Gilteritinib

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# Black Box Warning

# Overview
Gilteritinib is a signal transduction inhibitor that is FDA approved for the treatment of given to adults who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include adverse reactions that more than 20% of the patients have are myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting. These are the most common. 
If there is suspicion of an adverse reaction, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Plasma Concentration
- After 15 days, the plasma concentration becomes steady
- Maximum Concentration: 374 ng/mL
- AUC: 6943 ng.h/mL
The Data is different in people who are fasting
- The Maximum Concentration decreased by 26%
- AUC decreased by 10%

### Gilteritinib is indicated for
- Given to adult patients who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test.

### Limitations of Use
Patients with Acute Myeloid Lymphoma with the mutation of the receptor tyrosine kinase are administered Gilteritinib. Furthermore, it is prescribed to patients whose acute myeloid lymphoma of that mutation has worsened or returned after trials with other chemotherapy medications

### Dosing Considerations
- It is recommended to start off a patient with a dose of 120 mg orally everyday. It does not matter if the patient has had food or not. The response to the medication could take up to 6 months, so keep the dosing going if the patient does not develop hypersensitivity, adverse reactions, or disease progression.
- DO NOT CRUSH OR BREAK THE XOSPATA TABLETS. Make sure to keep a scheduled time everyday to administer the pill. If it could not be administered at the correct time, the patient may take the medication on the same day, as long as it is 12 hours before the next dose.
- Some dosing modifications include:
If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib
If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg.
- If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib
- If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg.

### Preparation of GILTERITINIB
- Patients should make sure they are not allergic to any of the ingredients in Gileritinib. Talk to the medical professional about any potential allergies with other medications or Gilteritinib.
- Patients should alert their doctor of the other medications, vitamins, nutritional supplements etc that they are planning on taking along with Gilteritinib.
- Patients should talk to their doctor about any prolonged QT intervals they might have had. Some of the symtoms of prolonged QT interval include fainting, loss of consciousness, seizures, or sudden death, a slow, fast, or irregular heartbeat, or low levels of potassium or magnesium in the blood.
- Patients should alert their doctors if they plan to or are pregnant, or want to father a child. People with the ability to become pregnant should take a pregnancy test at least 7 days before initiating treatment, use birth control during treatment, and up to 6 months after treatment. Anyone that does not have the ability to become pregent, but has a partner who can, should use birth control during their treatment and for 4 months after their final dose. Gilteritinib may harm the fetus, so patients should call their doctor is they or their partner becomes pregnant during treatment.
- Patients should not breastfeed during treatment and 2 months after the last dose.

### Administration of GILTERITINIB
- Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food.
- Patients should carefully read their prescription label and be aware of what it entails. Patients should follow their prescription label and clarify any misconceptions with their doctors.
- Patients should take their prescription exactly as prescribed on the prescription label, not any more or any less of it. They should continue to take the medication even if they do not feel sick.
- Gilteritinib should be swallowed as a whole tablet. DO NOT CHEW, SPLIT, OR CRUSH THE TABLETS BEFORE INGESTING THEM.
- Medical paractitioners will monitor their patients regularly, and change/stop temporarily or permanently the dose they are administering depending on how the patients react to the medication. Patients should talk to their doctors about how they are feeling.
- Patients should not stop taking their daily dose of Gilteritinib without their doctor's consent.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding GILTERITINIB Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding GILTERITINIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding GILTERITINIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
Gilteritinib is contraindicated in patients that seem to react badly to the medicine or any of its ingredients. Check the package label to get more information on the ingredients. It is important to note that clinical studies have shown effects of anaphylactic reactions.

# Warnings

### Delayed QT Interval
The delayed cardiac ventricular repolarization may require temporary discontinuation of Gilteritinib, and dosage reduction.
Patients should take an electrocardiogram to confirm proper heart rhythm prior to initializing Gilteritinib dosage, on days 8 and 15 of cycle 1, and before initiating the two successive cycles
If the electrocardiogram results demonstrate a QTcF >500 msec, then patients should temporarily discontinue Gilteritinib and reduce the dosage. Patients should talk to their doctor about the dosage reduction. 
There is a QT prolongation risk for patients who show signs of Hypokalemia or hypomagnesemia. It is important to correct these problems before initiating Gilteritinib. These could be fixed with a potassium rich diet, but patients should talk to their doctor to address the severity and the following steps needed to take.

### Posterior Reversible Encephalopathy Syndrome
Patients run a minor risk of developing Posterior Reversible Encephalopathy Syndrome. However, if symptoms such as seizures and altered mental statuses occur, patients should immediately report to a medical professional. Doctors will confirm the development through  brain imaging, usually magnetic resonance imaging (MRI). 
Patients who develop Posterior Encephalopathy Syndrome should IMMEDIATELY discontinue Gilteritinib
- There is limited information on monitoring disease manifestations after Gilteritinib Discontinuation

### Infusion Reactions
- There is limited information on infusion reactions pertaining to the administration of Gilteritinib
- See adverse reactions to monitor symptoms

# Adverse Reactions

## Clinical Trials Experience
- The clinical trial is based on 292 patients who have relapsed or refractory Acute Myeloid Leukemia (AML). They are given a dose of 120 mg of Gilteritinib daily. This trials course time was 3 months, the maximum amount of time patients were exposed to Gilteritinib.
- About 8% of the patients immediately discontinued Gilteritinib due to a serious adverse reaction. Some of the reactions that led patients to discontinue include pneumonia , sepsis, and dyspnea.

## Postmarketing Experience
There is limited information regarding Gilteritinib Postmarketing Experience in the drug label.

# Drug Interactions

### P-gp and Strong CYP3A Inducers
Combining use of Gilteritinib with P-gp and strong CYP3A inducers may result in decreased Gilteritinib exposure and decrease its efficacy. Patients should avoid using P-gp and strong CYP3A inducers with Gilteritinib.

### Strong CYP3A Inhibitors
Using strong CYP3A inhibitors with Gilteritinib increases Gilteritinib exposure that may lead to toxicity. Patients should talk to their doctors to consider alternative therapies to avoid strong CYP3A inhibitors. If both are essential for the patient's well-being and therapy, monitor patients carefully more frequently for adverse reactions. Immediately dicontinue concomitant use and treatment with Gilteritinib if unacceptable toxicity arises.

### Drugs Targeting 5HT2B Receptor or Sigma Nonspecific Receptor
Avoid using Gilteritinib with drugs that target 5HT2B receptors or sigma nonspecific receptors concomitantly because Gilteritinib reduce efficacy of those drugs. If using both are essential, patients and doctors should interact and monitor adverse reactions and drug effect carefully and routinely.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnant women run the risk of drug-associated developmental outcomes, if they are ingesting Gilteritinib. There are no studies available for pregnant women that indicate this, but clinical studies in rats have shown harm. Studies administered Gilteritinib to pregnant rats, and it resulted in fetal developmental outcomes including embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures. It is important to note that these outcomes occur regardless the health of the mother.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gilteritinib in women who are pregnant.

### Labor and Delivery
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

### Nursing Mothers
There has been no seen data that proves Gilteritinib or its metabolites were present in human milk. However, since there is a risk of adverse reactions for the child ingesting the milk, medical professionals have advised patients to abstain from breastfeeding until 2 months after the last dose of XOSPATA

### Pediatric Use
The safety and efficacy of GILTERITINIB for the treatment of PNH in pediatric patients have not been established.

### Geriatic Use
Clinical studies of GILTERITINIB of 292 patients show 41% of the patients were of the age 65 and older, and 13% were of the age 75 and older. There were no serious differences between the administration in younger patients compared to ones that aged 65 and up.

### Gender
There is no FDA guidance on the use of GILTERITINIB with respect to specific gender populations.

### Race
There is no FDA guidance on the use of GILTERITINIB with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of GILTERITINIB in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of GILTERITINIB in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of GILTERITINIB in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of GILTERITINIB in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food.
- Doctors will monitor patients for adverse reactions (see adverse reactions)

### Monitoring
There is limited information regarding Gilteritinib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Gilteritinib and IV administrations.

# Overdosage
There is limited information regarding Andexanet alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
Gilteritinib is a powerful and selective inhibitor that detects both the mutations internal tandem duplication(ITD) and the tyrosine kinase domain(TKD) which are both of the FLT3 receptor. Gilteritinib inhibits AXL and ALK as well, as AXL and FLT3 are molecules that contribute to the growth of cancer cells. Gilteritinib actively inhibits the phosphorylation of FLT3 and eventually downstream targets such as STAT5, ERK, and AKT. However, studies have shown in patients with acute myeloid lymphoma that about 30% had a "mutationally activated isoform." The muatations ITD results in poor patient outcomes, and TKD a resistance to the FLT3 tyrosine kinase inhibitors. Furthermore, AXL is associated with producing resistance mechanisms to chemotherapy. There was an interest in FLT3 transmembrane tyrosine kinases.

## Structure
There is limited information regarding GILTERITINIB Structure in the drug label.

## Pharmacodynamics

## Pharmacokinetics
- Inhibited the receptor tyrosine kinase which regulates FLT3 in acute myeloid luekemia
Trials Phase 1 and 2:
- Complete response: 41%
- Overall Response Rate: 52%
- Duration of Response(Median): 20 weeks
- Overall Survival(Median): 31 weeks
Phase 3:
- Complete Remission
- Complete Remission with limited blood recovery: 21% of patients
- Central Volume of Distribution is approximately 1092 L
- Peripheral Volume of Distribution is approximately 1100 L
- About 64.5% of the administered dose is excreted in the feces
- About 16.4% of the administered dose goes through the urine
- Patients are advised not to breastfeed while undergoing treatment with Gilteritinib.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Carcinogenesis have not yet been performed alongside Gilteritinib.
The effect of Gilteritinib on the impairment of human fertility is unknown. However, in a study with dogs administered 10 mg/kg per day Gilteritinib in the 4-week study, there was a result of degredation of germ cells and spermatid giant cell formation in the testis. There was also a single cell necrosis of "epididymal duct epithelia of the epididymal head."

# Clinical Studies
The medicinal value of Gilteritinib was analyzed from five clinical trials
Results:
- Elimination was through feces
- Exposure to the drug (effectiveness) was similar with and without fasting
- Administering Gilteritinib with itraconazole(strong P-glycoprotein and CYP3A4 inhibitor) or rifampicin(strong P-glycoprotein and CYP3A inducer) lowered the effectiveness of the drug and altered its structure
- Administering Gilteritinib with midazolam(CYP3A4 substrate) did not alter the effectiveness
- Hepatic impairment(liver impairment) does not affect the unbound exposure of the drug

# How Supplied
- The tablets appear light yellow, round-shaped, and film-coated. They have the inscription of Astellas logo and 235 on the same side.
- The tablets are 40 mg each, and they come in a child resistant container containing 90 tablets.
- The authorized dose for patients on Gilteritinib is 120 mg but may go up to 200 mg is the response from the patient is dissatisfactory

## Storage
- XOSPATA tablets should be stored at 20oC -25oC (about 68F to 77F)
- It is ok if the tablets are exposed to temperatures ranging from 15oC to 30oC ( about 59F to 86F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
It is recommended that patients read the FDA-approved patients labelling.
There is a risk that patients may develop Posterior Reversible Encephalopathy Syndrome. Clinical studies and patient reactions have shown rare cases of this reaction. 
Patients should immediately report any symptoms of PRES to their doctors. These symptoms may include, but are not limited to, seizures and an altered mental status. The medical practitioner will bring the patient in for further evaluation.

### Prolonged QT Interval
There is a slightly higher risk patients may develop a prolonged cardiac ventricular depolarization. FDA reports that about 8% of patients in the clinical trial have a period of prolongment greater than 60 milliseconds. 
If patients find symptoms such as feeling faint, losing consciousness, or arrhythmia, it is recommended they go see a healthcare professional immediately. 
Patients who may find signs/ symptoms or have a history with hypokalemia or hypomagnesemia should be made aware of the importance of monitoring their electrolytes.

## Pancreatitis
Pancreatitis development is rare solely based on taking Gilteritinib. Medical practitioners should advise patients of the risk of developing this disease, and research the symptoms associated with it. Patients should immediately call their doctor if any of the signs arise. 
Some of the signs and symptoms of pancreatitis include severe and persistent stomach pain, with or without nausea and vomiting

### Infusion reactions
- There is limited information on infusion reactions relating to Gilteritinib.
- See adverse reactions to monitor symtoms

# Precautions with Alcohol
Alcohol-Gilteritinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Xospata

# Look-Alike Drug Names
There is limited information regarding GILTERITINIB Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price