Infigratinib (Monograph)

Brand name: Truseltiq [Web]
Drug class: Antineoplastic Agents
Chemical name: 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl]-1-methylurea
Molecular formula: C₂₆H₃₁Cl₂N₇O₃•H₃PO₄
CAS number: 1310746-10-1

Medically reviewed by Drugs.com on Mar 15, 2024. Written by ASHP.

Introduction

Antineoplastic agent; small-molecule kinase inhibitor of fibroblast growth factor receptor (FGFR)1, FGFR 2, and FGFR3.

Uses for Infigratinib

Cholangiocarcinoma

Treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor (FGFR) 2 fusion or other rearrangement as detected by an FDA-approved test (designated an orphan drug by FDA for treatment of cholangiocarcinoma).

Accelerated approval based on overall response rate and median duration of response. Continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory studies.

Infigratinib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement prior to initiating therapy.

• Confirm pregnancy status prior to initiating therapy in females of reproductive potential.

• Perform comprehensive ophthalmic examination with optical coherence tomography prior to initiating therapy.

Patient Monitoring

• Perform comprehensive ophthalmic examinations with optical coherence tomography at 1 month, 3 months, and every 3 months thereafter during treatment.

• Monitor phosphate levels throughout treatment.

Administration

Oral Administration

Administer orally on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day.

Swallow capsules whole with a glass of water. Do not crush, chew, or dissolve.

If coadministration with histamine H₂ receptor antagonists is necessary, separate administration of infigratinib by 2 hours before or 10 hours after the H₂ receptor antagonist. If coadministration with an antacid is necessary, separate administration of infigratinib by 2 hours before or 2 hours after the antacid.

Dosage

Dosage of infigratinib phosphate is expressed in terms of infigratinib.

Adults

Cholangiocarcinoma

Oral

125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. Continue therapy until disease progression or unacceptable toxicity occurs.

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 dose of infigratinib as described in Table 1.

Recommended dosage modifications for ocular toxicity, hyperphosphatemia, and other adverse reactions are listed in Table 2.

Special Populations

Hepatic Impairment

Oral

Patients with mild hepatic impairment (total bilirubin >1–1.5 times the ULN or AST >ULN): Reduce dosage to 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Patients with moderate hepatic impairment (total bilirubin >1.5–3 times the ULN with any AST): Reduce dosage to 75 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Patients with severe hepatic impairment (total bilirubin >3 times the ULN with any AST): Dosage not established.

Renal Impairment

Oral

Patients with mild to moderate renal impairment (Cl_cr 30–89 mL/minute): Reduce dosage to 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Patients with severe renal impairment (Cl_cr <30 mL/minute) or those with end-stage renal disease receiving intermittent dialysis: Dosage not established.

Cautions for Infigratinib

Contraindications

• None.

Warnings/Precautions

Ocular Effects

Retinal Pigment Epithelial Detachment

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

Perform a comprehensive ophthalmic examination including optical coherence tomography prior to initiation of infigratinib, at 1 month, at 3 months, and then every 3 months thereafter during treatment. Refer patients for ophthalmic evaluation urgently for onset of visual symptoms, and follow up every 3 weeks until resolution or discontinuation of infigratinib. If RPED occurs, withhold infigratinib therapy as recommended (see Dosage Modification for Toxicity under Dosage and Administration).

Dry Eye

Dry eye symptoms also reported. Administer ocular demulcents as needed.

Hyperphosphatemia

Hyperphosphatemia reported.

Increased serum phosphate concentration is a consequence of inhibition of fibroblast growth factor receptor (FGFR). Median time to onset about 8 days (range 1–349 days).

Monitor serum phosphate concentrations during therapy. Initiate phosphate-lowering therapy if serum phosphate level >5.5 mg/dL. If serum phosphate level >7.5 mg/dL, withhold infigratinib and initiate phosphate-lowering therapy. Withhold therapy, reduce dosage, or permanently discontinue infigratinib based on duration and severity of hyperphosphatemia (see Dosage Modification for Toxicity under Dosage and Administration).

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm when administered to a pregnant woman. Malformations, fetal growth retardation, and embryofetal death demonstrated in animals. (See Females and Males of Reproductive Potential under Cautions.)

If used during pregnancy, apprise patient of the potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether infigratinib or its metabolites are distributed into human milk; effects on milk production or on nursing infant not known. Women should not breast-feed during therapy and for 1 month following the final dose.

Females and Males of Reproductive Potential

Can cause fetal harm. Verify pregnancy status before initiating therapy in females of reproductive potential. Effective contraception during therapy and for 1 month after the final dose is required for females of reproductive potential and males with female partners of reproductive potential.

Pediatric Use

Safety and efficacy not established in pediatric patients. In animal studies, decreased bone density/bone loss and tooth abnormalities (i.e., degeneration of enamel, loss of ameloblast layer) observed.

Geriatric Use

In clinical trials, 33% of patients receiving infigratinib were ≥65 years of age, and 10% were ≥75 years of age; no overall differences in safety or efficacy relative to younger adults.

Hepatic Impairment

Systemic exposure of infigratinib and its active metabolites increased by 47–62% in patients with mild hepatic impairment and by 99% in patients with moderate hepatic impairment. Effect of severe hepatic impairment not known.

Reduce dosage in patients with mild (total bilirubin >1–1.5 times the ULN or AST >ULN) or moderate (total bilirubin >1.5–3 times the ULN with any AST) hepatic impairment.

Dosage for severe (total bilirubin >3 times ULN with any AST) hepatic impairment not established.

Renal Impairment

Systemic exposure of infigratinib and its active metabolites increases by approximately 32–37% in patients with mild or moderate renal impairment. Effect of severe renal impairment or dialysis-dependent end-stage renal disease not known.

Reduce dosage for mild or moderate renal impairment (Cl_cr 30–89 mL/minute). Dosage for severe renal impairment (Cl_cr <30 mL/minute) or renal impairment requiring dialysis not established.

Common Adverse Effects

Most common (≥20%) adverse reactions include nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting.

Most common laboratory abnormalities (≥20%) include increased creatinine, increased phosphate, decreased phosphate, increased alkaline phosphatase, decreased hemoglobin, increased lipase, increased calcium, decreased lymphocytes, decreased sodium, increased triglycerides, increased ALT/AST, increased urate, decreased platelets, decreased leukocytes, decreased albumin, increased bilirubin, and decreased potassium.

Drug Interactions

Metabolized by CYP3A4. Does not inhibit or induce major CYP isoenzymes at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Strong or moderate CYP3A inducers: May decrease infigratinib plasma concentrations and reduce efficacy. Avoid concurrent use.

Strong or moderate CYP3A inhibitors: May increase infigratinib plasma concentrations and increase risk for toxicity. Avoid concurrent use.

Gastric Acid Reducing Agents

Avoid concurrent use with gastric acid reducing agents. If coadministration with a histamine H₂ receptor antagonist is necessary, separate administration of infigratinib by 2 hours before or 10 hours after the H₂ receptor antagonist. If coadministration with an antacid is necessary, separate administration of infigratinib by 2 hours before or after the antacid.

Specific Drugs and Foods

Infigratinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC increase more than proportionally across dose range of 5–150 mg. Steady state was achieved within 15 days; median time to peak plasma concentrations was 6 hours.

Food

After administration with a high-fat, high-calorie meal (800–1000 calories, approximately 50% of calories from fat), mean AUC of infigratinib increased by 80–120% and peak plasma concentration increased by 60–80%. The median time to maximum concentration increased from 4 to 6 hours.

After administration with a low-fat, low-calorie meal (approximately 330 calories, 20% of calories from fat), mean AUC of infigratinib increased by 70% and peak plasma concentration increased by 90%. The median time to maximum concentration did not change.

Distribution

Extent

Not known whether infigratinib is distributed into human milk.

Plasma Protein Binding

96.8%.

Elimination

Metabolism

Metabolized by CYP3A4 (about 94%) and flavin-containing monooxygenase 3 (FMO3) hepatic enzymes (6%).

Elimination Route

Eliminated primarily in feces (77%; 3.4% as unchanged drug) and urine (7.2%; 1.9% as unchanged drug).

Half-life

33.5 hours.

Special Populations

Clearance not affected by age (range 19–86 years), sex, race, or body weight (range 36.4–169 kg).

Stability

Storage

Oral

Capsules

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

Actions

• Inhibitor of fibroblast growth factor receptor (FGFR) 1, FGFR2, and FGFR3.

• FGFR signaling pathway involved in proliferation and processes critical to cell survival and tumor progression; aberrant expression of FGFR signaling implicated in pathogenesis of various solid tumors.

• Inhibited FGFR signaling and decreased cell proliferation in cancer cell lines with activating FGFR amplifications, mutations, or fusions.

• Serum phosphate concentration is a marker of FGFR inhibition.

• Exhibited anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including patient-derived xenograft models of cholangiocarcinoma that expressed FGFR2-TTC28 or FGFR2-TRA2B fusions.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).

• Advise patients that infigratinib may cause ocular toxicity, including retinal pigment epithelial detachment (RPED), 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. Inform patients that their healthcare provider will closely monitor for eye disorders with ophthalmic examinations.

• Inform patients that infigratinib may cause hyperphosphatemia and soft tissue mineralization and immediately inform their healthcare provider if any possible symptoms occur, such as muscle cramps, numbness, or tingling around the mouth.

• Advise patients that infigratinib may cause nail disorders.

• Instruct patients to take infigratinib on an empty stomach at least 1 hour before, or 2 hours after food, at approximately the same time each day.

• Instruct patients to swallow the capsules whole with a glass of water. Advise patients to not crush, chew, or dissolve capsules.

• Instruct patients that if a dose cannot be administered within 4 hours of the regularly scheduled time or if vomiting occurs, the dose should not be made up later that day. Dosing should resume at the usual time on the next day.

• Advise patients to avoid grapefruit products during treatment with infigratinib.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Inform females of the risk to a fetus and potential loss of pregnancy. Effective contraception is required for females of reproductive potential and for males with female partners of reproductive potential during treatment with infigratinib and for 1 month after the final dose. Advise patients not to breastfeed during treatment with infigratinib phosphate and for 1 month after the final dose.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Advise patients of other important precautionary information. (See Cautions.)

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.

Infigratinib is available through a specialty pharmacy network. Clinicians may consult the Truseltiq website at https://www.truseltiq.com or call 888-552-7434 for more information.

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