Futibatinib (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Dec 12, 2023. Written by ASHP.

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Introduction

Antineoplastic agent; small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, 3, and 4.

Uses for Futibatinib

Intrahepatic Cholangiocarcinoma

Treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements (designated an orphan drug by FDA for this use).

Futibatinib received accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Select patients for treatment with futibatinib based on the presence of an FGFR2 gene fusion or rearrangement; FDA-approved test for detection of FGFR2 gene fusions or other rearrangements not available.

FGFR inhibitors (e.g., pemigatinib, infigratinib, futibatinib) are recommended as second-line therapy in patients with FGFR2 fusions who progress on first-line chemotherapy.

Futibatinib Dosage and Administration

General

Pretreatment Screening

Confirm the presence of a fibroblast growth factor receptor 2 (FGFR2) gene fusion or rearrangement prior to initiating futibatinib.
Confirm pregnancy status prior to initiating futibatinib in females of reproductive potential.
Perform a comprehensive ophthalmological examination, including optical coherence tomography (OCT) of the macula, prior to initiating futibatinib.

Patient Monitoring

Perform a comprehensive ophthalmological examination, including OCT of the macula, every 2 months for the first 6 months of futibatinib therapy, and every 3 months thereafter; if visual symptoms occur, refer patients for ophthalmologic examination urgently with follow-up every 3 weeks until resolution or futibatinib discontinuation.
Monitor for hyperphosphatemia during treatment with futibatinib.

Administration

Oral Administration

Administer orally once daily.

Administer with or without food at approximately the same time each day. Swallow tablets whole; do not crush, chew, split, or dissolve.

If dose missed by ≥12 hours, or if vomiting occurs after dose is taken, resume dosing with the next scheduled dose.

Dosage

Adults

Intrahepatic Cholangiocarcinoma

Oral

20 mg (five 4 mg tablets) orally once daily. Continue treatment until disease progression or unacceptable toxicity occurs.

<C> Dosage Modification for Toxicity

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary if adverse effects occur. If dosage modification is required, reduce dosage of futibatinib as described in Table 1.

Permanently discontinue futibatinib if unable to tolerate 12 mg once daily.

Table 1. Recommended Dosage Reduction for Futibatinib Toxicity.1
Dosage Reduction	Recommended Dosage
First dosage reduction	16 mg (four 4 mg tablets) orally once daily
Second dosage reduction	12 mg (three 4 mg tablets) orally once daily

Recommended dosage modifications for specific adverse reactions listed in Table 2.

Table 2: Recommended Dosage Modifications for Futibatinib Adverse Reactions.1
Adverse Reaction	Severity	Recommendation
Retinal pigment epithelial detachment	Not applicable	Continue futibatinib therapy at the current dosage and continue periodic ophthalmic evaluations. If condition improves within 14 days, continue futibatinib at current dosage; if no improvement within 14 days, withhold therapy and resume at previous or lower dosage once the condition improves.
Hyperphosphatemia	Serum phosphate ≥5.5 to ≤7 mg/dL	Continue futibatinib therapy at the current dosage, initiate phosphate lowering therapy, and monitor serum phosphate weekly.
Serum phosphate >7 to ≤10 mg/dL	Initiate or adjust phosphate lowering therapy, monitor serum phosphate weekly, and reduce futibatinib to the next lower dosage. If serum phosphate resolves to ≤7 mg/dL within 2 weeks after dosage reduction, continue at this reduced dosage. If serum phosphate is not ≤7 mg/dL within 2 weeks, further reduce futibatinib to the next lower dosage. If serum phosphate is not ≤7 mg/dL within 2 weeks after second dosage reduction, withhold futibatinib until serum phosphate is ≤7 mg/dL and resume at the dosage prior to suspending.
Serum phosphate >10 mg/dL	Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly. Withhold futibatinib until phosphate is ≤7 mg/dL and resume futibatinib at the next lower dosage. Permanently discontinue futibatinib if serum phosphate is not ≤7 mg/dL within 2 weeks following 2 dosage interruptions and reductions.
Other toxicities	Grade 3	Withhold futibatinib until toxicity resolves to grade 1 or baseline, then resume futibatinib at the dosage prior to suspending for hematological toxicities resolving within 1 week, or at the next lower dosage level for other toxicities.
Grade 4	Permanently discontinue futibatinib therapy.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Use

No specific dosage recommendations.

