Consumer medicine information

Koselugo

Selumetinib

BRAND INFORMATION

Brand name

Koselugo

Active ingredient

Selumetinib

Schedule

SUMMARY CMI

KOSELUGO^®

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 taking KOSELUGO?

KOSELUGO contains the active ingredient selumetinib. KOSELUGO is used to treat paediatric patients (2 years and above) who have NF1 and a type of tumour (symptomatic plexiform neurofibromas) that cannot be completely removed by surgery.

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

2. What should I know before I take KOSELUGO?

Do not use if you have ever had an allergic reaction to KOSELUGO or any of the ingredients listed at the end of the CMI or if you have severe liver disease. 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 take KOSELUGO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KOSELUGO 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 take KOSELUGO

Take KOSELUGO twice a day, about 12 hours apart, with or without food.
Swallow the capsules whole with water.
Do not chew, dissolve or open the capsules.
If you have, or think you might have difficulty swallowing capsules whole, talk to your doctor before starting treatment.

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

5. What should I know while taking KOSELUGO?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking KOSELUGO Use effective contraception to avoid becoming pregnant (see Section 5 in the full CMI)
Things you should not do	Do not stop using this medicine or change the dose unless your doctor tells you to Do not become pregnant Do not give to child younger than 2 years of age and do not chew, dissolve or open the capsules
Call your Doctor straight away	If you experience any of the serious side effects listed in Section 6 in the full CMI. If you become pregnant while using KOSELUGO
Driving or using machines	Avoid driving or using machines if you feel tired or if you have problems with your vision
Looking after your medicine	KOSELUGO capsules should be kept in the original bottle Keep KOSELUGO in a cool dry place where the temperature stays below 30°C

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

6. Are there any side effects?

Call your doctor straight away if you notice any of these serious side effects: blurred vision, loss of vision, dark spots in your vision or other changes to your vision, persistent coughing and wheezing, shortness of breath, swelling of ankles/feet, tiredness, increased heart rate, diarrhoea, muscle aches or pains, muscle spasms and weakness, dark or reddish urine, rash that covers a large area of your body, blisters or peeling. Speak to your doctor if you have any of these most common side effects: vomiting, stomach pain, nausea, inflammation of the mouth, headache, redness around the fingernails, dry skin, rash, tiredness/ weakness/ lacking energy, muscle and bone pain, fever, itching. 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

KOSELUGO^®

Active ingredient(s): selumetinib

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking KOSELUGO?

KOSELUGO contains the active ingredient, selumetinib. Selumetinib is a type of medicine called a ‘MEK inhibitor’, it works by blocking certain proteins which are known to be involved in the growth of tumour cells. KOSELUGO may reduce the size of tumours that grow along nerves called Plexiform Neurofibromas (PNs). These tumours are caused by a genetic condition called Neurofibromatosis Type 1 (NF1).

KOSELUGO is used to treat paediatric patients aged 2 years and above with NF1, who have symptomatic PNs that cannot be completely removed by surgery.

2. What should I know before I take KOSELUGO?

Warnings

Do not take KOSELUGO if:

you are allergic to selumetinib, or any of the ingredients listed at the end of this leaflet.
- always check the ingredients to make sure you can use this medicine.
you have severe liver disease
you are pregnant or intend to become pregnant
you are breastfeeding

KOSELUGO should not be given to children below 2 years of age.

Check with your doctor if you:

think you might have difficulties swallowing the capsules whole
take any medicines for any other condition
take supplemental vitamin E (including multivitamins that contain vitamin E)
have any other medical conditions, especially the following:
- eye problems
- heart problems

KOSELUGO can cause eye problems. Tell your doctor as soon as possible if you get blurred vision or any other changes to your sight during treatment. Your doctor should examine your eyes if you have any new or worsening problems with your sight while you are taking KOSELUGO.

KOSELUGO can lower the amount of blood pumped by your heart. Your doctor should do tests before and during your treatment with KOSELUGO to check how well your heart can pump blood.

KOSELUGO capsules contain vitamin E that may make you bleed more easily. This means you should tell your doctor if you take other medicines that increase your risk of bleeding such as:

aspirin
blood thinners such as warfarin or other medicines for blood clots
supplements that include vitamin E (including multivitamins that contain vitamin E)

KOSELUGO may increase the level of an enzyme in your blood called creatine phosphokinase (CPK) and may be a sign of muscle damage. Your healthcare provider should do a blood test to check your blood levels of CPK before you start taking KOSELUGO and during treatment.

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

Talk to your doctor before taking KOSELUGO if you are pregnant, think you may be pregnant or are planning to have a baby. This is because KOSELUGO may harm an unborn child. You may be asked by your doctor to take a pregnancy test before starting treatment. If you are pregnant, you should not take KOSELUGO. You should not become pregnant while taking this medicine.

Female patients: If you are able to become pregnant you should use effective contraception while you are taking KOSELUGO and for at least 1 week after the last dose. It is not known whether KOSELUGO may interfere with how well hormonal contraceptives work. Please tell your doctor if you are taking a hormonal contraceptive, as your doctor may recommend the addition of a non-hormonal method of birth control. If you do become pregnant during treatment, tell your doctor straight away.

Before you start taking KOSELUGO, tell your doctor if you are breastfeeding. For the safety of your baby, you should not breastfeed during treatment with KOSELUGO

Male patients: You should use effective contraception while you are taking KOSELUGO and for 1 week after the last dose. If your partner becomes pregnant during your treatment with KOSELUGO, tell your doctor straight away

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.

Some medicines can affect the levels of KOSELUGO in your body. Also, KOSELUGO can affect the way some other medicines work. Tell your doctor if you are taking medicines that contain any of the following:

Clarithromycin or erythromycin used to treat bacterial infections
Carbamazepine or phenytoin used to treat seizures and epilepsy
Fluconazole, itraconazole or ketoconazole used to treat fungal infections
Rifampicin used to treat tuberculosis (TB)
St. John's wort (Hypericum perforatum), a herbal product, used to treat depression and other conditions
Fluoxetine used to treat depression and other mental disorders
Ticlopidine used to thin your blood and prevent clotting
Omeprazole used to treat heartburn

KOSELUGO may make you bleed more easily. This means you should tell your doctor or other healthcare professional you visit if you take other medicines that increase your risk of bleeding such as:

aspirin
blood thinners such as warfarin or other medicines for blood clots
supplements that include vitamin E (including multivitamins that contain vitamin E)

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

4. How do I take KOSELUGO?

How much to take:

your doctor will calculate the correct dose to use and tell you which and how many capsules of KOSELUGO to take. The amount you should take depends on your body surface area, which is measured in square metres (m²), and is worked out by the doctor from your height and weight.
your doctor may prescribe a lower dose if:
- you have problems with your liver (hepatic impairment)
- you have certain side effects while you are taking KOSELUGO
- your doctor may lower your dose or stop treatment, either for a short time or permanently
Follow the instructions provided and use KOSELUGO until your doctor tells you to stop.

When to take KOSELUGO

Take KOSELUGO twice a day, about 12 hours apart, with or without food.

How to take KOSELUGO

swallow KOSELUGO capsules whole with water.
do not chew, dissolve, or open the capsules
If you have, or think you might have difficulty swallowing capsules whole, talk to your doctor before starting treatment.

If you are sick

If you vomit at any time after taking KOSELUGO, do not take an additional dose. Take the next dose as scheduled.

If you forget to take KOSELUGO

What to do if you forget to take a dose of KOSELUGO depends on how long it is until your next dose:

if it is more than 6 hours until your next dose: Take the missed dose as soon as you remember. Then take the next dose at the normal time
if it is less than 6 hours until your next dose: Skip the missed dose. Then take the next dose at the normal time

Do not take a double dose (two doses at the same time) to make up for forgotten individual doses.

If you stop taking KOSELUGO

Do not stop taking KOSELUGO unless your doctor tells you.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If you take too much KOSELUGO

If you think that you have taken too much KOSELUGO, 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 KOSELUGO?

Things you should do

if you are about to be started on any new medicine or supplements remind your doctor and pharmacist that you are taking KOSELUGO.
if you are about to have any blood tests, tell your doctor that you are taking this medicine.
keep all of your doctor's appointments so that your progress can be checked.
use effective contraception to avoid becoming pregnant while being treated with KOSELUGO (see Section 2)
tell your doctor if you cannot swallow the capsule whole.

Call your doctor straight away if you:

get blurred vision or any other changes to your sight
get persistent coughing or wheezing, shortness of breath, swelling of your ankles and feet, tiredness and increased heart rate.
get diarrhoea for the first time during treatment with KOSELUGO. Your healthcare provider may give you medicine to help control your diarrhoea and may tell you to drink more fluids.
get a rash that covers a large area of your body, blisters or peeling skin
get muscle aches or pain, muscle spasms and weakness or dark, reddish urine
become pregnant while taking this medicine

Remind any doctor, dentist or pharmacist or other healthcare professional you visit that you are using KOSELUGO.

Things you should not do

do not stop using this medicine or change the dose without checking with your doctor.
do not give this medicine to anyone else, even if they have the same condition as you.
do not use this medicine to treat any other complaints unless your doctor tells you to.
do not give this medicine to a child younger than 2 years of age.
do not chew, dissolve, or open the capsules
Do not become pregnant while taking this medicine

Driving or using machines

KOSELUGO can cause side effects that may affect your ability to drive or use machines. Avoid driving or using machines if you feel tired or if you have problems with your vision (such as blurred vision).

Food and drink

You should not drink grapefruit juice while you are taking KOSELUGO.

Looking after your medicine

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

Store KOSELUGO it in a cool dry place where the temperature stays below 30°C.

Store in the original bottle to protect from moisture. Do not remove the desiccant pack.

Do not use KOSELUGO after the expiry date, which is stated on the bottle after EXP. The expiry date refers to the last day of that month.

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.

Do not throw away any medicines via wastewater.

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 effects	What to do
Stomach related - Vomiting - Stomach pain - Nausea - Constipation Mouth related - Inflammation of the mouth Head and hair related - Headache - Hair thinning (alopecia), hair colour change - Nosebleeds Skin and nails related - Rash - Dry skin - Redness around the fingernails General - feeling of tiredness, weakness or lacking energy - muscle and bone pain - fever - itching - Swelling of the face, hands or feet - Decreased appetite	Speak to your doctor if you have any of these less serious side effects and they worry you.
General - Blood in the urine	Speak to your doctor as soon as possible if you have this side effect.

Serious side effects

Serious side effects

What to do

Eye (vision) related
- blurred vision
- loss of vision
- dark spots in your vision (floaters)
- other changes to your vision
Heart related
- persistent coughing and wheezing
- shortness of breath
- swelling of your ankles and feet
- tiredness
- increased heart rate
Stomach related
- diarrhoea
Muscle related
- Muscle aches or pains, muscle spasms and weakness or dark, reddish urine
Skin related
- Rash that covers a large area of your body, blisters and peeling

Call your doctor straight away, 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 KOSELUGO 10 mg contains

Active ingredient (main ingredient)	Selumetinib (as sulfate)
Other ingredients (inactive ingredients)	Tocofersolan Hypromellose Carrageenan Potassium chloride Titanium dioxide Carnauba wax Purified water Shellac Iron oxide black Propylene glycol Strong ammonia solution

What KOSELUGO 25 mg contains

Active ingredient (main ingredient)	Selumetinib (as sulfate)
Other ingredients (inactive ingredients)	Tocofersolan Hypromellose Carrageenan Potassium chloride Titanium dioxide Indigo carmine Iron oxide yellow Purified water Carnauba wax Maize starch Iron oxide red Iron oxide yellow Indigo carmine aluminium lake Carnauba wax Shellac Glyceryl monooleate

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

What KOSELUGO looks like

KOSELUGO 10 mg hard capsule are white to off-white, opaque capsules, banded and marked with “SEL 10” in black ink. (Aust R 345973).

KOSELUGO 25 mg hard capsule are blue, opaque hard capsules, banded and marked with “SEL 25” in black ink (Aust R 345972).

Who distributes KOSELUGO

Alexion Pharmaceuticals Australasia Pty Ltd
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: - 1800 788 189

This leaflet was prepared in November 2024

KOSELUGO is a registered trademark of the AstraZeneca group of companies.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Koselugo

Active ingredient

Selumetinib

Schedule

1 Name of Medicine

Selumetinib sulfate.

