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Gilteritinib (Xospata) - Uses, Dose, MOA, Brands, Side effects

Gilteritinib (Xospata) is an FMS-like tyrosine kinase 3 inhibitor that is used to treat patients with relapsed or refractory acute myeloid leukemia (in patients with positive mutations for FMS-like tyrosine kinase 3.

Gilteritinib Uses:

Acute myeloid leukemia, relapsed or refractory to first-line of treatment:
- Used for treating the relapsed or refractory cases of acute myeloid leukemia (AML) in adult patients with an FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an approved test.

Gilteritinib (Xospata) Dose in Adults

Gilteritinib (Xospata) Dose in the treatment of FLT3-positive relapsed or refractory acute myeloid leukemia:

Dose:

Take 120 mg of gilteritinib once a day. This medicine is taken by mouth.

Time:

Try to take it at the same time every day.

Duration:

Keep taking it for at least 6 months. This gives the medicine time to work and help you feel better. You might take it for longer if it's still helping you or until your doctor says to stop.

Missed Dose:

If you forget a dose, take it as soon as you remember on the same day. But don't take two doses within 12 hours of each other. Just continue with your regular schedule the next day.

Use in Children:

Not indicated.

Pregnancy Risk Category: Not assigned (AU: D)

Because of how gilteritinib works and what we've learned from studies in animals, it could be risky for a baby if a pregnant woman takes it.
If a woman could become pregnant, her doctor should check if she's pregnant before she starts taking this medicine.
Women who can have babies should use good birth control while they're taking the medicine and for at least 6 months after they stop.
If a man is taking this medicine and his partner could get pregnant, they should also use birth control during his treatment and for around 4 months after he stops.
This is to make sure there's no harm to a developing baby.

Use of Gilteritinib while breastfeeding

We don't know if gilteritinib gets into breast milk.
But because there's a chance it could harm a baby who is breastfeeding, the maker of the medicine advises moms not to breastfeed while taking it and for 2 months after their last dose.

Gilteritinib Dose in Kidney Disease:

For kidneys working at a speed of 30 mL/minute or faster: The manufacturer doesn't suggest changing the dose of gilteritinib. Studies found that if the kidneys are working just a bit slow, it doesn't really change how the medicine works in the body.
For kidneys working slower than 30 mL/minute: The manufacturer doesn't give advice on how to adjust the dose because they haven't studied it in this situation.

Gilteritinib Dose in Liver Disease:

For people with mild or moderate liver issues (classified as Child-Pugh class A or B): The company making gilteritinib doesn't suggest changing the dose. Research shows that these levels of liver problems don't really affect how the drug works in the body.

For those with serious liver issues (classified as Child-Pugh class C): The company doesn't give advice on the dose because they haven't looked into it for people with this level of liver problem.

Common Side Effects of Gilteritinib (Xospata):

Cardiovascular:
- Edema
- Hypotension
- Hypertension
Central Nervous System:
- Fatigue
- Malaise
- Headache
- Dizziness
- Insomnia
Dermatologic:
- Skin Rash
Endocrine & Metabolic:
- Hyperglycemia
- Hypertriglyceridemia
- Hypocalcemia
- Hypoalbuminemia
- Hypophosphatemia
- Hypokalemia Hyponatremia
Gastrointestinal:
- Diarrhea
- Constipation
- Nausea
- Stomatitis
- Vomiting
- Abdominal Pain
- Decreased Appetite
- Dysgeusia
Hepatic:
- Increased Serum Alanine Aminotransferase
- Increased Serum Aspartate Aminotransferase
- Increased Serum Alkaline Phosphatase
- Increased Serum Transaminases
Infection:
- Sepsis
Neuromuscular & Skeletal:
- Arthralgia
- Myalgia
- Increased Creatine Phosphokinase
Renal:
- Increased Serum Creatinine
- Renal Insufficiency
Respiratory:
- Dyspnea
- Pneumonia
- Cough
Miscellaneous:
- Fever

Less Common Side Effects Of Gilteritinib (Xospata):

Cardiovascular:
- Prolonged QT Interval On ECG
- Cardiac Failure
- Pericardial Effusion
- Pericarditis
Central Nervous System:
- Reversible Posterior Leukoencephalopathy Syndrome
Hematologic & Oncologic:
- APL Differentiation Syndrome
Hypersensitivity:
- Anaphylaxis

Frequency of side effects not defined:

Central Nervous System:
- Altered Mental Status
- Seizure
Gastrointestinal:
- Pancreatitis

Contraindications to Gilteritinib (Xospata):

If someone is allergic to gilteritinib or any part of the medicine, they shouldn't take it.

Warnings and precautions

Gastrointestinal toxicities:

Taking gilteritinib can sometimes cause stomach and gut problems.
This includes issues like diarrhea (not from an infection), constipation, feeling nauseous, throwing up, or sores in the mouth.
These side effects are usually not too severe.

Hypersensitivity

Some people might have allergic reactions to gilteritinib, including severe ones like anaphylaxis.
If this happens, it's important to get medical help right away.

Pancreatitis

There have been rare cases where gilteritinib caused pancreatitis, which is an inflammation of the pancreas.
If someone taking the medicine starts showing signs of this problem, they need to be checked by a doctor quickly.
Depending on the situation, they might need to stop taking the medicine or take a lower dose.

The posterior reversible syndrome of encephalopathy:

There have been rare cases where gilteritinib caused a brain condition called Posterior Reversible Encephalopathy Syndrome (PRES).
Symptoms might include seizures or changes in thinking or behavior.
If someone thinks they might have this, a brain scan called an MRI can help diagnose it.
If they do have PRES, they should stop taking gilteritinib.
The good news is, as the name suggests, PRES is often reversible when the cause is removed or treated.

Extenuation of the QTc interval:

Taking gilteritinib can sometimes affect the heart's rhythm, making a part of the heartbeat (known as the QT interval) last longer than it should.
This can be seen on an ECG, a test that measures the heart's activity.
In a study, a few patients taking the drug had a QT interval longer than a specific time, and for some, it increased quite a bit from when they started the drug.
It's important to have an ECG before starting the medicine, then again on specific days during the first treatment cycle, and before starting the next two treatment rounds.
If someone's levels of potassium or magnesium in the blood are too low, it can make this heart problem more likely.
So, doctors will want to fix these levels before and during treatment.
If the QT interval gets too long, the patient might need to stop taking gilteritinib for a while or take a smaller dose.

Gilteritinib: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
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.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
QT-prolonging Antipsychotics (Moderate Risk)	May enhance the QTc-prolonging effect of QTprolonging 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.
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.
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.
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.
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).
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.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Risk Factor D (Consider therapy modification)
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
QT-prolonging Agents (Highest Risk)	Gilteritinib may enhance the QTc-prolonging effect of QTprolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias.
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
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.
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.
Risk Factor X (Avoid combination)
Combined Inducers of CYP3A4 and P-glycoprotein	May decrease the serum concentration of Gilteritinib.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Pimozide	May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk).

Monitoring parameters:

Blood Tests:
- Before starting the medicine
- At least once a week for the first month
- Every two weeks in the second month
- Once a month after that
Heart Test (ECG):
- Before starting the medicine
- On the 8th and 15th days of the first treatment cycle
- Before starting the next two treatment rounds
Pregnancy Test:
- For women who can get pregnant, a test is needed within 7 days before starting the medicine.

Things to Watch Out For

Signs of pancreas problems (pancreatitis)
Signs of a brain condition (posterior reversible encephalopathy syndrome)

Other Monitoring

Make sure the patient is taking the medicine as prescribed (adherence).

How to administer Gilteritinib (Xospata)?

Take them with or without food.
Try to take them at the same time every day.
Don't break or crush the tablets.

Mechanism of action of Gilteritinib (Xospata):

It's a medicine called a tyrosine kinase inhibitor.
It targets and blocks various proteins, especially one called FLT3.
By blocking FLT3, gilteritinib stops the growth of certain leukemia cells and can even make some of them die.

Onset:

It starts working quickly by blocking FLT3 phosphorylation, a process needed for cell growth. This happens within 24 hours after the first dose.

Distribution:

The medicine spreads throughout the body. It's found both in the central part (like your core) and the peripheral parts (like arms and legs).

Protein Binding:

About 94% of the medicine sticks to proteins in the blood.

Metabolism:

The liver primarily breaks down gilteritinib using a process involving CYP3A4. This creates different forms of the drug, like M17, M16, and M10. These forms don't make up more than 10% of the overall exposure.

Half-life: