Futibatinib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The Fibroblast Growth Factor receptor (FGFR) pathway plays a key role in cell proliferation, differentiation, migration, and survival. Notably, FGFR genomic aberrations and aberrant FGFR signaling pathways are observed in some cancers, as constitutive FGFR signaling can support the proliferation and survival of malignant cells. Futibatinib is a selective, irreversible inhibitor of FGFR 1, 2, 3, and 4 with IC50 values of less than 4 nM. It binds to the FGFR kinase domain by forming a covalent bond with cysteine in the ATP-binding pocket. Upon binding to FGFR, futibatinib blocks FGFR phosphorylation and downstream signaling pathways, such as the RAS-dependent mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3KCA)/Akt/mTOR, phospholipase Cγ (PLCγ), and JAK/STAT. Futibatinib ultimately decreases cell viability in cancer cell lines with FGFR alterations, including FGFR fusions or rearrangements, amplifications, and mutations.

Futibatinib is an anticancer agent with demonstrated anti-tumour activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations. Futibatinib is not expected to affect cell lines with no FGFR genomic aberrations. It suppresses the growth of tumors in a dose-dependent manner.

Indications

  • Futibatinib is indicated to treat adults with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Treatment of cholangiocarcinoma
  • Futibatinib is an FGF receptor 2 kinase inhibitor that is used in the treatment of unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma.
  • Locally Advanced Intrahepatic Cholangiocarcinoma
  • Metastatic Intrahepatic Cholangiocarcinoma
  • Unresectable Intrahepatic Cholangiocarcinoma

Use in Cancer

Futibatinib is approved to treat:

  • Intrahepatic cholangiocarcinoma (cancer that forms in the bile ducts inside the liver) has spread or cannot be removed with surgery. It is used in adults whose cancer has been treated and has an FGFR2 gene fusion or other change in the structure of the FGFR2 gene.

Futibatinib is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit in these patients.

Futibatinib is also being studied in the treatment of other types of cancer.

Contraindications

  • Pregnancy and lactation
  • Low Amount Of Phosphate In The Blood
  • Decreased Blood Platelets
  • Low Levels Of A Type Of White Blood Cell Called Neutrophils
  • A High Alanine Transaminase Level
  • A High Aspartate Transaminase Level
  • Detachment Of Retinal Pigment Epithelium
  • Severe renal failure patient
  • Low Amount Of Sodium In The Blood
  • Anemia
  • A Decreased Number Of Lymphocytes In The Blood

Dosage

Strengths: 4mg, 5mg, 20mg

Cholangiocarcinoma of the biliary tract

  • Usual dose: 20 mg (five 4 mg tablets) taken orally once daily
  • Confirm the presence of an FGFR2 gene fusion or another rearrangement prior to initiation of treatment.
  • Treatment is to be continued until disease progression or unacceptable toxicity occurs. Patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.

Dose Adjustments

DOSE MODIFICATION FOR ADVERSE REACTIONS:

  • First dose reduction: 16 mg (four 4 mg tablets) orally once daily
  • Second dose reduction: 12 mg (three 4 mg tablets) orally once daily
  • Permanently discontinue this drug if unable to tolerate 12 mg orally once daily.

DOSE MODIFICATION FOR RETINAL PIGMENT EPITHELIAL DETACHMENT (RPED):

  • Continue this drug at the current dose and continue periodic ophthalmic evaluation:
  • If resolved within 14 days, continue this drug at the current dose.
  • If not resolved within 14 days, withhold this drug until resolved; then resume at the previous or a lower dose.

DOSE MODIFICATION FOR HYPERPHOSPHATEMIA:
Serum phosphate 5.5 to 7 mg/dL:

  • Continue this drug at the current dose and start with phosphate-lowering therapy.
  • Monitor serum phosphate weekly.

Serum phosphate more than 7 to 10 mg/dL:

  • Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly.
  • If the serum phosphate resolves to 7 mg/dL or less within 2 weeks after dose reduction, continue at this reduced dose.
  • If serum phosphate is not 7 mg/dL or below within 2 weeks, further reduce to the next lower dose.
  • If serum phosphate is not 7 mg/dL or below within 2 weeks after the second dose reduction, withhold this drug until serum phosphate is 7 mg/dL or below and resume at the dose prior to suspending.

Serum phosphate more than 10 mg/dL:

  • Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly.
  • Withhold this drug until phosphate is 7 mg/dL or below and resume at the next lower dose.
  • Permanently discontinue this drug if serum phosphate is not equal to or less than 7 mg/dL within 2 weeks following 2 dose interruptions and reductions.

DOSE MODIFICATION FOR OTHER ADVERSE REACTIONS:
Grade 3:

  • Withhold this drug until toxicity resolves to Grade 1 or baseline, then resume.
  • For hematological toxicities that get resolved within 1 week, continue at the dose prior to suspending.
  • For other adverse reactions, continue at the next lower dose.

Grade 4:

  • Permanently discontinue this drug.

Administration advice:

  • Administer this drug with or without food at approximately the same time each day.
  • Swallow tablets whole. Do not crush, chew, split, or dissolve tablets.
  • If a dose is missed for more than 12 hours or if vomiting occurs, resume dosing the next day as scheduled.
  • Patients should be advised to read FDA-approved patient labeling (Patient Information).
  • Patients should be informed about potential adverse reactions of this drug which include ocular toxicity, hyperphosphatemia, and soft tissue mineralization and immediately reach out to a health care professional if any symptoms related to these events develop.
  • Patients should use artificial tears or hydrating or lubricating eye gels to prevent or treat dry eyes.
  • Inform patients that this drug may cause nail disorders.
  • Notify the health care provider if the patient is pregnant or becomes pregnant during treatment.
  • Patients should be cognizant of the risk to a fetus and the potential loss of a pregnancy during the treatment with this drug.
  • Male and female patients should use an effective method of contraception throughout treatment with this drug and for 1 week after the last dose of this drug.
  • Do not breastfeed during treatment with this drug and for 1 week after the last dose.
  • Do not consume grapefruit products during treatment with this drug.
  • Patients are advised to inform health care professional about all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products.

Side Effects

The Most Common

  • change in appearance or color of nails
  • muscle pain
  • constipation
  • diarrhea or loose stools
  • feeling tired or weak
  • dry mouth
  • hair loss
  • mouth sore
  • stomach area pain
  • dry skin
  • joint pain
  • changes in taste
  • dry eye
  • nausea or vomiting
  • decrease in appetite
  • difficulty or painful urination, lower back pain, or fever
  • redness, swelling, pain or tenderness on the hands or feet
  • dry or inflamed eyes, increased tears, blurred vision, flashes of light, or seeing black spots
  • muscle cramps or numbness or tingling around your mouth

More common

  • Bladder pain
  • bloody or cloudy urine
  • bone or joint pain
  • confusion
  • constipation
  • cracked lips
  • diarrhea
  • difficult, burning, or painful urination
  • difficulty in breathing
  • difficulty in swallowing
  • dry eyes
  • dry mouth
  • fever
  • frequent urge to urinate
  • irregular heartbeats
  • loss of appetite
  • lower back or side pain
  • mood or mental changes
  • muscle cramps in the hands, arms, feet, legs, or face
  • nausea
  • numbness and tingling around the mouth, fingertips, or feet
  • painful irritation of the clear front part of the eye
  • redness, swelling, or pain of the skin
  • scaling of the skin on the hands and feet
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • stomach cramps, tenderness, or pain
  • swelling, irritation, soreness, or inflammation of the mouth
  • tingling of the hands and feet
  • ulceration of the skin
  • vomiting
  • vomiting of blood or material that looks like coffee grounds
  • watering of the eyes
  • watery or bloody diarrhea
  • weakness

Rare

  • Black, tarry stools
  • bloody stools
  • pale skin
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Bluish-brownish hands
  • change in taste
  • difficulty in moving
  • lack or loss of strength
  • loss of taste
  • muscle aches, cramps, pains, or stiffness
  • redness or soreness around the fingernails or loosening of the fingernails

Drug Interactions

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

Based on findings in an animal study and its mechanism of action, LYTGOBI can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LYTGOBI in pregnant women. Oral administration of futibatinib to pregnant rats during the period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 20 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death (see Data). Advise pregnant
women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of futibatinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions from LYTGOBI in breastfed children, advise women not to breastfeed during treatment and for 1 week after the last dose.

Why is this medication prescribed?

Futibatinib is used in adults who have received previous therapy to treat a certain type of cholangiocarcinoma (bile duct cancer) that has spread to nearby tissues or other parts of the body and cannot be removed by surgery. Futibatinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.

How should this medicine be used?

Futibatinib comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take futibatinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take futibatinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

If you vomit after taking futibatinib, do not take another dose. Continue your regular dosing schedule.

Your doctor may decrease your dose or temporarily or permanently stop your treatment if you experience certain side effects. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with futibatinib.

Futibatinib may cause irritation and dry eyes. You should use artificial tears or lubricant eye drops while on treatment with futibatinib to prevent or treat the dry eyes. Your doctor will order an eye exam before and during treatment with futibatinib to watch for more severe eye problems. Make sure you keep all eye exam appointments. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking futibatinib,

  • tell your doctor and pharmacist if you are allergic to futibatinib, any other medications, or any of the ingredients in futibatinib tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take while taking futibatinib. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have vision or eye problems, diabetes, anemia, history of bleeding disorder, or if you have or ever had kidney or liver problems.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan on fathering a child. If you are female, you will need to take a pregnancy test before you start treatment and use birth control to prevent pregnancy during your treatment and for at least 1 week after your final dose. If you are a male, you and your partner should use birth control during your treatment and for 1 month after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. If you or your partner become pregnant while taking futibatinib, call your doctor immediately. Futibatinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking futibatinib and for 1 week after your final dose.

What special dietary instructions should I follow?

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medication.

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it has been more than 12 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214801s000lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213736s000lbl.pdf
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214801s000lbl.pdf
  4. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214622Orig1s000MultidisciplineR.pdf
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Futibatinib
  6. https://pubchem.ncbi.nlm.nih.gov/substance/354702259
  7. https://www.cancer.gov/about-cancer/treatment/drugs/futibatinib
  8. https://go.drugbank.com/drugs/DB15149
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  10. https://en.wikipedia.org/wiki/Futibatinib
  11. https://www.mayoclinic.org/drugs-supplements/futibatinib-oral-route/side-effects/drg-20539902
  12. https://www.webmd.com/drugs/2/drug-185121/futibatinib-oral/details