Gilteritinib – Uses, Dosage, Side Effects, Interaction

In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated, and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result _in vivo_ was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical? trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission? or complete remission with partial hematologic recovery in 21% of the patients.

Use in Cancer

Gilteritinib fumarate is approved to treat:

• Acute myeloid leukemia that has relapsed (come back) or is refractory (does not respond to treatment). It is used in adults whose cancer has a mutation in the FLT3 gene.

Gilteritinib fumarate is also being studied in the treatment of other types of cancer.

Contraindications

• Hypersensitivity to the active component or any of the ingredients
• Safety and efficacy have not been established in patients younger than 18 years.
• low amount of magnesium in the blood
• low amount of potassium in the blood
• prolonged QT interval on EKG
• abnormal EKG with QT changes from birth
• pregnancy
• a patient who is producing milk and breastfeeding
• pancreatitis?
• a type of brain disorder called posterior reversible encephalopathy syndrome?

Dosage?

Strengths: 40 mg

Acute Myeloid Leukemia

• 120 mg orally once a day until disease progression? or unacceptable toxicity
• The response may be delayed. In the absence of disease progression or unacceptable toxicity, patients should be treated for a minimum of 6 months to allow time for a clinical response.
• Select patients for the treatment of AML with this drug based on the presence of FLT3 mutations in the blood or bone marrow.

Dose Adjustments

DOSAGE MODIFICATIONS FOR TOXICITY:
DIFFERENTIATION SYNDROME:

• If differentiation syndrome is suspected, administer systemic? corticosteroids and initiate hemodynamic monitoring? until symptom resolution and for a minimum of 3 days.
• Interrupt therapy if severe? symptoms persist for more than 48 hours after initiation of corticosteroids.
• Resume therapy when symptoms improve to Grade 2 or lower.

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME:

• Discontinue therapy.

QTc INTERVAL GREATER THAN 500 MSEC:

• Interrupt therapy; resume therapy at 80 mg orally once a day when QTc interval returns to within 30 msec of baseline? or less than or equal to 480 msec.

QTc INTERVAL INCREASED BY MORE THAN 30 MSEC ON ECG? ON DAY 8 OF CYCLE 1:

• Confirm with ECG on Day 9; if confirmed, consider dose reduction to 80 mg orally once a day.
• Interrupt therapy until pancreatitis is resolved; resume therapy at 80 mg orally once a day.

OTHER GRADE 3 OR HIGHER TOXICITY CONSIDERED RELATED TO TREATMENT:

• Interrupt therapy until toxicity resolves to Grade 1; resume therapy at 80 mg orally once a day.

Administration advice:

• Do not break or crush tablets.
• This drug may be taken with or without food.
• Administer this drug at approximately the same time each day.
• If a dose is missed or not taken at the usual time, administer it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose; return to normal schedule the following day.
• Do not administer 2 doses within 12 hours.

Side Effects

The Most Common

• joint or muscle pain?
• extreme tiredness
• nausea?
• vomiting?
• diarrhea?
• mouth sores
• change in the ability to taste food
• headache?
• loss of appetite?
• difficulty falling asleep or staying asleep
• seizures; headache; decreased alertness; confusion; or vision changes
• fast, pounding, or irregular heartbeat; fainting; loss of consciousness; or seizures
• ongoing pain that begins in the stomach area but may spread to the back that may occur with or without nausea and vomiting

More common

• Bloody urine
• blurred vision
• chest pain or tightness
• chills
• confusion
• cough
• decreased frequency or amount of urine
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast or irregular heartbeat
• fever
• headache
• increased thirst
• lightheadedness
• loss of appetite
• lower back or side pain
• nausea
• nervousness
• pounding in the ears
• rapid, shallow breathing
• recurrent fainting
• slow heartbeat
• sneezing
• sore throat
• stomach pain
• sweating
• swelling of the face, fingers, or lower legs
• trouble breathing
• unusual tiredness or weakness
• vomiting
• weight gain

Rare

• Anxiety
• blue or pale skin
• chest discomfort
• chest pain, possibly moving to the left arm, neck, or shoulder
• difficulty swallowing
• the action of the mouth
• trouble sleeping
• stomach pain
• painting
• fever
• fluid build-up around the lungs (e.g., chest pain, cough, hiccups, rapid breathing)
• increased frequency or severity of infections (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• inflammation of the mouth and lips
• low magnesium levels in the blood (e.g., weakness, tremors, muscle cramps, seizures)
• low potassium levels in the blood (e.g., weakness, fatigue, muscle cramps, irregular heartbeat)
• pain, numbness, or weakness in the hands and feet
• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of heart problems (e.g., fast, irregular heartbeat or pulse; chest pain; sudden weight gain; difficulty breathing; leg swelling)
• signs of kidney failure (e.g., decreased urine production, swelling, fatigue, abdominal pain)
• signs of kidney problems (e.g., change in the amount or color of urine, increased urination at night, blood in the urine, swelling in the feet or legs)
• symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
• swelling in the feet, ankles, hands
•  vomiting, weakness
• shortness of breath
• fluid build-up around the heart (e.g., fever, fatigue, muscle aches, shortness of breath, nausea, vomiting, diarrhea, fast or pounding heartbeat, light-headedness)
• signs of an allergic reaction (e.g., wheezing, tightness in chest, troubled breathing, shortness of breath, or cough)
• signs of posterior reversible encephalopathy syndrome (e.g., headache, seizures, weakness, confusion, high blood pressure, vision changes, difficulty thinking clearly

Drug Interactions

Drug-Food Interactions

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

This medication should not be used during pregnancy due to the risk that it may cause harm to the unborn baby. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if gilteritinib passes into breast milk. If you are breast-feeding and are taking this medication, it may affect your baby. Women are advised to avoid breastfeeding while taking this medication and for 2 months after taking the last dose.

References