Cautions for Futibatinib

Contraindications

None.

Warnings/Precautions

Ocular Toxicity

Retinal Pigment Epithelial Detachment

Retinal pigment epithelial detachment (RPED) resulting in blurred vision reported.

Perform a comprehensive ophthalmological examination, including optical coherence tomography of the macula, prior to initiation of futibatinib, every 2 months for the first 6 months of therapy, and every 3 months thereafter. Refer patients for urgent ophthalmologic evaluation if visual symptoms occur; follow up every 3 weeks until resolution or futibatinib discontinuation.

If RPED occurs, withhold or reduce dosage as recommended.

Dry Eye/Corneal Keratitis

Dry eye reported.

Administer ocular demulcents as needed for management.

Hyperphosphatemia and Soft Tissue Mineralization

Hyperphosphatemia reported; can lead to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification. Increased serum phosphate concentration is a consequence of fibroblast growth factor receptor (FGFR) inhibition.

Monitor serum phosphate concentrations during therapy. For serum phosphate levels ≥5.5 mg/dL, initiate a low phosphate diet and phosphate-lowering therapy. For serum phosphate levels >7 mg/dL, initiate or intensify phosphate-lowering therapy and adjust, withhold, or permanently discontinue futibatinib based on the duration and severity of hyperphosphatemia.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm when administered to pregnant women. Fetal malformations, fetal growth retardation, and embryofetal death demonstrated in animals at clinically relevant exposures.

Confirm pregnancy status prior to initiating futibatinib in females of reproductive potential. Apprise patients of the potential hazard to the fetus if futibatinib used during pregnancy. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Specific Populations

Pregnancy

May cause fetal harm based on findings in an animal study and drug mechanism of action.

Human data on futibatinib use during pregnancy not available. Fetal malformations, fetal growth retardation, and embryofetal death reported in animals.

Confirm pregnancy status prior to initiating futibatinib in females of reproductive potential. Apprise patients of the potential hazard to the fetus if futibatinib used during pregnancy.

Lactation

Unknown whether futibatinib or its metabolites distribute into human milk; effects on milk production or the breast-fed infant unknown.

Advise women to not breast-feed during treatment and for 1 week after the last dose.

Females and Males of Reproductive Potential

Perform pregnancy testing in females of reproductive potential prior to treatment initiation.

Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clinical studies of futibatinib included patients ≥65 years of age. No overall differences in safety or efficacy observed between geriatric and younger patients.

No clinically important differences in futibatinib systemic exposures observed based on age (range, 18–82 years).

Hepatic Impairment

No clinically important differences in futibatinib systemic exposures observed with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1–1.5 times ULN and any AST).

Effect of moderate or severe hepatic impairment (total bilirubin >1.5 times ULN, irrespective of AST) on futibatinib pharmacokinetics not yet studied.

Renal Impairment

No clinically important differences in futibatinib systemic exposures observed with mild to moderate renal impairment (Cl_cr 30–89 mL/minute).

Effect of severe renal impairment (Cl_cr 15–29 mL/minute) or renal dialysis in end-stage renal disease (Cl_cr <15 mL/minute) on futibatinib pharmacokinetics not yet studied.

Common Adverse Effects

Adverse effects (≥20%) include nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, vomiting.

Laboratory abnormalities (≥20%) include increased phosphate, increased creatinine, decreased hemoglobin, increased/decreased glucose, increased calcium, decreased sodium, decreased phosphate, increased ALT/AST, increased alkaline phosphatase, decreased lymphocytes, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, increased prothrombin international normalized ratio, decreased potassium.

Drug Interactions

Primarily metabolized by CYP3A4, and to a lesser extent by CYP2C9 and CYP2D6.

Substrate of CYP3A4. Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A; does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.

Substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not organic anion transporting polypeptide (OATP) 1B1 or OATP1B3. Inhibits P-gp and BCRP, but not organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, OATP1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, or MATE2K at clinically relevant concentrations.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Dual P-gp and Strong CYP3A Inhibitors

May increase futibatinib exposure and consequently increase risk for toxicity.

Avoid concomitant use.

Effect of a strong CYP3A modulator (without P-gp modulation) on futibatinib exposures not studied.

Dual P-gp and Strong CYP3A Inducers

May decrease futibatinib exposure and consequently reduce efficacy of futibatinib.

Avoid concomitant use.

Effect of a strong CYP3A modulator (without P-gp modulation) on futibatinib exposures not studied.

Drugs Affecting or Affected by Transport Systems

P-gp or BRCP Substrates

Futibatinib may increase exposure of P-gp or BCRP substrates.

Consider more frequent monitoring for adverse reactions associated with concomitantly used drugs that are sensitive P-gp or BCRP substrates; reduce the dosage of these drugs as recommended in their prescribing information.

Effect of a P-gp modulator (without CYP3A modulation) on futibatinib exposures not studied.

Specific Drugs

Drug	Interaction	Comments
Grapefruit products		Avoid concomitant use
Itraconazole	Increased peak plasma concentrations and AUC of futibatinib by 51 and 41%, respectively	Avoid concomitant use
Lansoprazole	No effect on futibatinib AUC
Midazolam	No effect on midazolam AUC
Rifampin	Decreased peak plasma concentrations and AUC of futibatinib by 53 and 64%, respectively	Avoid concomitant use

Futibatinib Pharmacokinetics

Absorption

Bioavailability

Exposure (AUC) increases proportionally across dosage range of 4–24 mg once daily (0.2–1.2 times the approved recommended dosage).

Median time to peak plasma concentrations: 2 hours (range, 1.2–22.8 hours).

Food

After administration with a high-fat, high-calorie meal (900–1000 calories with approximately 50% of calories from fat), peak plasma concentrations and AUC of futibatinib decreased by 42 and 11%, respectively.

Special Populations

Systemic exposure not affected by age (range 18–82 years), sex, race, or body weight (range 36–152 kg).

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

95% (primarily bound to albumin and α1-acid glycoprotein).

Elimination

Metabolism

Primarily metabolized by CYP3A4, and to a lesser extent by CYP2C9 and CYP2D6.

Elimination Route

Following a single radiolabeled oral dose (20 mg), approximately 91 and 9% of the total recovered radioactivity was observed in feces and urine, respectively; negligible unchanged futibatinib in feces or urine.

Half-life

2.9 hours.

Stability

Storage

Oral

Tablets

20–25°C; excursions permitted between 15–30°C.

Actions

Highly selective, irreversible small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR); covalently binds to and inhibits FGFR1, FGFR2, FGFR3, and FGFR4.
Constitutive FGFR signaling can support proliferation and survival of malignant cells; inhibition of FGFR phosphorylation and downstream signaling by futibatinib results in decreased cell viability in cancer cell lines expressing FGFR genetic alterations.
Exhibited anti-tumor activity in rat and mouse xenograft models of human tumors with activating FGFR alterations.
Futibatinib-induced FGFR inhibition increases serum phosphate; risk of hyperphosphatemia increased at higher futibatinib exposures.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients that futibatinib may cause ocular toxicity, including retinal pigment epithelial detachment, and to immediately inform their clinician if they experience any visual changes. Advise patients to use artificial tears or hydrating or lubricating eye gels to prevent or treat dry eyes. Inform patients that their clinician will closely monitor for eye disorders with ophthalmic examinations.
Advise patients that futibatinib may cause hyperphosphatemia and soft tissue mineralization and to immediately inform their clinician if they experience symptoms such as muscle cramps, numbness, or tingling around the mouth.
Advise patients that futibatinib may cause nail disorders.
Advise patients to avoid grapefruit products during treatment with futibatinib.
Instruct patients to swallow futibatinib tablets whole, and to not crush, chew, split or dissolve the tablets.
Instruct patients that if they miss a futibatinib dose by ≥12 hours or if they vomit after taking a dose, they should resume dosing with the next scheduled dose; they should not take extra tablets to make up for the missed dose.
Advise women to inform their clinician if they are or become pregnant. Inform females of reproductive potential that futibatinib may cause fetal harm and potential loss of pregnancy. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with futibatinib and for 1 week after the last dose.
Advise women to inform their clinician if they are or plan to breast-feed. Advise women to not breast-feed during treatment with futibatinib and for 1 week after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.