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Infigratinib – Uses, Dosage, Side Effects, Interaction – Rxharun

Infigratinib – Uses, Dosage, Side Effects, Interaction

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.

Mechanism of Action

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that play a role in cell proliferation, differentiation, migration, survival, and angiogenesis. Upon binding of extracellular signals, primarily fibroblast growth factors, FGFR dimerizes to promote the phosphorylation of downstream molecules and activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. In some cancers, the FGFR signaling pathway is aberrant and disrupted, leading to unregulated cell proliferation and growth, including malignant cells. Alterations in the FGFR receptors, including mutations, amplifications, and fusions, are associated with a wide array of neoplasms, including prostate, urothelial, ovarian, breast, and liver cancer. In particular, FGFR2 fusion is closely related to intrahepatic cholangiocarcinoma: recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in FGFR2 fusion proteins. Alterations in FGFR in tumors can lead to constitutive FGFR signaling, supporting the proliferation and survival of malignant cells. Infigratinib is a reversible, non-competitive inhibitor of all four FGFR subtypes – FGFR1, FGFR2, FGFR3, and FGFR4 – that blocks FGFR signaling and inhibits cell proliferation in cancer cell lines with activating FGFR amplification, mutations, or fusions. Out of the four FGFR subtypes, infigratinib has the highest affinity for FGFR1, FGFR2, and FGFR3. Infigratinib binds to the allosteric site between the two kinase lobes of the FGFR – or more specifically, to the ATP-binding cleft. Binding to this cleft prevents autophosphorylation of the receptor and blocks downstream signaling cascades that would otherwise activate MAPK.

Infigratinib is an anti-tumour agent that works to suppress tumour growth in cholangiocarcinoma. It exhibits anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR2 or FGFR3 alterations, such as FGFR2-TTC28 or FGFR2-TRA2B fusions. In clinical trials, patients with cholangiocarcinoma who were treated with infigratinib had an overall response rate of 23% – where one patient had a complete response – and a duration of response of 5.5 months, with a range between 0.03 and 28.3 months. Some patients with cancers with FGFR mutations display intrinsic resistance to infigratinib, leading to negligible therapeutic efficacy: investigations are ongoing to target molecular pathways to combat drug resistance.

Indications

  • Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.
  • Treatment of cholangiocarcinoma
  • Treatment of achondroplasia
  • Infigratinib is an FGF receptor kinase inhibitor that is used in the treatment of unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma.
  • Infigratinib is an FGFR inhibitor used to treat locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) rearrangement.
  • Unresectable, locally advanced Cholangiocarcinomas
  • Unresectable, metastatic Cholangiocarcinomas

Use in Cancer

Infigratinib phosphate is approved to treat:

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

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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.

How should this medicine be used?

Infigratinib comes as a capsule to take by mouth. It is usually taken once daily on an empty stomach (at least 1 hour before or at least 2 hours after food) for the first 21 days of a 28-day cycle. The cycle may be repeated as recommended by your doctor. Take infigratinib 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 infigratinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with a glass of water; do not split, chew, dissolve, or open them.

If you vomit after taking infigratinib, 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 infigratinib.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Other uses for this medicine

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

What special precautions should I follow?

Before taking infigratinib,

  • tell your doctor and pharmacist if you are allergic to infigratinib, any other medications, or any of the ingredients in infigratinib capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: itraconazole (Sporanox, Tolsura); proton-pump inhibitors, such as lansoprazole (Prevacid), omeprazole (Prilosec), and pantoprazole (Protonix); and rifampin (Rifadin, Rimactane, in Rifamate). Many other medications may also interact with infigratinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • if you are taking antacids, such as aluminum hydroxide/magnesium hydroxide (Maalox), calcium carbonate (Tums), or calcium carbonate and magnesium (Rolaids), take infigratinib 2 hours before or 2 hours after you take the antacid. If you are taking H2 blockers, such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac), take infigratinib 2 hours before or 10 hours after you take the H2 blocker.
  • tell your doctor if you have vision or eye problems or if you have or ever had liver or kidney 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 month 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 infigratinib, call your doctor immediately. Infigratinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking infigratinib and for 1 month after your final dose.
  • you should know that this medication may cause dry eyes. Your doctor may tell you to use artificial tears or lubricant eye drops during your treatment with infigratinib.

References

Consumer Information – TrustArc The Leader in Privacy Management SoftwareLooking online for info on your child's health? Here are some tipsJanja Kristan - Chief Administrative Officer - AACI | LinkedIn
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