Version May 2024
Cholangiocarcinoma, unresectable, locally advanced or metastatic (with fibroblast growth factor receptor 2 [ FGFR2 ] gene fusion/rearrangement): Oral: 125 mg once daily for 21 consecutive days, followed by 7 days off therapy (28-day cycles), continue until disease progression or unacceptable toxicity (Ref).
Note: Infigratinib received approval under the FDA Accelerated Approval Program in May 2021 for the treatment of adult patients with unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. The manufacturer was unable to recruit/enroll study subjects for the confirmatory study to fulfill the FDA postmarketing requirement and has voluntarily withdrawn infigratinib from the market; the decision is not based on efficacy or safety.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Missed or vomited doses: If a dose is missed by ≥4 hours or if vomiting occurs, resume the regular infigratinib daily dose schedule the next day.
Note: CrCl estimated by Cockcroft-Gault equation.
CrCl 30 to 89 mL/minute: 100 mg once daily for 21 consecutive days, followed by 7 days off therapy (28-day cycles).
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been established).
End stage renal disease receiving intermittent hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been established).
Mild impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN): 100 mg once daily for 21 consecutive days, followed by 7 days off therapy (28-day cycles).
Moderate impairment (total bilirubin >1.5 to 3 times ULN with any AST): 75 mg once daily for 21 consecutive days, followed by 7 days off therapy (28-day cycles).
Severe impairment (total bilirubin >3 times ULN with any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been established).
|
Dose reduction level |
Infigratinib dose |
|---|---|
|
Usual dose |
125 mg on days 1 to 21 of a 28-day cycle |
|
First dose reduction |
100 mg on days 1 to 21 of a 28-day cycle |
|
Second dose reduction |
75 mg on days 1 to 21 of a 28-day cycle |
|
Third dose reduction |
50 mg on days 1 to 21 of a 28-day cycle |
|
Adverse reaction |
Severity |
Infigratinib dose modification |
|---|---|---|
|
Hyperphosphatemia |
Serum phosphate >5.5 to ≤7.5 mg/dL |
Continue infigratinib at the current dose and initiate or dose adjust phosphate binder (refer to phosphate binder monograph for dosing details). Monitor serum phosphate weekly. Note: Withhold phosphate binder dosing during the week off infigratinib each cycle (days 22 to 28) and during infigratinib dose interruptions for adverse events other than hyperphosphatemia. |
|
Serum phosphate >7.5 mg/dL or single serum phosphate >9 mg/dL regardless of phosphate-lowering therapy duration or dose |
Withhold infigratinib until serum phosphate level returns to ≤5.5 mg/dL. Resume infigratinib as below, with maximal phosphate binder dosing: If serum phosphate >7.5 mg/dL occurred for <7 days, then restart infigratinib at the same dose. If serum phosphate >7.5 mg/dL for >7 days or if a single (one-time) serum phosphate of >9 mg/dL occurred, resume infigratinib at the next lower dose level. | |
|
Serum phosphate with life-threatening consequences; urgent intervention (eg, dialysis) indicated |
Permanently discontinue infigratinib. | |
|
Ocular toxicity |
Retinal pigment epithelial detachment |
Continue infigratinib at the current dose and continue periodic ophthalmic evaluation. If resolving within 14 days, continue infigratinib at the current dose. If not resolving within 14 days, withhold infigratinib until resolving; then resume infigratinib at previous dose or at a lower dose. |
|
Dry eyes |
Manage with ocular demulcents as needed. | |
|
Other adverse reactions |
Grade 3 |
Withhold infigratinib until resolved to ≤ grade 1, then resume infigratinib at the next lower dose level. If not resolved within ≤14 days, permanently discontinue infigratinib. |
|
Grade 4 |
Permanently discontinue infigratinib. |
Refer to adult dosing.
Infigratinib can cause hyperphosphatemia, leading to soft tissue mineralization, cutaneous calcification, nonuremic calciphylaxis, vascular calcification, and myocardial calcification. In clinical trials, 83% of patients required phosphate-binder therapy.
Mechanism: Dose-related; related to the pharmacologic action. Infigratinib inhibits fibroblast growth factor receptor signaling in the proximal tubule, resulting in increased serum phosphate concentrations (Ref).
Onset: Varied; median time to onset is 8 days (range: 1 to 349 days).
Dry eye syndrome (some necessitating treatment with ophthalmic lubricant) has commonly occurred. Retinal pigment epithelial detachment (RPED) has frequently occurred as well as other ophthalmic disorders, including blurred vision, cataract, increased lacrimation, keratitis, and punctate keratitis.
Mechanism: Dose-related; related to the pharmacologic action. Infigratinib causes subretinal fluid accumulation potentially due to fibroblast growth factor receptor inhibition and the consequential inhibition of the mitogen-activating protein kinase pathway, resulting in dysregulation of the outer retinal barrier or functions of the retinal pigment epithelium (Ref).
