Consumer medicine information

Xospata

Gilteritinib

BRAND INFORMATION

Brand name

Xospata

Active ingredient

Gilteritinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xospata.

SUMMARY CMI

XOSPATA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using XOSPATA?

XOSPATA contains gilteritinib, a protein kinase inhibitor, which is used to treat adults with acute myeloid leukaemia (AML) who have a defect in a gene called FLT3 when the disease has come back or has not improved after previous treatment(s).

For more information, see Section 1. Why am I using XOSPATA? in the full CMI.

2. What should I know before I use XOSPATA?

Do not use if you have ever had an allergic reaction to XOSPATA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use XOSPATA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with XOSPATA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use XOSPATA?

  • The usual dose is three 40 mg film-coated tablets (120 mg) taken at the same time once a day.
  • Your doctor may decide to increase or lower your dose or temporarily interrupt treatment depending on your medical conditions.

More instructions can be found in Section 4. How do I use XOSPATA? in the full CMI.

5. What should I know while taking XOSPATA?

Things you should do
  • If you are about to be started on any new medicine, remind your doctor, dentist and pharmacist that you are taking XOSPATA.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not take XOSPATA to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or alter the dosage without checking with your doctor.
Driving or using machines
  • Do not drive or operate machinery until you know how XOSPATA affects you.
  • XOSPATA may have a moderate effect on your ability to drive or use any tools or machinery.
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them and keep it where children cannot reach it.
  • Keep your tablets in the original packaging in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while taking XOSPATA? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). Some of the serious side effects may include: fever, trouble breathing, rash, dizziness or lightheadedness, rapid weight gain, swelling of your arms or legs; seizure, worsening headache, confusion, blindness or other vision problems; have a change in your heartbeat, or feeling dizzy, lightheaded, or faint.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

XOSPATA®

Active ingredient(s): gilteritinib (as fumarate)

Consumer Medicine Information (CMI)

This leaflet answers some common questions about XOSPATA.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking XOSPATA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

Where to find information in this leaflet:

1. Why am I using XOSPATA?
2. What should I know before I use XOSPATA?
3. What if I am taking other medicines?
4. How do I use XOSPATA?
5. What should I know while taking XOSPATA?
6. Are there any side effects?
7. Product details

1. Why am I using XOSPATA?

XOSPATA contains gilteritinib, a protein kinase inhibitor, which is used to treat adults with acute myeloid leukaemia (AML) who have a defect in a gene called FLT3 when the disease has come back or has not improved after previous treatment(s).

AML is a form of cancer of certain white blood cells (called myeloid cells). This medicine works by blocking the action of certain enzymes (kinases) in the abnormal cells. By blocking kinases, XOSPATA stops the cancer cells from growing and dividing.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

XOSPATA is not for use in children and adolescents.

Safety and effectiveness in children and adolescents have not been established.

2. What should I know before I use XOSPATA?

Warnings

When you must not take it

Do not take XOSPATA if you have an allergy to:

  • any medicine containing gilteritinib
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Check with your doctor if you:

If you are not sure whether you should start taking this medicine.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6.

Pregnancy and breastfeeding

XOSPATA is not for use during pregnancy.

This medicine may harm your unborn baby and should not be used during pregnancy. Use an effective method of contraception during treatment with XOSPATA and for at least 6 months after stopping the treatment. Males who have female partners that are able to become pregnant should use an effective method of contraception during treatment of XOSPATA and for at least 4 months after stopping the treatment.

You should not breast-feed during treatment with XOSPATA.

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.

Talk with your doctor if you have questions about birth control. Your doctor can discuss with you the risks and benefits involved.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • a heart rhythm disorder, such as an irregular heartbeat or a condition called long QT syndrome
  • a history of low levels of potassium or magnesium in your blood, as this may increase the risk of an abnormal heart rhythm if you have severe pain in the upper abdomen and back, nausea and vomiting
  • severe pain in the upper abdomen and back, nausea and vomiting. These may be signs of an inflammation of the pancreas (pancreatitis)

Your doctor will perform regular blood tests before and during treatment with XOSPATA. Your doctor will also regularly check your heart function before and during treatment.

