Consumer medicine information

Xpovio

Selinexor

BRAND INFORMATION

Brand name

Xpovio

Active ingredient

Selinexor

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xpovio.

SUMMARY CMI

XPOVIO®

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 XPOVIO?

XPOVIO contains the active ingredient selinexor. XPOVIO is used in combination with dexamethasone, or in combination with dexamethasone and bortezomib, to treat multiple myeloma in adults who have received previous therapy.

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

2. What should I know before I use XPOVIO?

Do not use if you have ever had an allergic reaction to XPOVIO or any of the ingredients listed at the end of the CMI. Do not use if you are pregnant or intend to become pregnant or are breastfeeding. Do not use if you are less than 18 years of age.

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 or intend to breastfeed. Talk to your doctor if you are male and capable of sexually reproducing.

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

3. What if I am taking other medicines?

Some medicines may reduce the effect of XPOVIO or increase the risk of side effects.

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 XPOVIO?

  • It is important to use XPOVIO exactly as prescribed by your doctor.
  • Swallow the tablets whole with water. Do not crush, chew, break, or divide the tablets. Take the tablets with or without food.

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

5. What should I know while using XPOVIO?

Things you should do
  • Tell your doctor straight away if you become pregnant while taking this medicine.
  • Males and women capable of bearing children should abstain from sexual intercourse or use an effective form of contraception while taking this medicine and for at least 1 week after your last dose.
  • Remind any doctor, dentist, or pharmacist you visit that you are taking XPOVIO.
  • Keep your appointments with your doctor and any blood tests.
  • It is important you drink enough fluids and eat enough calories while taking XPOVIO.
Things you should not do
  • Do not stop taking this medicine or change the dose unless your doctor tells you to.
  • Do not breastfeed while taking this medicine and for at least 1 week after your last dose.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how XPOVIO affects you.
    XPOVIO may cause dizziness, drowsiness and sleepiness, and confusion.
Looking after your medicine
  • Store below 30°C.

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

6. Are there any side effects?

Common side effects of taking XPOVIO are nausea, fatigue, anaemia, decreased appetite. Serious side effects include long or excessive bleeding, infection including symptoms of chills, fever or sore throat, or allergic reactions symptoms including, problems with breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

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

XPOVIO® (x-poh-vee-oh)

Active ingredient(s): selinexor (seh-lih-nek-sor)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking XPOVIO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking XPOVIO.

Where to find information in this leaflet:

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

1. Why am I using XPOVIO?

XPOVIO contains the active ingredient selinexor. XPOVIO is an anti-cancer medicine.

XPOVIO is used in combination with bortezomib and dexamethasone for the treatment of multiple myeloma (a cancer of the bone marrow) in adults who have received at least one previous treatment.

XPOVIO is used in combination with dexamethasone for the treatment of multiple myeloma that has come back or did not respond to previous treatment, in adults who have received at least three previous treatments and whose disease did not respond to the following treatments:

  • at least one proteasome inhibitor,
  • at least one immunomodulatory medicine, and
  • an anti-CD38 monoclonal antibody

2. What should I know before I use XPOVIO?

Warnings

Do not use XPOVIO if:

  • you are allergic to selinexor, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have or have had any other medical conditions including the following:
    - low levels of platelets in your blood (thrombocytopenia)
    - bleeding problems
    - low levels of white blood cells (neutropenia)
    - serious infections
    - low levels of sodium in your blood (hyponatraemia)
    - eye problems, such as cataracts
    - Tumour Lysis Syndrome
    - problems with your liver or kidneys
  • take any medicines for any other condition

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. Are there any side effects?

Pregnancy and breastfeeding

Do not use XPOVIO if you are pregnant or intend to become pregnant.

If you are capable of bearing children, you should use an effective form of contraception or abstain from sexual intercourse while taking XPOVIO and for at least 1 week after your last dose.

Your doctor will ask you to complete a pregnancy test before you start taking XPOVIO.

Do not use XPOVIO if you are breastfeeding. If you intend to breastfeed, wait at least 1 week after your last dose.

Males

Males who are capable of sexually reproducing should use effective contraception or abstain from sexual intercourse while taking XPOVIO and for at least 1 week after your last dose.

Children

Children younger than 18 years of age should not use XPOVIO.

3. What if I am taking other medicines?

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

Medicines that may reduce the effect of XPOVIO include:

  • rifampicin
  • St. John's Wort
  • carbamazepine
  • phenytoin
  • phenobarbital
  • apalutamide
  • enzalutamide

Check with your doctor if you are taking any medicines that may increase the risk of the following side effects:

  • drowsiness
  • sleepiness
  • dizziness
  • fainting
  • confusion
  • hallucinations (seeing or hearing things that are not there)
  • problems with thinking clearly
  • make you less alert
  • make you less aware of things around you (delirious)

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect XPOVIO.

4. How do I use XPOVIO?

How much to take

Follow the instructions provided and use XPOVIO until your doctor tells you to stop.

You may experience side effects while taking XPOVIO. These side effects are usually temporary. Your doctor may manage these side effects by asking you to stop taking XPOVIO or prescribing a different dose from the recommended dose below.

If you vomit after taking XPOVIO, do not take an extra dose. Take your next dose when you are next meant to.

XPOVIO taken with bortezomib and dexamethasone

The recommended dose of XPOVIO in combination with bortezomib and dexamethasone is based on a 35-day cycle as follows:

  • Take 100 mg (5 XPOVIO 20 mg tablets) by mouth once a week on days 1, 8, 15, 22 and 29.
  • Bortezomib will be injected under the skin once a week on days 1, 8, 15 and 22.
  • Take 20 mg of dexamethasone by mouth on days 1, 2, 8, 9, 15, 16, 22, 23, 29 and 30.

XPOVIO taken with dexamethasone alone

The recommended starting dose of XPOVIO in combination with dexamethasone is two times a week as follows:

  • Take 80 mg (4 XPOVIO 20 mg tablets) by mouth twice a week on days 1 and 3 of each week.
  • Take 20 mg of dexamethasone by mouth on days 1 and 3 of each week.

When to take XPOVIO

Take XPOVIO at about the same time on the days you are required to take it.

How to take XPOVIO

Swallow the tablets whole with water. Do not crush, chew, break, or divide the tablets. Take the tablets with or without food.

If you forget to use XPOVIO

If you miss your dose at the usual time, skip the dose you missed and take your next dose when you are next meant to.

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

If you use too much XPOVIO

If you think that you have used too much XPOVIO, 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 using XPOVIO?

Things you should do

It is important for you to drink enough fluids to help prevent dehydration.

It is important to eat enough calories to help prevent weight loss.

Take all your medicines as prescribed by your doctor. These include dexamethasone and medicines to prevent or treat nausea, vomiting or diarrhoea.

Keep your appointments with your doctor and any blood tests.

Males and women capable of bearing children should abstain from sexual intercourse or use an effective form of contraception while taking this medicine and for at least 1 week after your last dose.

Take precautions against falling, especially if you are elderly. XPOVIO can cause dizziness, fainting, drowsiness, and fatigue.

Remind any doctor, dentist, or pharmacist you visit that you are taking XPOVIO.

Call your doctor straight away if you:

  • become pregnant while taking this medicine.

Things you should not do

  • Do not breastfeed while using this medicine and for at least 1 week after your last dose.
  • Do not stop using this medicine or change the dose unless your doctor tells you to.
  • Do not use this medicine for 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how XPOVIO affects you.

XPOVIO may cause fatigue, dizziness, and confusion in some people. Do not drive or use any machines if you experience any of these symptoms.

Looking after your medicine

  • Store below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example:

  • do not store it in the bathroom or near a sink, or
  • do not store it in the car or on window sills.

Keep it where young children cannot reach it.

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.

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
  • weakness
  • muscle spasms
  • bone pain
  • low red blood cell count (anaemia). Symptoms may include tiredness and shortness of breath
  • eye problems such as blurred vision
  • headache
  • problems with taste
  • insomnia
Nerve-related
  • numbness and tingling in the feet or hands
  • burning, stabbing, or sharp pain
Blood test-related
  • increased blood sugar
  • changes in kidney or liver function blood tests
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
Gut or stomach-related
  • nausea
  • vomiting
  • diarrhoea
  • constipation
  • dehydration
  • loss of appetite
  • weight loss
  • gut pain
Bleeding-related
  • long or excessive bleeding
  • easy bruising
  • nose bleeds
Brain-related
  • dizziness, fainting, confusion, delirious, or less alert
  • drowsiness and sleepiness
  • seeing or hearing things that are not there
  • problems with thinking clearly
Infection-related
  • chills or fever
  • cough
  • sore throat
  • difficulty breathing
  • rapid breathing
  • chest pain
  • problems passing urine
  • painful blisters
  • flu-like symptoms
Allergy-related
  • 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
Others
  • low sodium levels in your blood
  • low levels of white blood cells
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

This medicine is only available with a doctor's prescription.

What XPOVIO contains

Active ingredient
(main ingredient)		Each film-coated tablet contains 20 mg of selinexor
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • croscarmellose sodium
  • povidone
  • silicon dioxide
  • magnesium stearate
  • sodium lauryl sulfate
  • OPADRY 200 Optimized Performance Coatings 203A190001 Clear
  • OPADRY II Complete Film Coating System 85F90892 Blue
Potential allergensNot applicable

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

What XPOVIO looks like

XPOVIO is a blue, round, curved, film-coated tablet with K20 debossed on one side and blank on the other side (Aust R 346589).

XPOVIO tablets are packed in blister foils in cartons.

Each pack contains 8, 12, 16, 20, 24 or 32 tablets. Not all pack sizes are available.

Who distributes XPOVIO

Antengene (Aus) Pty Ltd
Level 34, 140 William St
Melbourne VIC 3000

Version 2.0

® Registered Trademark

This leaflet was prepared in February 2023.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Xpovio

Active ingredient

Selinexor

Schedule

S4

 

1 Name of Medicine

Selinexor.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 20 mg of selinexor.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Blue, round, bi-convex, round, film-coated tablets with "K20" debossed on one side and nothing on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Xpovio is indicated:
In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory medicinal product (IMiD), and an anti-CD38 monoclonal antibody (mAb).

4.2 Dose and Method of Administration

Treatment must be initiated and monitored under supervision of physicians experienced in the management of multiple myeloma.

Dosage.

In combination with bortezomib and dexamethasone (SVd).

The recommended starting dose of Xpovio in combination with bortezomib and dexamethasone is based on a 35-day cycle as follows:
Xpovio 100 mg (five 20 mg tablets) is taken orally once weekly on Days 1, 8, 15, 22 and 29.
Bortezomib 1.3 mg/m2 is administered subcutaneously once weekly on Days 1, 8, 15 and 22.
Dexamethasone 20-mg is taken orally on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30.
Treatment is administered until disease progression or unacceptable toxicity, for additional information regarding the administration of bortezomib and dexamethasone, refer to their respective prescribing information.

In combination with dexamethasone (Sd).

The recommended starting dose is 80 mg (four 20 mg tablets) of Xpovio on Days 1 and 3 of each week.
The recommended starting dose of dexamethasone is 20 mg taken orally on Days 1 and 3 of each week with Xpovio. For additional information regarding the administration of dexamethasone, refer to its product information.
Treatment should be continued until disease progression or unacceptable toxicity.

Dose modifications for adverse reactions.

Continued treatment of Xpovio may require appropriate dose modifications (reductions and/or interruptions) in the event of adverse reactions. Dose modifications utilised in clinical trials are presented in Tables 1-3.
Recommended Xpovio dose reduction steps for adverse reactions are presented in Table 1.
Recommended dosage modifications for hematologic adverse reactions in patients with multiple myeloma (both SVd and Sd) is presented in Table 2.
Recommended dosage modifications for non-hematologic adverse reactions in all Xpovio treated patients are presented in Table 3.
For information regarding dosage modification of drugs given in combination with Xpovio, see the drugs manufacturer's product information.

Method of administration.

The tablet should be swallowed whole with water. It should not be crushed, chewed, broken or divided in order to prevent risk of skin irritation from the active substance. It can be taken with or without food.
If a Xpovio dose is missed or delayed or a patient vomits after a dose of Xpovio , the patient should not repeat the dose. Patients should take the next dose on the next regularly scheduled day.
Advise patients to maintain adequate fluid and caloric intake throughout treatment.
Consider intravenous hydration for patients at risk of dehydration.

Dosage adjustment.

Use in hepatic impairment.

No dose adjustment is needed in patients with mild to moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dosage adjustment of Xpovio is recommended for patients with mild, moderate or severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

For medicinal products administered in combination with Xpovio, the product information of these medicinal products must be consulted prior to initiation of treatment, including for special warnings and precaution for use and recommended concomitant treatments.

Haematologic.

Patients should have their complete blood counts (CBC) assessed at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment.

Thrombocytopenia.

Xpovio can cause life-threatening thrombocytopenia or may increase thrombocytopenia induced by concomitant therapy, leading to potentially fatal haemorrhage.
Thrombocytopenia can be managed with dose interruptions, modifications, platelet transfusions, and/or other treatments as clinically indicated. Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). For dose modification guidelines, see Table 1, Table 2 and Table 3.

Neutropenia.

Xpovio can cause life-threatening neutropenia, potentially increasing the risk of infection.
Obtain white blood counts with differential at baseline and throughout, and as clinically indicated. Monitor more frequently during the first three months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g. G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)].

Gastrointestinal toxicity.

Xpovio can cause severe gastrointestinal toxicities (see Section 4.8 Adverse Effects (Undesirable Effects)).

Nausea/vomiting.

Grade 3 or higher nausea/vomiting events have occurred and there have been events that resulted in permanent discontinuation.
Provide prophylactic 5-HT3 antagonists and other anti-nausea agents, prior to and during treatment with Xpovio. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated (see Section 4.2 Dose and Method of Administration).

Diarrhoea.

Grade 3 or higher diarrhoea events have occurred and there have been events that resulted in permanent discontinuation.
Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction [see Section 4.2 Dose and Method of Administration]. Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.

Fatigue, weight loss and anorexia.

Xpovio can cause fatigue, weight loss, and anorexia. Grade 3 fatigue, weight loss and anorexia events have occurred and there have been events that resulted in permanent discontinuation.
Monitor patient weight, nutritional status and volume status at baseline, and throughout treatment and as clinically indicated. Monitor more frequently during the first three months of treatment. Interrupt, reduce dose or permanently discontinue based on severity of adverse reactions. Provide nutritional support, fluids and electrolyte repletion as clinically indicated. [See Section 4.2 Dose and Method of Administration]. For dose modification guidelines, see Table 1 and Table 3. Patients should be advised not to drive or operate heavy machinery (see Section 4.7 Effects on Ability to Drive and Use Machines).

Neurological toxicity.

Xpovio can cause life-threatening neurological toxicities including confusional state and dizziness (see Section 4.8 Adverse Effects (Undesirable Effects)).

Dizziness.

Coadministration of Xpovio with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Optimise hydration status, haemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.
Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate heavy machinery (see Section 4.7 Effects on Ability to Drive and Use Machines).

Hyponatraemia.

Xpovio can cause severe or life-threatening hyponatraemia (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycaemia (serum glucose > 150 mg/dL) and high serum paraprotein levels. Hyponatraemia should be treated as per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Patients may require Xpovio dose interruption and/or modification based on severity of adverse reaction (see Section 4.8 Adverse Effects (Undesirable Effects)). For dose modification guidelines, see Table 1, and Table 3.

Serious infection.

Xpovio can cause serious and fatal infections. Most of these infections were not associated with Grade 3 or higher neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Atypical infections reported after Xpovio include, but are not limited to, fungal pneumonia and herpesvirus infection. Monitor for signs and symptoms of infection, evaluate and treat promptly.

Cataracts.

New onset or exacerbation of cataract has occurred during Xpovio therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Manage cataracts per standard clinical guidelines. Monitor for signs and symptoms of cataract, perform ophthalmic evaluation, reduce dose and monitor for progression. If surgery is warranted, hold Xpovio dose 24 hours prior to cataract surgery and for 72 hours after surgery (see Section 4.2 Dose and Method of Administration).

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) has been reported in patients receiving therapy with Xpovio. Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with clinical guidelines.

Use in hepatic impairment.

No dose adjustment is needed in patients with mild to moderate hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dosage adjustment of Xpovio is recommended for patients with mild, moderate or severe renal impairment. Xpovio use in patients requiring dialysis has not been established (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Use in the elderly.

Multiple myeloma.

No overall difference in effectiveness was observed in patients over 65 years of age, including patients over 75 years of age, when compared with younger patients. When comparing patients 75 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction, a higher incidence of serious adverse reactions, and a higher incidence of fatal adverse reactions. Also see Section 5.2 Pharmacokinetic Properties, Special populations, Age, sex, race.

Paediatric use.

The safety and efficacy of Xpovio in children below the age of 18 years of age have not been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Exposure of Xpovio was not affected by co-administration with paracetamol at a daily dose up to 1000 mg.
Selinexor is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inducer might lead to lower exposure of Xpovio.
In vitro, selinexor was shown to not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5, or UGT1A1, 1A3, 1A4, 1A6, 1A9 or 2B7, at clinically relevant concentrations. Selinexor is not an inducer of CYP1A2, 2B6 or 3A4, and is not a substrate of P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1 or MATE2-K. Selinexor inhibits OATP1B3, but not OATP1B1, OAT1, OAT3, OCT2, MATE1 or MATE2-K, at clinically relevant concentrations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on findings in animals, Xpovio may impair fertility in females and males.
No fertility studies have been conducted with selinexor in animals. Impairment of male and female fertility in patients is suggested by findings in general repeat-dose toxicity studies. Selinexor reduced sperm, spermatids and germ cells in the epididymides and testes in rats at oral doses ≥ 0.25 mg/kg, decreased ovarian follicles in rats at ≥ 2 mg/kg, and produced single cell necrosis in the testes of monkeys with treatment at ≥ 1.5 mg/kg. These doses resulted in systemic exposure (plasma AUC) well below that of patients at the maximum recommended human dose. Reversibility of the male reproductive tract findings was not demonstrated in animals.

Women of childbearing potential/ contraception in males and females.

Women of childbearing potential should be advised to avoid becoming pregnant or abstain from sexual intercourse while being treated with Xpovio and for at least 1 week following the last dose of Xpovio. A pregnancy test is recommended for women of childbearing potential prior to initiating Xpovio treatment.
Male patients of reproductive potential should be advised to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with Xpovio and for at least 1 week following the last dose of Xpovio.
(Category D)
There are no data from the use of Xpovio in pregnant women. Based on findings in animal studies and its mechanism of action, Xpovio can cause fetal harm when administered to a pregnant woman.
Administration of selinexor to pregnant rats during organogenesis resulted in reduced fetal weight, impaired ossification and increased fetal skeletal variations at oral doses ≥ 0.75 mg/kg/day. Malformations (microphthalmia, fetal oedema, malpositioned kidney and persistent truncus arteriosus) were observed at 2 mg/kg/day. These doses yield systemic exposure well below that of patients at the maximum recommended clinical dose (4-16 times lower than the human AUC at 100 mg). At 5 mg/kg/day (estimated to yield 0.6 times the clinical AUC), selinexor was embryolethal in rats.
Xpovio is not recommended during pregnancy and in women of childbearing potential not using contraception. Verify the pregnancy status of females of reproductive potential prior to initiating Xpovio.
Advise pregnant women of the potential risk to a fetus. If the patient becomes pregnant while taking Xpovio, treatment should be immediately discontinued, and the patient should be apprised of the potential hazard to the fetus.
 It is unknown whether Xpovio or its metabolites are excreted in human milk, or their effects on the breastfed child or milk production. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with Xpovio and for 1 week after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Xpovio has the potential to have a major influence on the ability to drive and use machines. Xpovio can cause fatigue, confusional state and dizziness. Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate machines if they experience any of these symptoms.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety data of selinexor have been assessed in patients with multiple myeloma treated with selinexor in combination with dexamethasone (202 patients-STORM trial) or selinexor in combination with bortezomib and dexamethasone (195 patients-BOSTON trial).
In combination with bortezomib and dexamethasone (SVd, BOSTON trial). The safety data described are based on the BOSTON study, a global, randomised, open-label clinical trial in patients with previously treated multiple myeloma (n = 399). In BOSTON, once-weekly Xpovio 100 mg was administered with once-weekly bortezomib 1.3 mg/m2 and twice-weekly oral dexamethasone 20 mg (SVd) and compared to twice-weekly bortezomib 1.3 mg/m2 with twice-weekly dexamethasone 20 mg (Vd) (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).
Adverse events (AEs) and laboratory abnormalities described in Table 4 and Table 5 reflect exposure to Xpovio for a median treatment duration of 30 weeks (range: 1 to 120 weeks) and median dose of 80 mg/week (range: 30 to 137) for the SVd patient group (n = 195) and median treatment duration of 32 weeks (range: 1 to 122 weeks) for the Vd patient group (n = 204).
The most frequent (≥ 20%) non-hematologic AEs with a 5% greater incidence in the SVd arm compared to the Vd arm were nausea, fatigue, decreased appetite, diarrhea, upper respiratory tract infection, weight decreased, asthenia, cataract, and vomiting. Serious AEs were reported in 52% and 38% of SVd- and Vd-treated patients, respectively.
There was a similar number of fatal AEs in the SVd (12 patients) and in the Vd (11 patients) arms, within 30 days of last treatment. Fatal AEs occurred in 12 patients in both the SVd and Vd arms, within 60 days of last treatment. The most frequent fatal AEs in SVd-treated patients were pneumonia and septic shock (n = 3 each) and it was pneumonia (n = 3) in Vd-treated patients.
There were no serious AEs with a 5% greater incidence in the SVd arm compared to the Vd arm. Serious AEs with a 2% greater incidence in the SVd arm compared to the Vd arm were diarrhea (SVd 4% vs Vd 0%), vomiting (SVd 4% vs Vd 0%), cataract (SVd 2% vs Vd 0%), nausea (SVd 2%, Vd 0%), urinary tract infection (SVd 2%, Vd 0%), and septic shock (SVd 2%, Vd 0%).
A statistically significant reduction in all Grades and Grade ≥ 2 peripheral neuropathy was noted in patients receiving SVd (32% and 21%) compared with patients receiving Vd (47% and 34%) [odds ratio 0.52 and 0.50, respectively, one-sided p = 0.0013]. A nominal reduction in severe neuropathy (Grade ≥ 3) was also observed in SVd treated patients (5% SVd vs. 9% Vd).
The proportion of patients who discontinued any component of the treatment regimen due to AEs was 21% in the SVd arm and 16% in the Vd arm. Xpovio dose reductions and interruption occurred in 65% and 87% of SVd-treated patients. Bortezomib dose reduction and interruption occurred in 43% and 82% of the SVd-patient group and 45% and 74% of the Vd-patient group. Dexamethasone dose reduction and interruption occurred in 27% and 80% of the SVd-patient group and 36% and 73% of the Vd-patient group.
Clinically relevant AEs in < 10% of patients who received Xpovio in combination with bortezomib and dexamethasone included:

Neurologic disorders.

Mental status changes consisting of confusional state and delirium (9%) and syncope (3.6%).
Table 5 summarises selected new or worsening laboratory abnormalities in the BOSTON trial. Grade 3-4 laboratory abnormalities in ≥ 15% in the Xpovio combination with bortezomib and dexamethasone (SVd) arm included thrombocytopenia, lymphopenia, anemia, and hypophosphatemia. Grade 4 laboratory abnormalities in ≥ 5% were thrombocytopenia (13%), and lymphopenia (7%).
In combination dexamethasone (Sd; STORM trial). The most frequent AEs were nausea (75%), thrombocytopenia (75%), fatigue (66%), anaemia (60%), decreased appetite (56%), decreased weight (49%), diarrhoea (47%), vomiting (43%), hyponatraemia (40%), neutropenia (36%) and leukopenia (30%).
Serious AEs were pneumonia (7.5%), sepsis (6.1%) thrombocytopenia (4.7%), acute kidney injury (3.7%), anaemia (3.3%), hyponatraemia (2.8%), pyrexia (2.8%), and dehydration (2.3%).

Tabulated list of AEs.

AEs are presented by MedDRA system organ class and within each SOC and frequency grouping, AEs are presented in order of decreasing seriousness (see Table 6). Frequency categories are defined as: 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). AEs presented by any Grade and Grade are presented in Table 7.

Description of selected adverse events.

Infection.

In the BOSTON trial of patients with multiple myeloma, 69% of patients in the Xpovio 100 mg once weekly combined with bortezomib and dexamethasone (SVd, n = 195) arm and 59% of patients in bortezomib and dexamethasone arm (Vd, n = 204) experience any grade of infection. Grade ≥ 3 infections were reported in 32% and 18% of the SVd and Vd treated patients, respectively. Fatal infections were reported in 3.1% and 1.5% of SVd- and Vd-treated patients, respectively. The most common reported Grade ≥ 3 infection was pneumonia (14% SVd and 12% Vd), upper respiratory tract infection (3.6% SVd and 1.5% Vd) and sepsis (4.1% SVd and < 1% Vd).
In the STORM trial, infection was the most common non-haematological toxicity; occurring in 53% of patients. Of these, 22% were Grade 3 or 4. Upper respiratory tract infection and pneumonia were the most commonly reported infections (in 15% and 13% of patients, respectively) with 25% of reported infections being serious and fatal infections occurring in 3% of treated patients. Infection led to dose discontinuation in 7% of patients, treatment interruption in 19% patients, and a dose reduction in 1% of patients.

Thrombocytopenia.

In the BOSTON trial of patients with multiple myeloma (n = 399), thrombocytopenia (all Grades) and severe thrombocytopenia (Grade 3-4) were reported in 92% and 43% of patients in the Xpovio 100 mg once weekly combined with bortezomib and dexamethasone (SVd, n = 195) arm and in 51% and 19% of patients in the bortezomib and dexamethasone arm (Vd, n = 204), respectively. The median time to first onset was 22 days for any-grade thrombocytopenia in both the SVd and Vd arms. The median time to first onset for Grade 3 or higher thrombocytopenia was 43 and 32 days for the SVd and Vd arms, respectively. Bleeding/clinically significant bleeding occurred in 16%/4% and 7%/4% of SVd- and Vd-treated patients with thrombocytopenia, respectively. Fatal hemorrhage occurred in 1% and < 1% of patients with thrombocytopenia in the SVd and Vd arm, respectively. Discontinuations due to thrombocytopenia occurred in 2% of SVd- and < 1% of Vd-treated patients.
In the STORM trial, thrombocytopenia occurred in 75% of patients and 65% of these AEs were Grade 3 or 4. Thrombocytopenia was serious in 5% of patients. Of the 65% patients with Grade 3 or 4 thrombocytopenia, serious/grade 3 or higher concurrent bleeding events (concurrency defined as ± 5 days) were reported in 5% of patients. Thrombocytopenia led to dose discontinuation in 3% of patients, treatment interruption in 22% of patients, and a dose reduction in 32% of patients.

Neutropenia.

In the BOSTON trial of patients with multiple myeloma (n = 399), neutropenia (all Grades) and severe neutropenia (Grade 3-4) were reported in 48% and 12% of patients in the Xpovio 100 mg once weekly combined with bortezomib and dexamethasone (SVd, n = 192) arm, 19% and 7% of patients in the bortezomib and dexamethasone arm (Vd, n = 196). The median time to first onset was 23 and 36 days for any-grade neutropenia in the SVd and Vd arms, respectively. The median time to first onset for Grade 3 or higher neutropenia was 40 and 28 days for the SVd and Vd arms, respectively. Febrile neutropenia occurred in < 1% of SVd- and Vd-treated patients. Discontinuations due to neutropenia did not occur in SVd- nor Vd-treated patients.
In the STORM trial, neutropenia occurred in 36% of patients and 25% of these were Grade 3 or 4. Neutropenia was serious in less than 1% of patients. None of the patients had a dose discontinuation due to neutropenia, and neutropenia led to treatment interruption in 2% of patients, and a dose reduction in 6% of patients. Febrile neutropenia occurred in 3% of patients; all were Grade 3 or 4. Febrile neutropenia was reported to be serious in 2% of patients and led to a dose discontinuation, treatment interruption, or a dose reduction in less than 1% of patients (each). Of the 53 patients with grade 3 or higher neutropenia, serious/grade 3 or higher concurrent infections (concurrency defined as ± 5 days) were reported in 11 patients. Most commonly reported infections included pneumonia (4), sepsis (3), bacteraemia (2) and lung infection (2).

Anaemia.

In the BOSTON trial, anaemia was reported in the most frequent (≥ 10%) AEs with a 5% greater incidence in the SVd arm compared to the Vd arm. Thirty-six percent of patients were reported as having any Grade, with 16% as Grade 3.
In the STORM trial, anaemia occurred in 61% of patients and 44% of these were Grade 3 or 4. Anaemia was serious in 3% of patients and led to dose discontinuation in < 1% of patients, treatment interruption in 4% of patients, and a dose reduction in 1% of patients.

Gastrointestinal toxicity.

Prophylaxis with 5HT3 antagonists and other similar antiemetics should be administered prior to and during Xpovio treatment. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated. Nausea/vomiting can be managed by dose interruption, reduction and/or discontinuation. Diarrhoea can be managed with dose modification or administration of anti-diarrhoea medicinal products. For dose modification guidelines, see Table 1 and Table 3.
In the BOSTON trial, nausea (all Grades) and ≥ Grade 3 nausea were reported in 50% and 8% of patients in the SVd arm and in 10% and 0% of patients in the Vd arm. The median time to onset of the first event was 6 and 73 days in the SVd- and Vd-treated patients, respectively. Discontinuations due to nausea occurred in 3% of SVd-treated patients and none of Vd-treated patients.
Vomiting (all Grades) and ≥ Grade 3 vomiting was reported in 21% and 4% of patients in the SVd-treated patients and 4% and 0% in the Vd-treated patients. The median time to onset of the first event was 8 days and 49 days in the SVd- and Vd-treated patients, respectively. Discontinuations due to vomiting occurred in 2% of SVd-treated patients and none of Vd-treated patients.
Diarrhea (all Grades) and ≥ Grade 3 diarrhea were reported in 32% and 6% of patients in the SVd arm and 25% and < 1% of patients in the Vd arm. The median time to onset of the first event was 50 days in SVd- and 71 days in Vd-treated patients. Discontinuations due to diarrhea occurred in 1% and < 1% of SVd- and Vd-treated patients, respectively.
In the STORM trial, nausea/vomiting occurred in 79% of patients and 10% of these were Grade 3 or 4 and they were serious in 3% of patients. When anti-nausea treatment was administered, the median duration of nausea or vomiting improved by 3 days. Nausea/vomiting led to dose discontinuation in 5% of patients, treatment interruption in 8% of patients, and a dose reduction in 5% of patients.
Diarrhoea occurred in 47% of patients and 7% were Grade 3 or 4. Diarrhoea was serious in 2% of patients, and led to dose discontinuation in 1% of patients, treatment interruption in 2% of patients, and a dose reduction in 1% of patients.

Hyponatraemia.

Hyponatraemia can be managed with dose interruptions/reductions and with intravenous saline and/or salt tablets, including dietary review. Advise patients that levels of sodium will be monitored at baseline and during treatment as clinically indicated, with more frequent monitoring during the first two months of treatment. For additional supportive care information, please see Section 4.4 Special Warnings and Precautions for Use.
In the BOSTON trial of patients with multiple myeloma, hyponatremia (all Grades) and Grade 3-4 were reported in 58% and 14% of patients in the Xpovio 100 mg once weekly combined with bortezomib and dexamethasone (SVd, n = 195) arm and in 25% and 3% of patients in the bortezomib and dexamethasone arm (Vd, n = 201). The median time to first onset was 21 and 43 days for any-grade hyponatremia in the SVd and Vd arms, respectively. The median time to first onset for Grade 3 or higher hyponatremia was 22 and 14 days for the SVd and Vd arms, respectively. No treatment discontinuation due to hyponatremia occurred.
In the STORM trial, hyponatraemia occurred in 40% of patients and 24% were Grade 3 or 4. Hyponatraemia was serious in 3% of patients. Most cases of hyponatraemia were not associated with any symptoms. There were no reports of concurrent seizures. Hyponatraemia did not lead to any dose discontinuation, and it led to treatment interruption in 6% of patients, and a dose reduction in 1% of patients.

Tumour lysis syndrome.

Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with institutional guidelines (see Section 4.4 Special Warnings and Precautions for Use).
In the STORM trial, tumour lysis syndrome (TLS) occurred in one (< 1%) patient which was considered Grade 3 and serious.

Neurological toxicity.

Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, haemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.
In the BOSTON trial of patients with multiple myeloma, neurological AEs (excluding peripheral neuropathy) including dizziness, syncope, depressed level of consciousness, vertigo, amnesia and mental status changes (including delirium and confusional state) occurred in 26% and 9% of SVd-treated patients (Xpovio 100 mg once weekly combined with bortezomib and dexamethasone, n = 195) and Vd-treated patients (bortezomib and dexamethasone arm, n = 204), respectively. Severe events (Grade 3-4) occurred in 3.6% and 1.5% of patients treated with SVd and Vd, respectively. Median time to the first event was 29 days in the SVd arm and 61 days in the Vd arm. Discontinuations due to neurological AEs occurred in 2.1% of SVd-treated patients and 1% of Vd-treated patients.
In the STORM trial, neurological AEs including dizziness, dysgeusia and headache were reported as very common, with syncope a common Grade 3-4 reaction. Other common neurological AEs included peripheral neuropathy, disturbance in attention, ageusia and cognitive disorders. Encephalopathy was considered an uncommon Grade 3-4 reaction.

Anorexia/weight loss.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.
In the BOSTON trial, anorexia (all Grades) and ≥ Grade 3 anorexia was reported in 35% and 4% of patients in the SVd arm and in 5% and 0% of patients in the Vd arm. The median time to onset of the first event was 35 and 63 days in the SVd- and Vd-arms, respectively. Discontinuations due to anorexia occurred in 2% and < 1% of SVd and Vd treated patients, respectively.
Weight loss (all Grades) and Grade 3 weight loss was reported in 26% and 2% of patients in the SVd arm and in 12% and 1% of patients in the Vd arm. The median time to onset of the first event was 58 and 110 days in the SVd and Vd arms, respectively. Discontinuations due to weight loss occurred in 1% and < 1% of the SVd and Vd-treated patients, respectively.

Cataracts.

Manage cataract per standard clinical guidelines.
In the BOSTON study, the incidence of new onset or worsening all Grades cataract requiring clinical intervention was reported in 22% and 6% in the SVd- and Vd-treated patients, respectively. Grade 3/4 cataracts occurred in 9%/0% and 0%/1% of SVd- and Vd-treated patients, respectively. In patients who received Xpovio, cataract did not result in treatment discontinuation.

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

Overdose due to accidental excessive ingestion of selinexor has been reported. Please refer to selinexor dosing instructions to avoid dosing errors (see Section 4.2 Dose and Method of Administration).

Symptoms.

In general, overdoses have been associated with similar side effects to those reported for standard dosing and have generally been reversible within 1 week.
Potential acute symptoms include nausea, vomiting, diarrhoea, dehydration and confusion. Potential signs include low sodium levels, elevated liver enzymes, and low blood counts. Patients should be monitored closely and provided supportive care as appropriate. No fatalities due to overdose have been reported to date.

Management.

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
In the event of an overdose, monitor the patient for any adverse reactions and appropriate symptomatic treatment should be provided immediately.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1). XPO1 is a major nuclear export protein that transports cargo proteins and several classes of mRNA from the nucleus to the cytoplasm. XPO1 cargoes include many tumour suppressor proteins (TSPs), growth regulator proteins (GRPs) and mRNAs of growth promoting (oncogenic) proteins. XPO1 inhibition by selinexor leads to marked accumulation of TSPs and GRPs (such as p53, p21, FOXO and IκB) in the nucleus (their site of action), and reduced expression of several oncoproteins (such as c-Myc, Bcl2 and cyclin D1) and translation/chaperon proteins (Hsp70), resulting in cell cycle arrest and apoptosis of cancer cells. The combination of selinexor and dexamethasone or bortezomib demonstrated synergistic cytostatic and cytotoxic effects in multiple myeloma in vitro and in vivo models, including those resistant to proteasome inhibitors. Selinexor demonstrated pro apoptotic activity in vitro in multiple myeloma and diffuse large B-cell lymphoma cell lines, in murine xenograft models as well as in patient tumour samples.

Cardiac electrophysiology.

The effect of multiple doses of selinexor up to 175 mg twice weekly on the QTc interval was evaluated in patients with heavily pre-treated haematologic malignancies. Selinexor had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.

Clinical trials.

Multiple myeloma.

In combination with bortezomib and dexamethasone (SVd), BOSTON trial.

The efficacy of Xpovio plus dexamethasone was evaluated in BOSTON (KCP-330-023; NCT03110562). BOSTON, a global, randomized, open label, active-controlled Phase 3 study, compared treatment of once weekly Xpovio 100 mg (Days 1, 8, 15, 22, 29) in combination with once-weekly subcutaneous bortezomib 1.3 mg/m2 (Days 1, 8, 15, 22) and twice weekly low-dose dexamethasone 20 mg (Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30) of a repeated 35-day cycle [SVd arm] to treatment with twice-weekly subcutaneous bortezomib 1.3 mg/m2 (Days 1, 4, 8, 11) and low-dose dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12) of a standard 21-day cycle for the first 8 cycles, followed by weekly subcutaneous bortezomib 1.3 mg/m2 (Days 1, 8, 15, 22), low-dose dexamethasone 20 mg (Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30) of 35-day cycle (Cycle ≥ 9) [Vd arm].
Treatment was continued in both arms until disease progression or unacceptable toxicity. Upon confirmed progressive disease (PD), patients in the control arm (Vd) could cross over to receive Xpovio-based therapy in the form of weekly SVd (BOSTON regimen) or weekly Sd (Xpovio 100 mg Days 1, 8, 15, 22, 29 and low-dose dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30) of each 35-day cycle.
Antiemetic prophylaxis was used in 88% and 36% of patients in the SVd arm and Vd arm, respectively.
A total of 402 patients were randomized: 195 to SVd arm and 207 to Vd arm. Baseline patient and disease characteristics were well balanced and comparable between the two arms as described in Table 8 and Table 9, respectively.
The primary endpoint was progression free survival (PFS) according to the International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma, as assessed by an Independent Review Committee (IRC). BOSTON demonstrated a statistically significant improvement in PFS in the SVd arm compared to the Vd arm; hazard ratio (HR) = 0.70 (95% CI: 0.53-0.93; p = 0.0075).
Efficacy results are shown in Table 10 and Figure 1.
The median time to response was 1.1 month in the SVd-treated patients and 1.4 month in the Vd-treated patients. The median duration of response, among responding patients, was 20.3 months and 12.9 months in the SVd and Vd arms, respectively.
At the time of the pre-planned OS interim analysis (median follow up of 17.3 and 17.5 months for SVd and Vd arms, respectively), a total of 109 OS events have occurred; there were 47 and 62 deaths in the SVd and Vd arms respectively (HR = 0.84 [95% CI: 0.58, 1.23]).

In combination with dexamethasone (Sd, STORM trial).

In a phase 2, multi-centre, single-arm, open-label, study, 123 patients with RRMM were treated with 80 mg selinexor in combination with 20 mg dexamethasone on Days 1 and 3 of every week.
Treatment continued until disease progression, death or unacceptable toxicity. The median duration of selinexor treatment was 9 weeks (range: 1 to 76 weeks). The median total dose of selinexor received was 920 mg (range 160 to 6,220 mg), with a median dose of 113.6 mg (range: 22 to 240 mg) received per week.
Table 11 provides patients disease and prior treatment characteristics.
The primary efficacy endpoint was overall response rate (ORR) as assessed by an independent review committee based on the International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. Responses were assessed monthly and as per IMWG guidelines. Secondary efficacy endpoints included duration of response (DOR), defined as the duration from start of response to disease progression, and overall survival (OS), defined as the duration from start of study treatment to death due to any cause. Table 12 provides an overview of the efficacy results.
No difference in ORR was observed based on baseline characteristics. Both patients relapsing from prior CAR-T therapy had a PR on selinexor plus dexamethasone.

5.2 Pharmacokinetic Properties

Following a single-dose administration of Xpovio 100 mg, the mean (standard deviation) peak plasma concentration (Cmax) was 693 (201) nanogram/mL and the mean AUC was 6998 (818) nanogram.h/mL.
Selinexor Cmax and AUC increased proportionally over doses from 3 mg/m2 to 85 mg/m2 (0.045 to 1.8 times the approved recommended dose based on 1.7 m2 body surface area). No clinically relevant accumulation at steady state was observed.

Absorption.

Following oral administration of selinexor peak plasma concentration, Cmax is reached within 4 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not have a clinically significant effect on the pharmacokinetics of selinexor.

Distribution.

Selinexor is 95% bound to human plasma proteins. In a population pharmacokinetic (PK) analysis, the apparent volume of distribution (Vd/F) of selinexor was 133 L in cancer patients.

Metabolism.

Selinexor is metabolised by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).

Excretion.

Following a single dose of 80 mg selinexor the mean half-life (t1/2) is 6 to 8 hours. In a population PK analysis, the apparent total clearance (CL/F) of selinexor was 18.6 L/h in cancer patients.

Special populations.

Age, sex, race.

Age (18 to 94 years of age), body weight (36 to 168 kg), sex, or race had no clinically significant effect on the pharmacokinetics of selinexor.
In the population pharmacokinetic dataset, the median age was 68 years. Although age was identified as a significant covariate for the absorption rate constant (ka), the estimate was very small. The overall exposure (AUC and Cmax) was similar between younger (18-64 years of age) and older patients (65 years of age and older).
There was no clinically significant effect of gender; although it was identified as a significant covariate.

Renal impairment.

No clinically significant differences in the pharmacokinetics of selinexor were observed based on age, mild to severe renal impairment (CLCR: 15 to 89 mL/min, estimated by the Cockcroft-Gault equation), and disease type (hematological non-DLBCL, solid tumor, DLBCL). The effect of end-stage renal disease (CLCR < 15 mL/min) or hemodialysis on selinexor pharmacokinetics is unknown. Mild renal impairment had no clinically significant effect on the pharmacokinetics of selinexor.

Hepatic impairment.

Mild hepatic impairment had no clinically significant effect on the pharmacokinetics of selinexor. The effect of moderate and severe hepatic impairment on selinexor pharmacokinetics is unknown. No dose adjustment is needed in patients with mild to moderate hepatic impairment according to the National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG) criteria.

5.3 Preclinical Safety Data

Genotoxicity.

Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro chromosomal aberration assay in human lymphocytes or in the in vivo rat micronucleus assay.

Carcinogenicity.

Carcinogenicity studies have not been conducted with selinexor.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose (PH-101), croscarmellose sodium, povidone, silicon dioxide, magnesium stearate, microcrystalline cellulose (PH-102), sodium lauryl sulfate, Opadry 200 optimized performance coatings 203A190001 Clear, Opadry II complete film coating system 85F90892 Blue.

6.2 Incompatibilities

Not applicable.

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 below 30°C.

6.5 Nature and Contents of Container

PVC/PCTFE/PVC-aluminium blisters.
Each pack contains an outer carton containing 16, 20, 24 or 32 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Selinexor is (2Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)prop-2-enehydrazide. It is a white to off-white powder and has the molecular formula C17H11F6N7O and a molecular mass of 443.31 g/mol.

Chemical structure.


Molecular formula: C17H11F6N7O.

CAS number.

1393477-72-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes