Gilteritinib

Gilteritinib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[2]

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Black Box Warning

WARNING: DELAYED QT INTERVAL See full prescribing information for complete Boxed Warning. 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.

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

Recommended Vaccination and Prophylaxis

Recommended Weight-Based Dosage Regimen - PNH

Recommended Weight-Based Dosage Regimen - aHUS

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.

Preparation of GILTERITINIB

Administration of GILTERITINIB

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.

Non–Guideline-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.

Non–Guideline-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

WARNING: DELAYED QT INTERVAL See full prescribing information for complete Boxed Warning. 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.

Serious Meningococcal Infections

Other Infections

Monitoring Disease Manifestations after GILTERITINIB Discontinuation

Infusion Reactions

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Gilteritinib Clinical Trials Experience in the drug label.

Postmarketing Experience

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

Drug Interactions

There is limited information regarding Gilteritinib Drug Interactions in the drug label.

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

There is limited information regarding Gilteritinib Administration in the drug label.

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

Gilteritinib
Systematic (IUPAC) name
?
Identifiers
CAS number	1803171-55-2
ATC code	?
PubChem	?
Chemical data
Formula	?
Mol. mass	188303.705 Da
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?

Mechanism of Action

There is limited information regarding Gilteritinib Mechanism of Action in the drug label.

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

Distribution

• Central Volume of Distribution is approximately 1092 L
• Peripheral Volume of Distribution is approximately 1100 L

Elimination

• About 64.5% of the administered dose is excreted in the feces
• About 16.4% of the administered dose goes through the urine

Specific Populations

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 68°F to 77°F)
• It is ok if the tablets are exposed to temperatures ranging from 15ºC to 30ºC ( about 59°F to 86°F)

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

It is recommended that patients read the FDA-approved patients labelling.

Posterior Reversible Encephalopathy Syndrome

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”

Discontinuation

Infusion reactions

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

References

The contents of this FDA label are provided by the National Library of Medicine.