If you have not told your doctor about any of the above, tell him/her before you start taking XOSPATA.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and XOSPATA may interfere with each other. These include certain medicines used to:

  • treat tuberculosis (e.g. rifampicin)
  • treat epilepsy (e.g. phenytoin)
  • treat depression (e.g. escitalopram, fluoxetine, sertraline or the herbal medicine St. John's Wort (also known as Hypericum perforatum))
  • treat fungal infections (e.g. voriconazole, posaconazole or itraconazole)
  • treat bacterial infections (e.g. erythromycin, clarithromycin or azithromycin)
  • treat high blood pressure (hypertension) (e.g. captopril or carvedilol)
  • treat infections with the human immunodeficiency virus (HIV) (e.g. ritonavir)
  • treat heart problems (e.g. digoxin)
  • treat blood clots (e.g. dabigatran extexilate)

These medicines may be affected by XOSPATA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

4. How do I use XOSPATA?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dose is three 40 mg film-coated tablets (120 mg) taken at the same time once a day. Your doctor may decide to increase or lower your dose or temporarily interrupt treatment depending on your medical conditions. Continue treatment at the dose prescribed by your doctor.

How to take it

Swallow the tablets whole with a full glass of water. Do not break or crush the tablets before swallowing.

You can take XOSPATA with or without food.

When to take XOSPATA

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

It is important to keep taking your medicine even if you feel well.

Do not stop treatment with XOSPATA unless your doctor tells you to.

If you forget to take XOSPATA

Take it as soon as you remember, and then go back to taking your medicine as you would normally.

If you forget to take XOSPATA for the whole day, take your usual dose the following day.

If you forget to take XOSPATA for more than one day, talk to your doctor immediately.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much XOSPATA

If you think that you have used too much XOSPATA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
    contact your doctor, or
    go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking XOSPATA?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking XOSPATA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you or your partner becomes pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you should not do

Do not take XOSPATA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or alter the dosage without checking with your doctor.

Driving or using machines

Do not drive or operate machinery until you know how XOSPATA affects you.

XOSPATA may have a moderate effect on your ability to drive or use any tools or machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep your tablets in the pack until it is time to take them.

Keep your tablets in the original packaging in a cool dry place where the temperature stays below 25°C.

Do not store XOSPATA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

When to discard your medicine (as relevant)

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

Do not throw away any medicines via wastewater or household waste.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • diarrhoea
  • nausea
  • constipation
  • tiredness
  • swelling due to fluid retention (oedema)
  • loss of energy, weakness (asthenia)
  • abnormal blood test results which can indicate to your doctor how well certain parts of your body are functioning: high levels of blood creatine phosphokinase (indicative of muscle or heart function), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or blood alkaline phosphatase (indicative of liver function)
  • pain in limbs
  • joint pain (arthralgia)
  • muscle pain (myalgia)
  • cough
  • shortness of breath (dyspnoea)
  • dizziness
  • low blood pressure (hypotension)
  • a vague feeling of discomfort, feeling unwell (malaise)
  • muscle stiffness
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Differentiation syndrome.
    Contact your doctor straight away if you have any of the following symptoms: fever, trouble breathing, rash, dizziness or lightheadedness, rapid weight gain, swelling of your arms or legs. These may be signs of a condition called differentiation syndrome (may affect up to 1 in 10 people). Differentiation syndrome can happen as early as 1 day after starting XOSPATA treatment and during the first 3 months of treatment. Your doctor may monitor you and give you a medicine to treat your condition. Your doctor may pause XOSPATA treatment until symptoms have been reduced.
  • Posterior Reversible Encephalopathy Syndrome (PRES)
    There have been uncommon reports of PRES, a rare, reversible condition involving the brain, in patients treated with XOSPATA (may affect up to 1 in 100 people). If you have a seizure, worsening headache, confusion, blindness or other vision problems, please contact your doctor as soon as possible.
  • Heart rhythm problems (QT prolongation)
    XOSPATA may cause a heart problem called QT prolongation (may affect up to 1 in 10 people). Contact your doctor straight away if you have a change in your heartbeat, or if you feel dizzy, lightheaded, or faint.
  • collection of fluid around the heart, which, if severe, can decrease the heart's ability to pump blood (pericardial effusion)
  • a severe life-threatening allergic reaction, e.g., swelling in the mouth, tongue, face and throat, itching, hives (anaphylactic reaction)
  • inflammation of the heart (pericarditis)
  • heart failure (cardiac failure)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

