Gilteritinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as fumarate:

Xospata: 40 mg

Pharmacology

Mechanism of Action

Gilteritinib is a tyrosine kinase inhibitor which inhibits multiple tyrosine kinases, such as FMS-like tyrosine kinase 3 (FLT3). Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells expressing FLT3 (including FLT3-ITD), tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y; it induces apoptosis in FLT3-ITD-expressing leukemia cells.

Pharmacokinetics/Pharmacodynamics

Distribution

Central: 1,092 L; Peripheral: 1,100 L

Metabolism

Primarily hepatic via CYP3A4; primary human metabolites include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N-dealkylation), none of which exceed 10% of overall parent exposure

Excretion

Feces: 64.5%; Urine: 16.4% as unchanged drug and metabolites

Onset of Action

Inhibition of FLT3 phosphorylation: Rapid (within 24 hours after the initial dose)

Time to Peak

~4 to 6 hours

Half-Life Elimination

113 hours

Protein Binding

~94% to human plasma proteins

Use: Labeled Indications

Acute myeloid leukemia, relapsed or refractory: Treatment of relapsed or refractory acute myeloid leukemia (AML) in adult patients with an FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an approved test.

Contraindications

Hypersensitivity to gilteritinib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Acute myeloid leukemia, relapsed or refractory, FLT3-positive: Oral: 120 mg once daily for a minimum of 6 months (to allow time for a clinical response) or until disease progression or unacceptable toxicity.

Missed doses: If a dose is missed, administer the missed dose as soon as possible on the same day (and at least 12 hours prior to the next scheduled dose). Return to the normal dosing schedule the following day; do not administer 2 doses within 12 hours.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Differentiation syndrome: If differentiation syndrome is suspected, administer systemic corticosteroids (dexamethasone 10 mg IV every 12 hours [or equivalent oral/IV corticosteroid]) for a minimum of 3 days and initiate hemodynamic monitoring until symptom resolution, and then taper corticosteroid. Interrupt gilteritinib therapy if severe signs/symptoms of differentiation syndrome continue for more than 48 hours after corticosteroid initiation. Resume gilteritinib when signs/symptoms improve to ≤ grade 2 (mild to moderate symptoms).

Pancreatitis: Interrupt gilteritinib; when pancreatitis is resolved, resume therapy at a reduced dose of 80 mg once daily.

Posterior reversible encephalopathy syndrome: Discontinue gilteritinib.

QTc interval prolongation:

QTc interval >500 msec: Interrupt gilteritinib; when QTc interval returns to within 30 msec of baseline or ≤480 msec, resume therapy at a reduced dose of 80 mg once daily.

QTc interval increased by >30 msec on ECG on day 8 of cycle 1: Confirm with a repeat ECG on day 9. If confirmed, consider dose reduction to 80 mg once daily.

Other toxicity: ≥ Grade 3 toxicity (considered related to treatment): Interrupt gilteritinib; when toxicity resolves or improves to grade 1, resume therapy at a reduced dose of 80 mg once daily.

Administration

Oral: Administer with or without food at approximately the same time each day. Do not break or crush the tablets.

Storage

Store at 20ºC to 25ºC (68°F to 77°F); excursions permitted between 15ºC to 30ºC (59°F to 86°F). Store in original container until dispensed. Protect from light, moisture, and humidity.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Citalopram: May enhance the QTc-prolonging effect of Gilteritinib. Gilteritinib may diminish the therapeutic effect of Citalopram. Management: Avoid use of this combination if possible. If use is necessary, monitor for reduced response to citalopram and for QTc prolongation and arrhythmias. Patients with other risk factors may be at greater risk for these serious toxicities. Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Combined Inducers of CYP3A4 and P-glycoprotein: May decrease the serum concentration of Gilteritinib. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of a strong CYP3A4 inhibitor with gilteritinib. If the combination cannot be avoided, monitor more closely for evidence of gilteritinib toxicities. Exceptions: Ceritinib; Clarithromycin; Saquinavir; Voriconazole. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Doxepin-Containing Products: May enhance the QTc-prolonging effect of Gilteritinib. Management: Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these potentially life-threatening toxicities. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Escitalopram: May enhance the QTc-prolonging effect of Gilteritinib. Gilteritinib may diminish the therapeutic effect of Escitalopram. Management: Avoid use of this combination if possible. If use is necessary, monitor for reduced response to escitalopram and for QTc prolongation and arrhythmias. Patients with other risk factors may be at greater risk for these serious toxicities. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Haloperidol: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Avoid combination

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Avoid combination

QT-prolonging Agents (Highest Risk): Gilteritinib may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Consider therapy modification

QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Domperidone. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk). Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Gilteritinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of gilteritinib with strong CYP3A4 inhibitors that prolong the QTc interval whenever possible Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: Gilteritinib may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Avoid use of this combination if possible. If the combination cannot be avoided, monitor closely for evidence of reduced response to the selective serotonin reuptake inhibitor. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (40%), hypotension (22%)

Central nervous system: Fatigue (≤44%), malaise (≤44%), headache (24%), dizziness (22%), neuropathy (18%), insomnia (15%)

Dermatologic: Skin rash (36%)

Endocrine & metabolic: Decreased serum phosphate (grades 3/4: 14%), decreased serum sodium (grades 3/4: 12%)

Gastrointestinal: Stomatitis (41%; grades ≥3: 7%), diarrhea (35%), nausea (30%), constipation (28%), vomiting (21%), abdominal pain (18%), decreased appetite (15%), dysgeusia (11%)

Hematologic & oncologic: Febrile neutropenia (17% to 27%; grade ≥3: 17% to 26%)

Hepatic: Increased serum transaminases (51%), increased serum alanine aminotransferase (grade 3/4: 13%)

Neuromuscular & skeletal: Arthralgia (≤50%), myalgia (≤50%)

Ophthalmic: Eye disease (25%)

Renal: Renal insufficiency (21%)

Respiratory: Dyspnea (35%), cough (28%)

Miscellaneous: Fever (41%)

1% to 10%:

Cardiovascular: Prolonged QT interval on ECG (1% to 10%), increased serum creatine kinase (grades 3/4: 6%), cardiac failure (4%), pericardial effusion (4%), myocarditis (≤2%), pericarditis (≤2%)

Central nervous system: Reversible posterior leukoencephalopathy syndrome (1%)

Dermatologic: Dermatologic disorder (acute febrile neutrophilic dermatosis: 3%)

Endocrine & metabolic: Decreased serum calcium (grades 3/4: 6%), increased serum triglycerides (grades 3/4: 6%)

Gastrointestinal: Pancreatitis (4%), gastrointestinal perforation (1%)

Hematologic & oncologic: Differentiation syndrome (3%)

Hepatic: Increased serum aspartate aminotransferase (grades 3/4: 10%), increased serum alkaline phosphatase (grades 3/4: 2%)

Hypersensitivity: Hypersensitivity condition (8%)

Renal: Increased serum creatinine (grades 3/4: 3%)

Frequency not defined:

Hypersensitivity: Anaphylaxis, angioedema, drug-induced hypersensitivity reaction

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: [US Boxed Warning]: Patients treated with gilteritinib have experienced symptoms of differentiation syndrome (rapid proliferation and differentiation of myeloid cells), which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. Concomitant acute febrile neutrophilic dermatosis has been observed in some cases. The onset of differentiation syndrome (with or without concomitant leukocytosis) ranged from 2 to 75 days after gilteritinib initiation; the majority of patients who experienced this syndrome recovered after treatment or therapy interruption. If differentiation syndrome is suspected, administer dexamethasone 10 mg IV every 12 hours (or equivalent oral/IV corticosteroid) and monitor hemodynamics until improvement. Administer corticosteroids for a minimum of 3 days; once symptoms resolve, taper corticosteroid. Differentiation syndrome symptoms may recur if corticosteroids are discontinued early. If severe signs/symptoms of differentiation syndrome continue for more than 48 hours after corticosteroid initiation, interrupt gilteritinib therapy until symptoms are no longer severe.
• Gastrointestinal toxicity: Diarrhea (non-infectious), constipation, nausea, vomiting, and stomatitis may occur (usually mild).
• Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions, have been observed.
• Pancreatitis: Pancreatitis has been reported. Evaluate for signs/symptoms of pancreatitis. May require therapy interruption and dosage reduction.
• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported rarely. Symptoms included seizure and altered mental status, and have resolved after gilteritinib discontinuation. Magnetic resonance imaging (MRI) is the preferred diagnostic brain imaging; discontinue gilteritinib in patients who develop confirmed PRES.
• QTc interval prolongation: Prolonged cardiac ventricular repolarization (QT interval) has been reported with gilteritinib. A small percentage of patients in a clinical trial were found to have a QTc interval >500 msec; some patients had an increase from baseline >60 msec. Obtain an ECG prior to therapy initiation, on days 8 and 15 of cycle 1, and prior to the start of the next 2 subsequent treatment cycles. Hypokalemia and/or hypomagnesemia may increase the risk for QTc interval prolongation; correct electrolyte abnormalities prior to (and during) gilteritinib therapy. QTc interval prolongation may require therapy interruption and dosage reduction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• FLT3 mutation positivity: In the treatment of acute myeloid leukemia, gilteritinib is approved for use only in patients who are FLT3 mutation-positive in the blood or bone marrow (as detected by an approved test). Information on approved tests may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

Blood counts and serum chemistries (including creatine phosphokinase) prior to therapy initiation, at least once weekly for the first month, once every other week for the second month, and once monthly thereafter; ECG prior to therapy initiation, on days 8 and 15 of cycle 1, and prior to the start of the next 2 subsequent cycles; pregnancy test (within 7 days prior to starting gilteritinib treatment in females of reproductive potential). Monitor for signs/symptoms of differentiation syndrome, pancreatitis, and posterior reversible encephalopathy syndrome. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and information from animal reproductions studies, gilteritinib may cause fetal harm following maternal use during pregnancy.

Pregnancy status should be evaluated within 7 days prior to starting therapy in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last gilteritinib dose. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 4 months after the last gilteritinib dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, nausea, vomiting, diarrhea, back pain, muscle pain, joint pain, neck pain, loss of strength and energy, constipation, mouth irritation, mouth sores, change in taste, abdominal pain, lack of appetite, or difficulty sleeping. Have patient report immediately to prescriber bone pain, cough, shortness of breath, difficulty breathing, sudden weight gain, swelling of arms or legs, swollen glands, signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), fast heartbeat, abnormal heartbeat, dizziness, passing out, vision changes, eye pain, severe eye irritation, burning or numbness feeling, fast breathing, edema, skin irritation, or redness or irritation of palms or soles of feet (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.