDiagnostics.
  • Assess serum phosphate levels 14–21 days after starting therapy. Restrict phosphate intake to 600–800 mg daily in all patients. If serum phosphate <6.99 mg/dL and no ocular disorders or ≥Grade 2 adverse reactions, continue at current dose. Monitor phosphate levels monthly for hyperphosphatemia.  If serum phosphate 7–8.99 mg/dL ,  continue erdafitinib at same dose. Start phosphate binder with food until phosphate level is <7 mg/dL. Reduce dose if serum phosphate remains ≥7 mg/dL for a period of 2 mo or if clinically necessary.  If serum phosphate 9.0–10 mg/dL,  hold erdafitinib with weekly reassessments until level <5.5 mg/dL (or baseline). Start phosphate binder with food until phosphate level is <7 mg/dL. Reduce dose if serum phosphate remains ≥7 mg/dL for a period of 2 mo or if clinically necessary. Then restart at same dose level. Dose reduction may be used for hyperphosphatemia lasting >1 wk.  If serum phosphate >10 mg/dL,  hold erdafitinib with weekly reassessments until level returns to <7 mg/dL. Then may restart at first reduced dose level. If hyperphosphatemia (≥10 mg/dL) for >2 wk, discontinue erdafitinib permanently. Medical management of symptoms as clinically relevant.

Implementation

  • Limit phosphate intake to 600–800 mg daily. If serum phosphate >7.0 mg/dL, may add oral phosphate binder until serum phosphate levels <5.5 mg/dL.
  • Recommended Dose Modifications : If 9-mg dose,   1st dose reduction:  to 8 mg,  2nd dose reduction:  to 6 mg,  3rd reduction:  to 5 mg,  4th reduction:  to 4 mg,  5th dose reduction  discontinue therapy.  If 8-mg dose,   1st dose reduction:  to 6 mg,  2nd reduction:  to 5 mg,  3rd reduction:  to 4 mg,  4th reduction  discontinue therapy.
  • PO Administer once daily without regard to food.  DNC: Swallow tablets whole; do not crush, break, or chew.  

Patient/Family Teaching

  • Instruct patient to take erdafitinib as directed. If vomiting occurs any time after taking, take next dose the next day as scheduled. Take missed doses as soon as remembered on the same day. Resume regular schedule next day; do not double doses. Advise patient to read  Patient Information  before starting and with Rx refill in case of changes.
  • Advise patient to notify health care professional immediately if eye problems (dry or inflamed eyes, blurred vision, loss of vision or other visual changes). Instruct patient to use artificial tear substitutes, hydrating or lubricating eye gels or ointments at least every 2 hr during waking hours to help prevent dry eyes.
  • Advise patient to notify health care professional promptly if nail or skin problems (nails separating from nail bed, nail pain, nail bleeding, breaking of nails, color or texture changes in nails, infected skin around nail, itchy skin rash, dry skin, cracks in skin) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception and avoid breastfeeding during and for 1 mo after last dose. May impair fertility in females of reproductive potential.
  • Emphasize the importance of routine lab tests and eye exams.

Evaluation/Desired Outcomes

Decreased spread of locally advanced or metastatic urothelial carcinoma.