What XOSPATA contains

Active ingredient
(main ingredient)		XOSPATA contains 40 mg of gilteritinib as the active ingredient.
Other ingredients
(inactive ingredients)
  • mannitol
  • hyprolose
  • magnesium stearate
  • hypromellose
  • purified talc
  • macrogol 8000
  • titanium dioxide
  • iron oxide yellow

Do not take this medicine if you are allergic to any of these ingredients.

What XOSPATA looks like

XOSPATA 40 mg film-coated tablets (AUST R 321060) are round, light yellow film-coated tablets with the company logo and ‘235’ debossed on one side of the tablet.

XOSPATA is available in packs of 84 tablets (in 4 blisters of 21 tablets each).

Who distributes XOSPATA

XOSPATA is supplied in Australia by:

Astellas Pharma Australia Pty Ltd
Suite 2.01, 2 Banfield Road
Macquarie Park NSW 2113
Tel (Medical Information):
1800 751 755
Website: www.astellas.com/au

® = Registered Trademark

This leaflet was prepared in September 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Xospata

Active ingredient

Gilteritinib

Schedule

S4

 

1 Name of Medicine

Gilteritinib fumarate.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 44.2 mg gilteritinib fumarate (corresponding to 40 mg gilteritinib).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Round, light yellow film-coated tablet, debossed with the Astellas logo and '235' on the same side.

4 Clinical Particulars

4.1 Therapeutic Indications

Xospata is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation.

4.2 Dose and Method of Administration

Treatment with Xospata should be initiated and supervised by a physician experienced in the use of anti-cancer therapies.
Before taking Xospata, relapsed or refractory AML patients must have confirmation of FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]).

Dosage.

The recommended starting dose of Xospata is 120 mg (three 40 mg tablets) once daily.
Blood chemistries, including creatine phosphokinase, should be assessed prior to initiation of treatment, on day 15 and monthly for the duration of treatment.
An electrocardiogram (ECG) should be performed before initiation of Xospata treatment, on day 8 and 15 and prior to the start of the next three subsequent months of treatment. In addition, an ECG should be performed following the same schedule in case of dose increase (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Treatment should continue until the patient is no longer clinically benefiting from Xospata or until unacceptable toxicity occurs. Response may be delayed; therefore, continuation of treatment at the prescribed dose for up to 6 months should be considered to allow time for a clinical response.
In the absence of a response (patient did not achieve a CRc) after 4 weeks of treatment, the dose can be increased to 200 mg (five 40 mg tablets) once daily, if tolerated or clinically warranted.

Dose modifications.

For dose interruption, reduction and discontinuation recommendations, see Table 1.

Missed dose.

Administer Xospata at about the same time each day. If a dose is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. If vomiting occurs after dosing, patients should not take another dose but should return to the normal schedule the following day.

Method of administration.

For oral use.
Xospata can be taken with or without food. The tablets should be swallowed whole with water and should not be broken or crushed.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.
Anaphylactic reactions have been observed in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.4 Special Warnings and Precautions for Use

Differentiation syndrome.

Xospata has been associated with differentiation syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)). Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome include fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, and renal dysfunction. If differentiation syndrome is suspected, corticosteroid therapy should be initiated along with hemodynamic monitoring until symptom resolution. Corticosteroids can be tapered after resolution of symptoms and should be administered for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, Xospata should be interrupted until signs and symptoms are no longer severe (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Posterior reversible encephalopathy syndrome.

There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xospata (see Section 4.8 Adverse Effects (Undesirable Effects)). PRES is a rare, reversible, neurological disorder with which can present with rapidly evolving symptoms including seizure, headache, confusion, visual and neurological disturbances, with or without associated hypertension and altered mental status. If PRES is suspected, it should be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xospata in patients who develop PRES is recommended (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Prolonged QT interval.

Gilteritinib has been associated with prolonged cardiac ventricular repolarisation (QT Interval) (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties). QT prolongation can be observed in the first three months of treatment with Xospata. Therefore, electrocardiogram (ECG) should be performed prior to initiation of treatment, on day 8 and 15 of cycle 1, and prior to the start of the next three subsequent months of treatment. In addition, an ECG should be performed in case of dose increase, following the same schedule. Hypokalaemia or hypomagnesaemia may increase the QT prolongation risk. Hypokalaemia or hypomagnesaemia should therefore be corrected prior to and during Xospata treatment.
Xospata should be interrupted in patients who have a QTcF > 500 msec (see Section 4.2 Dose and Method of Administration).

Pancreatitis.

There have been reports of pancreatitis. Patients who develop signs and symptoms suggestive of pancreatitis should be evaluated and monitored. Xospata should be interrupted and can be resumed at a reduced dose when the signs and symptoms of pancreatitis have resolved (see Section 4.2 Dose and Method of Administration).

Interactions.

Coadministration of CYP3A/P-gp inducers may lead to decreased gilteritinib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of Xospata with strong CYP3A4/P-gp inducers should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Caution is required when concomitantly prescribing Xospata with medicinal products that are strong inhibitors of CYP3A and/or P-gp (such as, but not limited to, voriconazole, itraconazole, posaconazole and clarithromycin) because they can increase gilteritinib exposure. Alternative medicinal products that do not strongly inhibit CYP3A and/or P-gp activity should be considered. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for toxicities during administration of Xospata (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Xospata may reduce the effects of medicinal products that target 5HT2B receptor or sigma nonspecific receptors. Therefore, concomitant use of Xospata with these products should be avoided unless use is considered essential for the care of the patient (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Embryofetal toxicity and contraception.

Pregnant women should be informed of the potential risk to a fetus (see Section 4.6 Fertility, Pregnancy and Lactation). Females of reproductive potential should be advised to have a pregnancy test within seven days prior to starting treatment with Xospata and to use effective contraception during treatment with Xospata and for at least 6 months after stopping treatment. Women using hormonal contraceptives should add a barrier method of contraception. Males with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of Xospata.

Use in hepatic impairment.

No dose adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Xospata has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dose adjustment is necessary in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Severe renal impairment.

Gilteritinib exposure may be increased in patients with severe renal impairment or end stage renal disease. Patients should be closely monitored for toxicities and QT prolongation during administration of Xospata (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dose adjustment is required in patients ≥ 65 years of age (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Xospata in children aged below 18 years has not yet been established.
No data are available. Xospata should not be used in children from birth to less than 6 months of age because of potential safety concerns. Due to in vitro binding to 5HT2B (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), there is a potential impact on cardiac development in patients less than 6 months of age.

Effects on laboratory tests.

No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Gilteritinib is primarily metabolised by CYP3A enzymes, which can be induced or inhibited by a number of concomitant medications.

Effects of other medicinal products on Xospata.

CYP3A/P-gp inducers.

Concomitant use of Xospata with strong CYP3A/P-gp inducers (e.g. phenytoin, rifampin and St. John's wort) should be avoided because they can decrease gilteritinib plasma concentrations. In healthy subjects, co-administration of rifampicin (600 mg), a strong CYP3A/P-gp inducer, to steady state with a single 20 mg dose of gilteritinib decreased gilteritinib mean Cmax by 27% and mean AUCinf by 70%, respectively, compared to subjects administered a single dose of gilteritinib alone (see Section 4.4 Special Warnings and Precautions for Use).

CYP3A inhibitors and/or P-gp inhibitors.