Onset: Delayed; median time to first onset of RPED was 26 days in clinical trials; various ocular toxicities in a small prospective open-label trial occurred within 2 months (Ref); resolution or improvement of ocular toxicities can occur after dose adjustments of cessation of therapy (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (17%, including peripheral edema)
Dermatologic: Alopecia (38%), nail disease (57%, including ingrown nail, nail bed changes, nail discoloration, onycholysis, onychomadesis, onychomycosis, paronychia), palmar-plantar erythrodysesthesia (21%) (Lacouture 2021), xeroderma (23%)
Endocrine & metabolic: Decreased serum albumin (24%), decreased serum phosphate (64%), decreased serum potassium (21%), decreased serum sodium (41%), hyperphosphatemia (82%; grades 3/4: 13%), hyperuricemia (37%), increased serum cholesterol (18%), increased serum potassium (17%), increased serum triglycerides (38%), weight loss (15%)
Gastrointestinal: Abdominal pain (26%), constipation (30%), decreased appetite (22%), diarrhea (24%), dysgeusia (32%), dyspepsia (17%), increased serum lipase (44%), nausea (19%), stomatitis (56%; grade 3/4: 15%), vomiting (21%), xerostomia (25%)
Hematologic & oncologic: Decreased neutrophils (14%; grade 3/4: 2%), decreased platelet count (37%; grade 3/4: 4%), leukopenia (26%; grade 3/4: 3%), lymphocytopenia (43%; grade 3/4: 9%)
Hepatic: Increased serum alanine aminotransferase (51%), increased serum alkaline phosphatase (54%), increased serum aspartate aminotransferase (38%), increased serum bilirubin (24%)
Nervous system: Fatigue (44%), headache (17%)
Neuromuscular & skeletal: Arthralgia (32%), limb pain (17%)
Ophthalmic: Abnormal eyelash growth (25%, including hyperpigmentation of eyelashes, hypertrichosis of eyelid, including increased eyelash growth, and increased eyelash thickness), blurred vision (21%), cataract (12%), dry eye syndrome (44%, including blepharitis, increased lacrimation, keratitis, and punctate keratitis), retinal pigment epithelium detachment (11%)
Renal: Increased serum creatinine (93%)
Respiratory: Epistaxis (18%)
Miscellaneous: Fever (15%)
1% to 10%:
Endocrine & metabolic: Decreased serum calcium (10%), hypercalcemia (≥2%)
Hematologic & oncologic: Anemia (≥2%)
Infection: Infection (≥2%), sepsis (≥2%)
Neuromuscular & skeletal: Bone fracture (1%)
Frequency not defined:
Cardiovascular: Vascular calcification (Lacouture 2021)
Dermatologic: Cutaneous calcification (Lacouture 2021)
Ophthalmic: Retinopathy (subretinal fluid)
There are no contraindications listed in the manufacturer's labeling.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• Fibroblast growth factor receptor 2 fusion/rearrangement: Select patients for treatment of unresectable locally advanced or metastatic cholangiocarcinoma with infigratinib based on the presence of a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. Information on approved tests may be found at http://www.fda.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Therapy Pack, Oral, as phosphate:
Truseltiq (100MG Daily Dose): 100 mg (21 ea [DSC])
Truseltiq (125MG Daily Dose): 100 & 25 MG (42 ea [DSC])
Truseltiq (50MG Daily Dose): 25 mg (42 ea [DSC])
Truseltiq (75MG Daily Dose): 25 mg (63 ea [DSC])
No
Capsule Therapy Pack (Truseltiq (100MG Daily Dose) Oral)
100 mg (per each): $1,290.00
Capsule Therapy Pack (Truseltiq (125MG Daily Dose) Oral)
100 & 25 mg (per each): $645.00
Capsule Therapy Pack (Truseltiq (50MG Daily Dose) Oral)
25 mg (per each): $645.00
Capsule Therapy Pack (Truseltiq (75MG Daily Dose) Oral)
25 mg (per each): $430.00
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Oral: Administer on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day. Swallow capsule whole with a glass of water; do not crush, chew, or dissolve capsules.
Acid-reducing agents: Avoid concomitant administration of infigratinib with proton pump inhibitors, and if possible, avoid concomitant administration of infigratinib with H2-receptor antagonists and locally-acting antacids. If coadministration cannot be avoided, administer infigratinib 2 hours before or 10 hours after an H2-receptor antagonist or administer infigratinib 2 hours before or 2 hours after locally-acting antacids.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Infigratinib may cause teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Cholangiocarcinoma, unresectable locally advanced or metastatic: Treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an approved test.
Note: Infigratinib received approval under the FDA Accelerated Approval Program in May 2021 for the treatment of adult patients with unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. The manufacturer was unable to recruit/enroll study subjects for the confirmatory study to fulfill the FDA postmarketing requirement and has voluntarily withdrawn infigratinib from the market; the decision is not based on efficacy or safety.
Infigratinib may be confused with erdafitinib, imatinib, infliximab, pemigatinib.
Truseltiq may be confused with Trulicity.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of BCRP/ABCG2, CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antacids: May decrease serum concentrations of the active metabolite(s) of Infigratinib. Antacids may decrease the serum concentration of Infigratinib. Management: Avoid coadministration of infigratinib with antacids or other gastric acid-lowering agents. If antacids cannot be avoided, administer infigratinib 2 hours before or after administration of antacids. Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Infigratinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Infigratinib. Risk X: Avoid combination
Erdafitinib: Serum Phosphate Level-Altering Agents may diminish the therapeutic effect of Erdafitinib. Management: Avoid coadministration of serum phosphate level-altering agents with erdafitinib before initial dose increase period based on serum phosphate levels (Days 14 to 21). Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Histamine H2 Receptor Antagonists: May decrease serum concentrations of the active metabolite(s) of Infigratinib. Histamine H2 Receptor Antagonists may decrease the serum concentration of Infigratinib. Management: Avoid coadministration of infigratinib with histamine receptor antagonists (H2RAs) or other gastric acid-lowering agents. If H2RAs cannot be avoided, administer infigratinib 2 hours before or 10 hours after administration of H2RAs. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease serum concentrations of the active metabolite(s) of Infigratinib. Inhibitors of the Proton Pump (PPIs and PCABs) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination
Following administration of infigratinib with a high-fat/high-calorie meal (800 to 1,000 calories with ~50% of calories from fat) in healthy subjects, the mean infigratinib AUCinf increased by 80% to 120%, Cmax increased by 60% to 80%, and the median Tmax shifted from 4 to 6 hours. Following administration of infigratinib with a low-fat/low-calorie meal (~330 calories with 20% of calories from fat), the mean infigratinib AUCinf increased by 70%, Cmax increased by 90%, and the median Tmax was unchanged. Management: Administer infigratinib on an empty stomach at least 1 hour before or 2 hours after food.
Verify pregnancy status prior to use in patients who may become pregnant.
Patients who may become pregnant should use effective contraception during therapy and for 1 month after the last infigratinib dose. Patients with partners who may become pregnant should also use effective contraception during therapy and for 1 month after the last infigratinib dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to infigratinib may cause fetal harm.
It is not known if infigratinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 1 month after the last infigratinib dose.
Assess for susceptible fibroblast growth factor receptor 2 (FGFR2) genetic alteration. Monitor serum phosphate level throughout treatment as clinically necessary (monitor weekly for serum phosphate >5.5 mg/dL). Evaluate pregnancy status prior to treatment initiation (in patients who may become pregnant). Perform a comprehensive ophthalmic exam (including optical coherence tomography) at baseline, at 1 month, at 3 months, and then every 3 months thereafter throughout treatment and as clinically necessary (if visual symptoms occur, refer patients for urgent ophthalmic evaluation and follow-up every 3 weeks until resolution or infigratinib is discontinued). Monitor for signs/symptoms of hyperphosphatemia, visual changes, and dry eyes. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Infigratinib is a selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor with activity against tumors harboring FGFR alterations (Javle 2018). Infigratinib inhibits FGFR signaling and decreases cell proliferation in cancer cell lines with activating FGFR amplifications, mutations, or fusions. Constitutive FGFR signaling can support malignant cell proliferation and survival.
Distribution: Vdss: 1,600 L.
Protein binding: 96.8%; primarily to lipoprotein.
Metabolism: Primarily via CYP3A4 (~94%) and to a lesser extent by FMO3 (6%). The major plasma moiety is unchanged infigratinib (38% of dose), followed by 2 active metabolites (BHS697 and CQM157; each at >10% of dose). BHS697 is primarily metabolized via CYP3A4 and contributes ~16% to 33% of overall pharmacologic activity. CQM157 is metabolized via phase I and II biotransformation pathways and contributes ~9% to 12% of overall pharmacologic activity.
Half-life elimination: 33.5 hours (at steady state).
Time to peak: 6 hours (at steady state).
Excretion: Feces (~77%; ~3% as unchanged drug); Urine (~7%; ~2% as unchanged drug).
Clearance: 33.1 L/hour (at steady state).
Altered kidney function: The relative potency adjusted steady state plasma AUC of infigratinib plus active metabolites BHS697 and CQM157 increased by 32% in patients with CrCl 60 to 89 mL/minute and by 37% in patients with CrCl 30 to 59 mL/min, compared to patients with CrCl ≥ 90 mL/minute.
Hepatic function impairment: The relative potency adjusted steady state plasma AUC of infigratinib plus active metabolites BHS697 and CQM157 increased by 47 to 62% in patients with mild impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN) and by 99% in patients with moderate impairment (total bilirubin >1.5 to 3 times ULN with any AST), compared to patients with normal hepatic function (total bilirubin ≤ ULN and AST ≤ ULN).
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