Infigratinib Phosphate is the phosphate salt form of infigratinib, an orally bioavailable pan-inhibitor of human fibroblast growth factor receptors (FGFRs) with potential antiangiogenic and antineoplastic activities. Upon administration, infigratinib selectively binds to and inhibits the activities of FGFRs, which may result in the inhibition of angiogenesis and cell proliferation, and the induction of cell death in tumors with activating FGFR amplifications, mutations, or fusions. FGFRs are a family of receptor tyrosine kinases that are involved in tumor cell differentiation and proliferation, tumor angiogenesis, and tumor cell survival. Activating FGFR amplifications, mutations, or fusions occur in various cancer cell types.

Infigratinib Mesylate is the mesylate salt of infigratinib, an orally bioavailable pan-inhibitor of human fibroblast growth factor receptors (FGFRs) with potential antiangiogenic and antineoplastic activities. Upon administration, infigratinib selectively binds to and inhibits the activities of FGFRs, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. FGFRs are a family of receptor tyrosine kinases that may be upregulated in various tumor cell types and may be involved in tumor cell differentiation and proliferation, tumor angiogenesis, and tumor cell survival.

Use in Cancer

Infigratinib phosphate is approved to treat:

• Cholangiocarcinoma (bile duct cancer) has spread and 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.

Infigratinib phosphate 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.

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

Contraindications

• high amount of phosphate in the blood
• liver problems
• pregnancy
• a patient who is producing milk and breastfeeding
• chronic kidney disease stage 3B (moderate)
• chronic kidney disease stage 4 (severe)
• kidney disease with likely reduction in kidney function
• detachment of retinal pigment epithelium
• Child-Pugh class A liver impairment
• Child-Pugh class B liver impairment

Dosage

Strengths: 125 mg daily dose; 100 mg daily dose; 75 mg daily dose; 50 mg daily dose.

Cholangiocarcinoma of biliary tract

• 125 mg (one 100 mg capsule and one 25 mg capsule) orally once a day for 21 days on 7 days off of a 28-day cycle
• Continue treatment until disease progression or unacceptable toxicity.
• Select patients for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma based on the presence of an FGFR2 fusion or rearrangement.
• Information on FDA-approved test(s) for the detection of FGFR2 fusions or rearrangements in cholangiocarcinoma is available at: http://www.fda.gov/CompanionDiagnostics.

Renal Dose Adjustments

• Mild or moderate renal dysfunction (CrCl 30 to 89 mL/min): 100 mg orally once a day for 21 days on 7 days off of a 28-day cycle
• Severe renal dysfunction (CrCl 15 to less than 30 mL/min): Data not available

Liver Dose Adjustments

• Mild liver dysfunction (total bilirubin greater than the upper limit of normal [ULN] to 1.5 × ULN or AST greater than ULN ): 100 mg orally once a day for 21 days on 7 days off of a 28-day cycle
• Moderate liver dysfunction (total bilirubin greater than 1.5 to 3 × ULN with any AST): 75 mg orally once a day for 21 days on 7 days off of a 28-day cycle
• Severe liver dysfunction (total bilirubin greater than 3 × ULN with any AST): Not established

Dose Adjustments

Dose Reduction for Adverse Reactions:

• First dose reduction: 100 orally once a day
• Second dose reduction: 75 mg orally once a day
• Third dose reduction: 50 mg orally once a day

Dose Modification for Adverse Reactions:
Retinal Pigment Epithelial Detachment (RPED):

• Continue treatment at the current dose and continue periodic ophthalmic evaluation.
• If resolved within 14 days, continue treatment at the current dose.
• If unresolved within 14 days, withhold treatment until resolved; then resume at previous dose or at a lower dose.

Hyperphosphatemia:
If serum phosphate greater than 5.5 to 7.5 or less mg/dL:

• Continue treatment at the current dose and start or adjust the phosphate binder dose according to clinical practice.
• Monitor serum phosphate weekly.
• Phosphate binder dosing should be held during the week off therapy each cycle (Days 22-28) and during dose interruptions for non-hyperphosphatemia adverse events.
• If serum phosphate greater than 7.5 mg/dL or single phosphate greater than 9 mg/dL independent of duration of dose of the phosphate lowering therapy:
• Withhold treatment until level returns to serum phosphate of 5.5 mg/dL or less.
• If serum phosphate greater than 7.5 mg/dL occurred for less than 7 days: Restart treatment at the same dose with maximal phosphate binder dosing.
• If serum phosphate greater than 7.5 mg/dL for greater than 7 days or if patient had a one-time serum phosphate of greater than 9 mg/dL: Resume treatment at the next lower dose level with maximal phosphate binder dosing.
• Serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis): Permanently discontinue treatment.

Other Adverse Reactions:

• Grade 3: Withhold dose until resolved to Grade 1 or less, then resume at the next lower dose level. If not resolved within 14 days or less, permanently discontinue treatment.
• Grade 4: Permanently discontinue treatment.

Dosage Modification for Concomitant Use of Gastric Acid Reducing Agents:

• It is recommended to avoid the coadministration of a proton pump inhibitor (PPI), a histamine-2 (H2) receptor antagonist, or a locally-acting antacid.
• If H2-antagonist coadministration cannot be avoided it is recommended to separate the administration of this drug by 2 hours before or 10 hours after.
• If locally-acting antacid coadministration cannot be avoided it is recommended to separate the administration of this drug by 2 hours before or 2 hours after.

Administration advice:

• Take on an empty stomach at least 1 hour before or 2 hours after food.
• Swallow capsules whole with water.
• Do not crush, chew, or dissolve capsules.
• Advise the patient to read the FDA-approved patient labeling (Patient Information).
• Advise lactating women not to breastfeed during therapy and for at least 1 month after the last dose.
• Advise females of reproductive potential to use effective contraception during treatment with and for at least 1 month after the last dose.
• Advise males that are partnered with females of reproductive potential to use effective contraception during treatment with and for at least 1 month after the last dose.
• Advise patients that if a dose is missed and it has passed 4 hours or more or if vomiting, skip the dose and take the next scheduled dose at its regular time.
• Advise patients that this drug may cause nail disorders.
• Advise patients that this drug may cause ocular toxicity and to immediately inform their healthcare provider if they experience any visual changes.
• Advise patients to use artificial tear substitutes or hydrating or lubricating eye gels to prevent or treat dry eyes.
• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products.
• Advise patients that this drug may cause hyperphosphatemia and soft tissue mineralization and to immediately inform their healthcare provider of any symptoms related to acute changes in phosphate levels such as muscle cramps, numbness, or tingling around the mouth.
• Advise patients to avoid grapefruit products during treatment.

Side Effects

The Most Common

• diarrhea
• nausea
• vomiting
• constipation
• loss of appetite
• changes in taste
• heartburn or indigestion
• stomach pain
• sores on the lips, mouth, or throat
• dry mouth and/or skin
• nail disorders
• hair loss
• headache
• fatigue
• swelling of hands, feet, legs or ankles
• pain in joints, arms, or legs
• nose bleeds
• blurred vision, floaters in the eye, seeing flashes of light, or other changes in vision
• muscle cramps, numbness, or tingling around the mouth
• fever, chills, or other signs of infection
• blistering and peeling skin

More common

• Blindness
• blurred vision
• confusion
• constipation
• decreased vision
• depression
• difficulty in breathing
• dry eye
• dry mouth
• eyelash changes
• headache
• incoherent speech
• increased urination
• irregular heartbeats
• loss of appetite
• metallic taste
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• muscle weakness
• nausea
• numbness and tingling around the mouth, fingertips, or feet
• redness, swelling, or itching of the eyelid
• redness, swelling, pain, or ulceration of the skin
• scaling of the skin on the hands and feet
• seizures
• stomach cramps
• thirst
• tingling of the hands and feet
• tremor
• unusual tiredness
• vomiting
• weight loss

Rare

• Chills
• cough or hoarseness
• dizziness, lightheadedness, or fainting
• dry mouth
• fast heartbeat
• fever or chills
• lower back or side pain
• painful or difficult urination
• rapid, shallow breathing
• Acid or sour stomach
• belching
• bloody nose
• change in taste
• decreased weight
• diarrhea
• difficulty in moving
• dry skin
• hair loss, thinning of hair
• heartburn
• indigestion
• lack or loss strength
• loss of taste
• muscle pain or stiffness
• pain in the arms or legs
• pain in the joints
• redness or soreness around the fingernails or loosening of the fingernails
• stomach discomfort, upset, or pain
• swelling of the hands, ankles, feet, or lower legs
• swelling or inflammation of the mouth

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings in animal studies and its mechanism of action TRUSELTIQ can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (13.1)]. There are no available data on the use of TRUSELTIQ during pregnancy. Oral administration of infigratinib to pregnant animals during the period of organogenesis at maternal exposures below the human exposure at the clinical dose of 125 mg resulted in 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 infigratinib 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 in breastfed children from TRUSELTIQ, advise women not to breastfeed during treatment and for 1 month after the final dose.

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