Strong inhibitors of CYP3A (e.g. voriconazole, itraconazole, posaconazole, clarithromycin, erythromycin, captopril, carvedilol, ritonavir, azithromycin) should be used with caution during Xospata treatment because they can increase gilteritinib plasma concentrations. A single, 10 mg dose of gilteritinib co-administered with itraconazole (200 mg once daily for 28 days), a strong CYP3A and/or P-gp inhibitor, to healthy subjects resulted in an approximate 20% increase in mean Cmax and 2.2 fold increase in mean AUCinf relative to subjects administered a single dose of gilteritinib alone. Gilteritinib exposure increased approximately 1.5-fold in patients with relapsed or refractory AML when co-administered with a strong CYP3A and/or P-gp inhibitor (see Section 4.4 Special Warnings and Precautions for Use).

Effects of Xospata on other medicinal products.

Gilteritinib as an inhibitor or inducer.

Gilteritinib is not an inhibitor or inducer of CYP3A4 or an inhibitor of MATE1 in vivo. The pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) were not significantly (Cmax and AUC increased approximately 10%) affected after once-daily administration of gilteritinib (300 mg) for 15 days in patients with FLT3-mutated relapsed or refractory AML. Additionally, the pharmacokinetics of cephalexin (a sensitive MATE1 substrate) were not significantly (Cmax and AUC decreased by less than 10%) affected after once daily administration of gilteritinib (200 mg) for 15 days in patients with FLT3-mutated relapsed or refractory AML.
Gilteritinib is an inhibitor of P-gp, breast cancer resistant protein (BCRP) and OCT1 in vitro. As gilteritinib may inhibit transporters at a therapeutic dose, caution is advised during coadministration of gilteritinib with substrates of P-gp (e.g. digoxin, dabigatran etexilate), BCRP (e.g. mitoxantrone, rosuvastatin) and OCT1 (e.g. metformin).

5HT2B receptor or sigma nonspecific receptor.

Based on in vitro data, gilteritinib may reduce the effects of medicinal products that target 5HT2B receptor or sigma nonspecific receptor (e.g. escitalopram, fluoxetine, sertraline). Avoid concomitant use of these medicinal products with Xospata unless use is considered essential for the care of the patient.

Transporter drug-drug interactions.

In vitro experiments demonstrated that gilteritinib is a substrate of P-gp and BCRP. Gilteritinib may potentially inhibit BCRP and P-gp in the small intestine, OCT1 in the liver at clinically relevant concentrations.

4.6 Fertility, Pregnancy and Lactation

Pregnancy testing is recommended for females of reproductive potential seven days prior to initiating Xospata treatment. Women of childbearing potential are recommended to use effective contraception (methods that result in less than 1% pregnancy rates) during and up to 6 months after treatment. It is unknown whether Xospata may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method of contraception. Males of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of Xospata (see Section 4.4 Special Warnings and Precautions for Use).

Effects on fertility.

There are no data on the effect of gilterinitib on human fertility.
(Category D)
Xospata can cause fetal harm when administered to pregnant women. There are no or limited amount of data from the use of Xospata in pregnant women. Gilteritinib crossed the placenta in rats (fetal tissue levels were similar to maternal plasma levels), causing embryofetal lethality and teratogenicity at doses resulting in subclinical exposures (≥ 20 mg/kg/day PO). Xospata should not be used during pregnancy or in women of childbearing potential not using effective contraception. For more information regarding contraception and appropriate wash-out periods see Section 4.4 Special Warnings and Precautions for Use, Embryofetal toxicity and contraception.
 It is unknown whether gilteritinib or its metabolites are excreted in human milk. Available animal data have shown excretion of gilteritinib and/or its metabolites in the animal milk of lactating rats with levels higher than maternal plasma levels. Distribution to the tissues in infant rats via the milk was evident.
A risk to breast-fed children cannot be excluded. Breastfeeding should be discontinued during treatment with Xospata and for at least two months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Gilteritinib has minor influence on the ability to drive and use machines. Dizziness has been reported in patients taking Xospata and should be considered when assessing a patient's ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of Xospata was evaluated in 319 patients with relapsed or refractory AML who received at least one dose of 120 mg gilteritinib.
The most frequent adverse drug reactions with gilteritinib were alanine aminotransferase (ALT) increased (82.1%), aspartate aminotransferase (AST) increased (80.6%), blood alkaline phosphatase increased (68.7%), blood creatine phosphokinase increased (52.9%), diarrhoea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral oedema (24.1%), dyspnea (24.1%), dizziness (20.4%), hypotension (17.2%), pain in extremity (14.7%), asthenia (13.8%), arthralgia (12.5%) and myalgia (12.5%).
The most frequent serious adverse reactions were acute kidney injury (6.6%), diarrhoea (4.7%), ALT increased (4.1%), dyspnea (3.4%), AST increased (3.1%) and hypotension (2.8%). Other clinically significant serious adverse reactions included differentiation syndrome (2.2%), electrocardiogram QT prolonged (0.9%) and posterior reversible encephalopathy syndrome (0.6%).

Tabulated list of adverse reactions.

Adverse reactions observed during clinical studies are listed in Table 2 by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions.

Differentiation syndrome.

Of 319 patients treated with Xospata in the clinical trials, 11 (3%) experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with Xospata included fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as one day and up to 82 days after Xospata initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of Xospata. For recommendations in case of suspected differentiation syndrome see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

PRES.

Of the 319 patients treated with Xospata in the clinical trials, 0.6% experienced posterior reversible encephalopathy syndrome (PRES). PRES is a rare, reversible, neurological disorder, which can present with rapidly evolving symptoms including seizure, headache, confusion, visual and neurological disturbances, with or without associated hypertension. Symptoms have resolved after discontinuation of treatment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

QT prolongation.

Of the 317 patients treated with Xospata at 120 mg with a post-baseline QTC value in clinical trials, 4 patients (1%) experienced a QTcF > 500 msec. Additionally, across all doses, 12 patients (2.3%) with relapsed/refractory AML had a maximum post-baseline QTcF interval > 500 msec (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no known specific antidote for Xospata. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic and supportive treatment initiated, taking into consideration the long half-life estimated at 113 hours.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: protein kinase inhibitors, ATC code: L01EX13.

Pharmacodynamic effects.

In patients with relapsed or refractory AML receiving gilteritinib 120 mg, substantial (> 90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after first dose) and sustained, as characterised by an ex vivo plasma inhibitory activity (PIA) assay.

Prolonged QT interval.

A concentration-related increase in change from baseline of QTcF was observed across gilteritinib doses ranging from 20 to 450 mg. The predicted mean change from baseline of QTcF at the mean steady-state Cmax (282.0 nanogram/mL) at the 120 mg daily dose was 4.96 msec with an upper 1-sided 95% CI = 6.20 msec.

Mechanism of action.

Gilteritinib fumarate is a FMS-like tyrosine kinase 3 (FLT3) and AXL (as well as other kinases) inhibitor.
Gilteritinib inhibits FLT3 receptor signalling and proliferation in cells expressing FLT3 including FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y, and it induced apoptosis in leukaemic cells expressing FLT3-ITD.

Clinical trials.

Relapsed or refractory AML. Efficacy and safety was evaluated in the active-controlled, phase 3 trial (2215-CL-0301).

ADMIRAL trial (2215-CL-0301).

The ADMIRAL trial is a Phase 3, open-label, multicentre, randomised clinical trial of adult patients with relapsed or refractory AML with a FLT3 mutation as determined by the LeukoStrat CDx FLT3 Mutation Assay. In this trial, 371 patients were randomized in a 2:1 ratio to receive gilteritinib or one of the following salvage chemotherapies (247 in the gilteritinib arm and 124 in the salvage chemotherapy arm):
cytarabine 20 mg twice daily by subcutaneous (SC) or intravenous (IV) for 10 days (days 1 through 10) (LoDAC);
azacitidine 75 mg/m2 once daily by SC or IV for 7 days (days 1 through 7);
mitoxantrone 8 mg/m2, etoposide 100 mg/m2 and cytarabine 1000 mg/m2 once daily by IV for 5 days (days 1 through 5) (MEC);
granulocyte colony-stimulating factor 300 microgram/m2 once daily by SC for 5 days (days 1 to 5), fludarabine 30 mg/m2 once daily by IV for 5 days (days 2 through 6), cytarabine 2000 mg/m2 once daily by IV for 5 days (days 2 through 6), idarubicin 10 mg/m2 once daily by IV for 3 days (days 2 through 4) (FLAG-Ida).
Gilteritinib was given orally at a starting dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. Dose reductions were allowed, to manage adverse reactions, and dose increases were allowed, for those patients who did not respond at the starting dose of 120 mg.
MEC and FLAG-Ida were given for up to two cycles depending on response to first cycle. LoDAC and azacitidine were given in continuous 4-week cycles until unacceptable toxicity or lack of clinical benefit.
The demographic and baseline characteristics were well-balanced between the two treatment arms. The median age at randomisation was 62 years (range 20 to 84 years) in the gilteritinib arm and 62 years (range 19 to 85 years) in the salvage chemotherapy arm. Fifty-four percent of the patients were female. Most patients in the study were Caucasian (59.3%); 27.5% Asian, 5.7% Black, 4% other races and 3.5% unknown. The majority of patients (83.8%) had an ECOG performance status score of 0 or 1. Patients had the following confirmed mutations: FLT3-ITD alone (88.4%), FLT3-TKD alone (8.4%) or both FLT3-ITD and -TKD (1.9%). Prior to treatment with gilteritinib, 39.4% of patients had primary refractory AML, 19.7% had relapsed AML after an allogeneic haematopoietic stem cell transplant (HSCT) and 41% had relapsed AML with no allogenic HSCT. Majority of patients had AML with intermediate risk cytogenetics (73%), 10% had unfavourable, 1.3% had favourable and 15.6% had unclassified cytogenetics.
The primary efficacy endpoint for the final analysis was OS in the intent-to-treat (ITT) population, measured from the date of randomisation until death by any cause (number of events analysed was 261). Patients randomised to the gilteritinib arm had significantly longer survival compared to the chemotherapy arm (HR 0.637; 95% CI 0.490 - 0.830; 1 sided p-value: 0.0004). The median OS was 9.3 months for patients receiving gilteritinib and 5.6 months for those receiving chemotherapy. Efficacy was further supported by the rate of complete remission (CR)/complete remission with partial haematologic recovery (CRh), the duration of CR/CRh (DOR) and a modified analysis of event free survival (EFS) (Table 3, Figure 1).
For patients who achieved a CR/CRh, the median time to first response was 3.7 months (range, 0.9 to 10.6 months) in the gilteritinib arm and 1.2 months (range: 1 to 2.6 months) in the salvage chemotherapy arm. The median time to best response of CR/CRh was 3.8 months (range, 0.9 to 16 months) in the gilteritinib arm and 1.2 months (range: 1 to 2.6 months) in the salvage chemotherapy arm.
Among the 197 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 68 (34.5%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. For the 49 patients who were independent of both RBC and platelet transfusions at baseline, 29 (59.2%) remained transfusion-independent during any 56-day post-baseline period.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of gilteritinib, peak plasma concentrations are observed at a median tmax approximately between 4 and 6 hours in healthy volunteers and patients with relapsed or refractory AML. Gilteritinib undergoes first-order absorption with an estimated absorption rate (ka) of 0.43 h-1 with a lag time of 0.34 hours based on population pharmacokinetic (PK) modelling. Median steady-state maximum concentration (Cmax) is 282.0 nanogram/mL (CV% = 50.8), and area under the plasma concentration curve during 24-hour dosing interval (AUC0-24) is 6180 nanogram.h/mL (CV% = 46.4) after once-daily dosing of 120 mg gilteritinib. Steady-state plasma levels are reached within 15 days of once-daily dosing with an approximate 10-fold accumulation.

Effect of food.

In healthy adults, gilteritinib Cmax and AUC decreased by approximately 26% and less than 10%, respectively, when a single 40 mg dose of gilteritinib was co-administered with a high fat meal compared to gilteritinib exposure in fasted state. Median tmax was delayed 2 hours when gilteritinib was administered with a high-fat meal.

Distribution.

The population estimate of central and peripheral volume of distribution were 1092 L and 1100 L, respectively. These data indicate gilteritinib distributes extensively outside of plasma, which may indicate extensive tissue distribution. In vivo plasma protein binding in humans is approximately 90% and gilteritinib is primarily bound to albumin.

Metabolism.

Based on in vitro data, gilteritinib is primarily metabolised via CYP3A4. The primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N-dealkylation) and were observed in animals. None of these three metabolites exceeded 10% of overall parent exposure. The pharmacological activity of the metabolites against FLT3 and AXL receptors is unknown.

Excretion.

After a single dose of [14C]-gilteritinib, gilteritinib is primarily excreted in faeces with 64.5% of the total administered dose recovered in faeces. Renal excretion is a minor elimination pathway with 16.4% of the total dose recovered in urine as unchanged drug and metabolites. Gilteritinib plasma concentrations declined in a bi-exponential manner with a population mean estimated half-life of 113 hours. The estimated apparent clearance (CL/F) based on the population PK model is 14.85 L/h.

Linearity/non-linearity.

In general, gilteritinib exhibited linear, dose-proportional pharmacokinetics after single and multiple dose administration at doses ranging from 20 to 450 mg in patients with relapsed or refractory AML.

Special populations.

Based on population pharmacokinetic analyses, no clinically meaningful effect on the pharmacokinetics of gilteritinib was observed for the following covariates: age (20 years to 90 years), race (Caucasian, Black, Asian or Other), sex, body weight (36 kg to 157 kg), and body surface area (1.29 to 2.96 m2).

Hepatic impairment.

The effect of hepatic impairment on gilteritinib pharmacokinetics was studied in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment. Results indicate unbound gilteritinib exposure in subjects with mild or moderate hepatic impairment is comparable to that observed in subjects with normal hepatic function. The effect of mild hepatic impairment [as defined by NCI-ODWG] on gilteritinib exposure was also assessed using the population PK model and the results demonstrate little difference in predicted steady-state gilteritinib exposure relative to a typical patient with relapsed or refractory AML and normal liver function.
Gilteritinib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Renal impairment.

The pharmacokinetics of this drug were evaluated in nine subjects with severe (CrCL 15 < 30 mL/min) renal impairment or end stage renal disease (CrCL < 15 mL/min). A 1.4-fold increase in mean Cmax and 1.5-fold increase in mean AUCinf of this drug was observed in subjects with severe renal impairment or end stage renal disease compared to subjects with normal renal function. No dose adjustment is necessary for patients with mild, moderate or severe renal impairment. As gilteritinib exposure may be increased in patients with severe renal impairment or end stage renal disease, additional monitoring may be required in these patients (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Gilteritinib did not induce gene mutation in an in vitro bacterial reverse mutation assay and chromosome aberration in an in vitro chromosome aberration assay with Chinese hamster lung cells. However, the in vivo micronucleus test showed that gilteritinib induced micronuclei in mouse bone marrow cells at oral doses ≥ 65 mg/kg/day (resulting in subclinical exposures.

Carcinogenicity.

Carcinogenicity studies have not been performed with gilteritinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Mannitol, hyprolose, magnesium stearate.

Coating.

Hypromellose, purified talc, macrogol 8000, titanium dioxide, iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in the original container.
Store below 25°C.
This medicinal product does not require any special storage conditions.

6.5 Nature and Contents of Container

OPA/aluminium/PVC/aluminium blisters containing 21 film coated tablets.
Each pack contains 84 film-coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Gilteritinib is a tyrosine kinase inhibitor. The chemical name is 2-Pyrazinecarboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[(tetrahydro-2H-pyran-4-yl) amino]-, (2E)-2-butenedioate (2:1). The molecular weight is 1221.50 and the molecular formula is (C29H44N8O3)2.C4H4O4. The structural formula is:
Gilteritinib fumarate is a light yellow to yellow powder or crystals that is sparingly soluble in water and very slightly soluble in anhydrous ethanol.

CAS number.

1254053-84-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes