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Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including fms-like tyrosine kinase-3 (Flt-3).

Uses for Gilteritinib (Systemic)

Acute Myeloid Leukemia (AML)

For the treatment of adults with relapsed or refractory AML harboring Flt-3 mutation (designated an orphan drug by FDA for this use).

FDA-approved companion diagnostic test (e.g., LeukoStrat CDx Flt-3 mutation assay) required to confirm presence of Flt-3 mutation prior to initiation of therapy.

Safety and efficacy of gilteritinib in this use is based principally on the results of a phase 3, open-label, controlled trial in adults with relapsed or refractory AML with an internal tandem duplication (ITD) or a point mutation in the tyrosine kinase domain (TKD) of Flt-3 kinase.

The National Cancer Institute states there is no standard treatment regimen for relapsed or refractory AML; patients who are unable or unwilling to undergo intensive therapy may be candidates for reduced-intensity therapies, including gilteritinib.

Gilteritinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Confirm presence of the Flt-3 mutation (peripheral blood or bone marrow) by an FDA-approved companion diagnostic test prior to initiation of therapy with gilteritinib in patients with AML.

• Assess CBC counts and blood chemistries, including CK, prior to initiation of therapy.

• Perform ECG prior to initiation of therapy.

• Correct hypokalemia or hypomagnesemia prior to initiation of therapy.

• Confirm pregnancy status in females of reproductive potential within 7 days prior to initiation of gilteritinib therapy.

Patient Monitoring

• Correct hypokalemia or hypomagnesemia during gilteritinib therapy.

• Perform ECG prior to initiation of gilteritinib therapy, on days 8 and 15 of cycle 1, and prior to the start of the next 2 subsequent cycles.

• Monitor for signs and symptoms of pancreatitis.

• Monitor CBC counts and blood chemistries at least weekly for the first month of therapy, every other week for the following month of therapy, and then monthly thereafter.

• If the concomitant use of strong cytochrome P-450 (CYP) 3A inhibitors cannot be avoided, monitor patients more frequently for adverse effects of gilteritinib.

• If the concomitant use of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic cation transporter 1 (OCT1) substrates cannot be avoided, monitor patients more frequently for adverse effects of these substrates.

Dispensing and Administration Precautions

• Handling and Disposal: Intact gilteritinib tablets can be handled without gloves; however, if the tablets are accidentally broken or crushed, chemically resistant protective gloves should be worn.

• Based on the Institute of Safe Medication Practices (ISMP), gilteritinib is a high-alert medication that has a heightened risk of causing significant patient harm.

Administration

Oral Administration

Administer orally once daily without regard to meals. Take at approximately the same time each day.

Swallow tablets whole with water; do not chew, crush, or break.

If a dose of gilteritinib is missed by ≤12 hours, take the prescribed dose as soon as possible and take the next dose at the regularly scheduled time on the following day. If a dose is missed by >12 hours, administer prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose. Do not take 2 doses within a 12-hour period.

Dosage

Available as gilteritinib fumarate; dosage expressed in terms of gilteritinib.

Adults

AML

Oral

120 mg once daily. Continue therapy for ≥6 months to allow time for response or until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Differentiation Syndrome

If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptoms resolve and for a minimum of 3 days.

Interrupt treatment with gilteritinib if severe signs and/or symptoms continue for >48 hours after initiation of corticosteroids. Resume gilteritinib when signs and symptoms improve to grade 2 (i.e., moderate) or lower.

Posterior Reversible Encephalopathy Syndrome

If posterior reversible encephalopathy syndrome occurs, discontinue therapy.

Prolongation of QT Interval

If corrected QT (QT_c) interval >500 msec occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when QT_c interval improves to ≤480 msec or ≤30 msec from baseline.

If QT_c interval increase of >30 msec from baseline on day 8 of cycle 1 occurs, confirm with ECG on day 9. If QT_c interval increase is confirmed on day 9, consider reduced dosage of 80 mg daily.

Pancreatitis

If pancreatitis occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when pancreatitis resolves.

Other Toxicity

If other grade 3 or 4 adverse reaction occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when toxicity improves to grade 1 or less.

Special Populations

Geriatric Patients

No specific dosage recommendations at this time.

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Contraindications

• Hypersensitivity to gilteritinib or any ingredient in the formulation.

Warnings/Precautions

Warnings

Differentiation Syndrome

Boxed warning regarding the risks of differentiation syndrome, which can be fatal or life-threatening if untreated. In clinical trials, 3% of patients experienced differentiation syndrome; 82% recovered after treatment or dose interruption of gilteritinib. If differentiation syndrome suspected, initiate corticosteroid therapy with dexamethasone 10 mg IV every 12 hours (or equivalent dose of alternative oral or IV corticosteroid) and hemodynamic monitoring until symptom resolution. Following symptom resolution, taper corticosteroids and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur if corticosteroid treatment is prematurely discontinued. If severe signs and/or symptoms continue for more than 48 hours after corticosteroid initiation, interrupt gilteritinib until signs and symptoms are no longer severe.

Other Warnings/Precautions

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome reported rarely; may manifest as seizure and altered mental status. Brain imaging, preferably MRI, necessary to confirm diagnosis. Manifestations may resolve following discontinuance of therapy. If posterior reversible encephalopathy syndrome occurs, discontinue gilteritinib.

Prolongation of QT Interval

QT_c interval prolongation reported.

Monitor ECG prior to initiation of gilteritinib, on days 8 and 15 of cycle 1, and prior to initiation of cycles 2 and 3.

Monitor serum electrolytes (e.g., potassium, magnesium) prior to initiation of gilteritinib therapy and at least weekly for the first month of therapy, every other week for the following month of therapy, and then monthly thereafter. Correct hypokalemia and hypomagnesemia prior to initiation of and during gilteritinib therapy.

If QT_c interval prolongation occurs, temporary interruption and/or dosage reduction of gilteritinib may be necessary.

Pancreatitis

Pancreatitis reported in 4% of patients in clinical trials. Evaluate patients who develop manifestations of pancreatitis (e.g., severe and persistent abdominal pain, which may be accompanied by nausea or vomiting). If pancreatitis occurs, temporary interruption followed by dosage reduction may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryofetal toxicity and teratogenicity demonstrated in animals.

Placental transfer of gilteritinib observed in rats.

Confirm pregnancy status within 7 days prior to initiating gilteritinib therapy. Avoid pregnancy during therapy. Advise females of reproductive potential to use effective methods of contraception while receiving the drug and for ≥6 months after the drug is discontinued. Advise male patients who are partners of such females to use effective methods of contraception while receiving the drug and for ≥4 months after drug is discontinued. If used during pregnancy, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Confirm pregnancy status within 7 days prior to initiating gilteritinib therapy.

Lactation

Gilteritinib and/or its metabolite(s) distribute into milk in rats. Not known whether the drug or its metabolites distribute into human milk or if drug affects milk production or the nursing infant. Advise patients not to breast-feed during therapy and for ≥2 months following drug discontinuance.

Females and Males of Reproductive Potential

Effect on fertility in humans is unknown; based on animal studies, may impair male fertility . Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of gilteritinib. Advise males of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of gilteritinib.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical trials in patients with relapsed or refractory AML, no overall differences observed in safety and efficacy relative to younger adults.

Hepatic Impairment

In a hepatic impairment study, systemic exposure of unbound gilteritinib not altered by mild or moderate hepatic impairment (Child-Pugh class A or B) in noncancer patients.

Effects of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not established.

Renal Impairment

In a population pharmacokinetic analysis, systemic exposure not substantially altered by changes in S_cr concentrations in patients with relapsed or refractory AML.

Mild or moderate renal impairment (Cl_cr 30–80 mL/minute) not expected to have clinically important effects on systemic exposure of the drug.

Effects of severe renal impairment (Cl_cr ≤29 mL/minute) on pharmacokinetics not established.

Common Adverse Effects

Adverse effects occurring in ≥20% of patients with relapsed or refractory AML receiving gilteritinib include increased transaminase, myalgia/arthralgia, fatigue/malaise, fever, mucositis, edema, rash, noninfectious diarrhea, dyspnea, nausea, cough, constipation, eye disorders, headache, dizziness, hypotension, vomiting, and renal impairment.

General

Pretreatment Screening

• Confirm presence of the Flt-3 mutation (peripheral blood or bone marrow) by an FDA-approved companion diagnostic test prior to initiation of therapy with gilteritinib in patients with AML.

• Assess CBC counts and blood chemistries, including CK, prior to initiation of therapy.

• Perform ECG prior to initiation of therapy.

• Correct hypokalemia or hypomagnesemia prior to initiation of therapy.

• Confirm pregnancy status in females of reproductive potential within 7 days prior to initiation of gilteritinib therapy.

Patient Monitoring

• Correct hypokalemia or hypomagnesemia during gilteritinib therapy.

• Perform ECG prior to initiation of gilteritinib therapy, on days 8 and 15 of cycle 1, and prior to the start of the next 2 subsequent cycles.

• Monitor for signs and symptoms of pancreatitis.

• Monitor CBC counts and blood chemistries at least weekly for the first month of therapy, every other week for the following month of therapy, and then monthly thereafter.

• If the concomitant use of strong cytochrome P-450 (CYP) 3A inhibitors cannot be avoided, monitor patients more frequently for adverse effects of gilteritinib.

• If the concomitant use of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic cation transporter 1 (OCT1) substrates cannot be avoided, monitor patients more frequently for adverse effects of these substrates.

Dispensing and Administration Precautions

• Handling and Disposal: Intact gilteritinib tablets can be handled without gloves; however, if the tablets are accidentally broken or crushed, chemically resistant protective gloves should be worn.

• Based on the Institute of Safe Medication Practices (ISMP), gilteritinib is a high-alert medication that has a heightened risk of causing significant patient harm.

Administration

Oral Administration

Administer orally once daily without regard to meals. Take at approximately the same time each day.

Swallow tablets whole with water; do not chew, crush, or break.

If a dose of gilteritinib is missed by ≤12 hours, take the prescribed dose as soon as possible and take the next dose at the regularly scheduled time on the following day. If a dose is missed by >12 hours, administer prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose. Do not take 2 doses within a 12-hour period.

Dosage

Available as gilteritinib fumarate; dosage expressed in terms of gilteritinib.

Adults

AML

Oral

120 mg once daily. Continue therapy for ≥6 months to allow time for response or until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Differentiation Syndrome

If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptoms resolve and for a minimum of 3 days.

Interrupt treatment with gilteritinib if severe signs and/or symptoms continue for >48 hours after initiation of corticosteroids. Resume gilteritinib when signs and symptoms improve to grade 2 (i.e., moderate) or lower.

Posterior Reversible Encephalopathy Syndrome

If posterior reversible encephalopathy syndrome occurs, discontinue therapy.

Prolongation of QT Interval

If corrected QT (QT_c) interval >500 msec occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when QT_c interval improves to ≤480 msec or ≤30 msec from baseline.

If QT_c interval increase of >30 msec from baseline on day 8 of cycle 1 occurs, confirm with ECG on day 9. If QT_c interval increase is confirmed on day 9, consider reduced dosage of 80 mg daily.

Pancreatitis

If pancreatitis occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when pancreatitis resolves.

Other Toxicity

If other grade 3 or 4 adverse reaction occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when toxicity improves to grade 1 or less.

Special Populations

Geriatric Patients

No specific dosage recommendations at this time.

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Principally metabolized by CYP3A4.

Weak inhibitor of CYP3A4.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Potent inhibitor of multidrug and toxin extrusion (MATE) transporter 1 and organic cation transporter (OCT) 2; inhibits BCRP, P-gp, and OCT 1.

Drugs Affecting Hepatic Microsomal Enzymes and/or Efflux Transport Systems

Potent CYP3A inhibitors: Possible increased gilteritinib exposure. Avoid concomitant use; consider alternative agent with less CYP3A inhibition potential. If concomitant use cannot be avoided, monitor frequently for signs of toxicity; may need to interrupt therapy and reduce dosage if serious or life-threatening adverse effects occur.

Combined P-gp and potent CYP3A inducers: Possible decreased gilteritinib exposure and reduced gilteritinib efficacy. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: Possible increased exposure of the CYP3A substrate.

Drugs Affected by Multidrug and Toxin Extrusion Transporter

MATE1 substrates: Possible decreased exposure of the MATE1 substrate.

Drugs that Interact with Serotonin Type 2B Receptor or Nonspecific σ-receptors

Possible pharmacokinetic interaction (reduced efficacy of drugs that bind to 5-HT_2B or nonspecific σ-receptors). Avoid concomitant use unless such use is necessary.

Substrates of P-gp, BCRP, and OCT1

Coadministration of gilteritinib may increase exposure of P-gp, BCRP, and OCT1 substrates. For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of substrate and monitor for adverse reactions as recommended in the respective prescribing information.

Specific Drugs