2 Qualitative and Quantitative Composition

Each 10 mg hard capsule contains 10 mg of selumetinib (as sulfate).
Each 25 mg hard capsule contains 25 mg of selumetinib (as sulfate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule, hard.

Koselugo 10 mg hard capsule.

White to off-white, opaque, size 4 hard capsule, banded and marked with "SEL 10" in black ink.

Koselugo 25 mg hard capsule.

Blue, opaque, size 4 hard capsule, banded and marked with "SEL 25" in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Koselugo is indicated for the treatment of paediatric patients aged 2 years and above, with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

4.2 Dose and Method of Administration

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours.

Recommended dosage.

The recommended dosage of Koselugo is 25 mg/m² orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.
The recommended dose of Koselugo is based on body surface area (BSA) and is shown in Table 1.

Method of administration.

Koselugo can be taken with or without food.
Koselugo capsules should be swallowed whole with water, and should not be chewed, dissolved, or opened.
Do not administer to patients who are unable or unwilling to swallow a whole capsule. Patients should be assessed for their ability to swallow a capsule before starting treatment. Standard medicine swallowing techniques are expected to be sufficient to swallow selumetinib capsules. For patients who have difficulties swallowing the capsule, referral to an appropriate health care professional such as a speech and language therapist could be considered to identify suitable methods that can be tailored to the particular patient.

Missed dose.

If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the next scheduled dose.

Vomiting.

Do not take an additional dose if vomiting occurs after Koselugo administration but continue with the next scheduled dose.

Dose adjustments.

For adverse reactions. The recommended dose reductions for adverse reactions are provided in Table 2.

Dosage modifications for adverse reactions are in Table 3.

For drug interactions.

Co-administration with CYP3A4 or CYP2C19 inhibitors.

Concomitant use of strong or moderate CYP3A4 or CYP2C19 inhibitors is not recommended and alternative agents should be considered. If a strong or moderate CYP3A4 or CYP2C19 inhibitor must be co-administered, the recommended Koselugo dose reduction is as follows:
If a patient is currently taking 25 mg/m² twice daily, dose reduce to 20 mg/m² twice daily.
If a patient is currently taking 20 mg/m² twice daily, dose reduce to 15 mg/m² twice daily (see Table 4; see Section 4.5).

Special patient populations.

Renal impairment.

Based on clinical studies no dose adjustment is recommended in patients with mild, moderate, severe renal impairment or those with End Stage Renal Disease (ESRD) (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

Based on clinical studies, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m² BSA, twice daily (see Table 4). Koselugo is not recommended for use in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Ethnicity.

Increased systemic exposure has been seen in adult Asian subjects, although there is considerable overlap with Western subjects when corrected for body weight. No specific adjustment to the starting dose is recommended for paediatric Asian patients, however, these patients should be closely monitored for adverse events (see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

Safety and effectiveness have been established in paediatric patients 3 years of age and older with NF1 who have inoperable PN and information supporting this use is discussed throughout the Product Information. This indication was expanded to paediatric patients who are 2 years of age and older, because the safety, efficacy and pharmacokinetics of Koselugo in patients who are 2 years of age is expected to be similar to patients at 3 years of age and older.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

LVEF reduction.

Asymptomatic decreases in ejection fraction have been reported in 26% of paediatric patients in the pivotal clinical study (see Section 4.8 Adverse Effects (Undesirable Effects)). Median time to initial onset of events was 232 days. A small number of serious reports of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program.
Paediatric patients with a history of impaired left ventricular function or a baseline LVEF below institutional LLN have not been studied. LVEF should be evaluated before initiation of treatment to establish baseline values. Prior to starting Koselugo treatment, patients should have an ejection fraction above the institutional LLN.
Evaluate LVEF at approximately 3 month intervals, or more frequently as clinically indicated, during treatment. Reduction in LVEF can be managed using treatment interruption, dose reduction or treatment discontinuation (see Section 4.2 Dose and Method of Administration).

Ocular toxicity.

Advise patients to report any new visual disturbances. Adverse events of blurred vision have been reported in paediatric patients receiving selumetinib. Isolated cases of RPED, CSR and RVO in adult patients with multiple tumour types, receiving treatment with selumetinib monotherapy and in combination with other anti-cancer agents, and in a single paediatric patient with pilocytic astrocytoma on selumetinib monotherapy, have been observed (see Section 4.8 Adverse Effects (Undesirable Effects)).
In line with clinical practice an ophthalmological evaluation prior to treatment initiation and at any time a patient reports new visual disturbances is recommended. In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. If RPED or CSR is diagnosed and visual acuity is affected selumetinib therapy should be interrupted and the dose reduced when treatment is resumed (see Table 2). If RVO is diagnosed, treatment with selumetinib should be permanently discontinued (see Section 4.2 Dose and Method of Administration).

Gastrointestinal toxicity.

Diarrhoea occurred in 81% of 74 paediatric patients who received Koselugo in SPRINT, including Grade 3 in 15% of patients. Diarrhoea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhoea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhoea was 20 days and the median duration was 2 days.
Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumour types who received Koselugo as a single agent or in combination with other anti-cancer agents. Colitis occurred in an unapproved population of paediatric patients with multiple tumour types who received Koselugo as a single agent.
Advise patients to start an anti-diarrhoeal agent (e.g. loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhoea episodes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction (see Section 4.2 Dose and Method of Administration).

Skin toxicity.

Rash occurred in 93% of 74 paediatric patients who received Koselugo in SPRINT. The most frequent rashes included dermatitis acneiform (61%), maculopapular rash (50%), and eczema (26%). Grade 3 rash occurred in 9% of patients. Rash resulted in dose interruption in 14% of patients and dose reduction in 4% of patients.
Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome, occurred in an unapproved population of adult patients with multiple tumour types who received Koselugo as a single agent or in combination with other anti-cancer agents.
Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction (see Section 4.2 Dose and Method of Administration).

Increased creatine phosphokinase.

Increased creatine phosphokinase (CPK) occurred in 77% of 74 paediatric patients who received Koselugo in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued Koselugo for myalgia.
Rhabdomyolysis occurred in an unapproved adult population who received Koselugo as a single agent.
Obtain serum CPK prior to initiating Koselugo, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue Koselugo based on severity of adverse reaction (see Section 4.2 Dose and Method of Administration).

Embryo-fetal toxicity.

Based on findings from animal studies and its mechanism of action, Koselugo can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures > 5 times the human exposure at the clinical dose of 25 mg/m² twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Koselugo and for 1 week after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation).

Risk of choking.

Selumetinib is available as a capsule which must be swallowed whole. Some patients, in particular children < 6 years of age, may be at risk of choking on a capsule formulation due to developmental, anatomical or psychological reasons. Therefore, selumetinib should not be administered to patients who are unable or unwilling to swallow the capsule whole (see Section 4.2 Dose and Method of Administration).

Vitamin E supplementation.

Advise patients not to take any supplemental vitamin E.
Koselugo 10 mg capsules contain 32 mg vitamin E as the excipient, Tocofersolan (Australian Approved Name). Koselugo 25 mg capsules contain 36 mg vitamin E as Tocofersolan. High doses of vitamin E may increase the risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medications (e.g. warfarin or aspirin). Perform anticoagulant assessments, including international normalized ratio (INR) or prothrombin time (PT) more frequently to detect when the dose adjustments of the anticoagulant or antiplatelet medications are warranted (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No data are available for use in elderly patients.

Paediatric use.

Effects on laboratory tests.

Please see Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Interaction studies have only been performed in healthy adults (aged ≥ 18 years).

Active substances that may increase selumetinib plasma concentration.

Co-administration with a strong CYP3A4 inhibitor (200 mg itraconazole twice daily for 11 days and 25 mg selumetinib, single oral dose at Day 8) increased selumetinib C_max by 19% (90% CI 4, 35) and AUC by 49% (90% CI 40, 59) in healthy adult volunteers.
Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (400 mg fluconazole single dose at Day 1 followed by 200 mg fluconazole once daily for 10 days and 25 mg selumetinib single oral dose at Day 8) increased selumetinib C_max by 26% (90% CI 10, 43) and AUC by 53% (90% CI 44, 63) in healthy adult volunteers.
Concomitant use of erythromycin (moderate CYP3A4 inhibitor) or fluoxetine (moderate CYP2C19/strong CYP2D6 inhibitor) is predicted to increase selumetinib AUC by ~30-40% and C_max by ~20%.
Co-administration with strong inhibitors of CYP3A4 (e.g. clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g. ticlopidine) should be avoided. Co-administration with moderate inhibitors of CYP3A4 (e.g. erythromycin and fluconazole) or CYP2C19 (e.g. omeprazole) should be avoided. If co-administration is unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced (see Section 4.2; see Table 4).

Active substances that may decrease selumetinib plasma concentrations.

Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib C_max by -26% (90% CI -17, -34) and AUC by -51% (90% CI -47, -54).
Avoid concomitant use of strong CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine, St. John's Wort) or moderate CYP3A4 inducers with Koselugo.

Active substances whose plasma concentrations may be altered by selumetinib.

In vitro, selumetinib is an inhibitor of OAT3 and the potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.
The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using hormonal contraceptives.

Interactions with minimal clinical impact.

In vitro, selumetinib is not an inhibitor of, CYP2A6, CYP2C8, CYP3A4 or CYP2E1, not an inducer of, CYP1A2 and CYP2B6, and did not cause time-dependent inhibition of CYP2C9, CYP2D6 or CYP3A4/5.
In vitro, selumetinib is a reversible inhibitor of CYP2C9, CYP2B6, CYP2D6, an inhibitor of UGT1A3, UGT1A4, UGT1A6 and UGT1A9, an inducer of CYP3A4 and a time-dependent inhibitor of CYP1A2 and CYP2C19; however these effects are not expected to be clinically relevant.

Interactions with transport proteins.

Based on in vitro studies, selumetinib is a substrate for breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transporters but is unlikely to be subjected to clinically relevant drug interactions at the recommended paediatric dose. Based on in vitro studies selumetinib is not a substrate for, OATP1B1, or OATP1B3 transporters. In vitro, selumetinib is an inhibitor of BRCP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 and MATE2K but does not inhibit P-gp or OCT1. These in vitro inhibitory effects are not expected to be clinically relevant with the exception of OAT3 where a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.

Vitamin E.

Koselugo capsules contain vitamin E as the excipient TPGS. Therefore, patients should avoid taking supplemental vitamin E and anticoagulant assessments should be performed more frequently in patients taking concomitant anticoagulant or antiplatelet medications (see Section 4.4 Special Warnings and Precautions for Use).

Effect of food on Koselugo.

In separate clinical studies, in healthy adult subjects and in adult patients with advanced solid malignancies at a dose of 75 mg, co-administration of Koselugo with a high-fat meal resulted in a mean decrease in C_max of 50% and 62%, respectively, compared to fasting administration. Selumetinib mean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration (t_max) was delayed by approximately 1.5 hours to 3 hours (see Section 4.2 Dose and Method of Administration).
In healthy adult subjects at a dose of 50 mg, co-administration of Koselugo with a low-fat meal resulted in 60% lower C_max when compared to fasting administration. Selumetinib AUC was reduced by 38%, and t_max was delayed by approximately 0.9 hours (see Section 4.2 Dose and Method of Administration).
In adolescent patients with NF1 and inoperable PN treated with multiple doses of 25 mg/m² bid, co-administration of selumetinib with a low-fat meal resulted in 24% lower C_max when compared to fasting administration. Selumetinib AUC was reduced by 8%, and t_max was delayed by approximately 0.57 hours (see Section 4.2 Dose and Method of Administration).
A population PK analysis including children and adolescent patients with NF1 and inoperable PN, adult patients with advanced solid malignancies and healthy adult subjects taken from 15 studies showed that concomitant administration of a low or high fat meal resulted in a mean decrease in the exposure (AUC) of selumetinib when compared to fasted administration (23.1% and 20.7%, respectively) which was not considered clinically relevant.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of Koselugo on human fertility.
In mice, selumetinib did not affect male mating performance after 10 weeks of dosing up to 20 mg/kg twice daily corresponding to approximately 28 times the human clinical exposure based on AUC at the MRHD. In female mice exposed to selumetinib at up to 37.5 mg/kg twice daily (approximately 90 times the human clinical exposure at the MRHD based on AUC), mating performance and fertility were not affected, but the number of live fetuses was slightly reduced at ≥ 12.5 mg/kg twice daily (27 times the human clinical exposure). Following a three-week treatment withdrawal period, no effects were apparent on any parameter. The no observed adverse effect level (NOAEL) for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5 times the human clinical exposure).
(Category D)
There are no data on the use of selumetinib in pregnant women.
In embryofetal development studies in mice, administration of selumetinib during organogenesis-caused a reduction in the number of live fetuses due to an increase in post-implantation loss, a reduction in mean fetal and litter weights, an increase in unossified or incompletely ossified bones, increased occurrence of open eye and cleft palate at dose levels that did not induce significant maternal toxicity. These effects were seen at ≥ 2.5 mg/kg twice daily (> 4.5 times the clinical exposure at the MRHD based on AUC) and indicate that selumetinib may have potential to cause defects in the fetus in patients.
Administration of selumetinib to pregnant mice from gestation Day 6 through to lactation Day 20 resulted in reduced pup body weights, and fewer pups met the pupil constriction criterion on Day 21 post-partum at 7.5 mg/kg twice daily (approximately 6 times the clinical exposure based on C_max). The incidence of malformations (prematurely open eye(s) and/ or cleft palate) was increased at all dose levels (0.5 -7.5 mg/kg twice daily). Malformations occurred at maternal exposure 0.6 times the mean clinical exposure at MRHD based on C_max.
Koselugo is not recommended during pregnancy.
It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment.
Advise women of childbearing potential to avoid becoming pregnant while receiving selumetinib. If a female patient or a female partner of a male patient receiving Koselugo becomes pregnant, she should be apprised of the potential hazard to the fetus.
Both male and female patients (of reproductive potential) should be advised to use effective contraception during and for at least 1 week after completion of treatment with Koselugo. It cannot be excluded that selumetinib may reduce the effectiveness of oral contraceptives, therefore women using hormonal contraceptives should be recommended to add a barrier method.
Koselugo is not recommended in women of child-bearing potential not using contraception.
Selumetinib and its active metabolite are excreted in the milk of lactating mice. It is not known whether selumetinib, or its metabolites, are excreted in human milk. A risk to the breast-fed infant cannot be excluded, therefore breast-feeding mothers are advised not to breast-feed during treatment with Koselugo.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Koselugo may have a minor influence on the ability to drive and use machines. Fatigue, asthenia and visual disturbances have been reported during treatment with selumetinib and patients who experience these symptoms should observe caution when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of selumetinib monotherapy has been evaluated in a combined safety population of 74 paediatric patients (20-30 mg/m² twice daily) with NF1 PN and 347 adult patients (75-100 mg twice daily) with multiple tumour types.

Neurofibromatosis type 1 (NF1) with inoperable plexiform neurofibromas (PN).

The safety of Koselugo was evaluated in SPRINT Phase II Stratum 1 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Eligible patients were 2-18 years of age with NF1 who had inoperable PN that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure > the 95^th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received Koselugo 25 mg/m² orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer, 70% were exposed for more than 2 years and 56% were exposed for more than 4 years.
Serious adverse reactions occurred in 30% of patients who received Koselugo. Serious adverse reactions that occurred in 2 or more patients were anaemia, hypoxia, diarrhoea, skin infection and fracture.
Permanent discontinuation due to an adverse event occurred in 12% of patients who received Koselugo. Adverse events resulting in permanent discontinuation of Koselugo included increased blood creatine phosphokinase, increased weight, diarrhoea, paronychia, malignant peripheral nerve sheath tumour, acute kidney injury, and skin ulcer.
Dosage interruptions and dose reductions due to adverse events occurred in 86% and 32% of patients who received Koselugo, respectively. Adverse events requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, nausea, paronychia, influenza-like illness, diarrhoea, pyrexia, fracture, skin infection, abdominal pain and weight gain.
The most common adverse events (≥ 40%) were vomiting, abdominal pain, diarrhoea, nausea, dry skin, pyrexia, rash (non-acneiform), musculoskeletal pain, paronychia, fatigue, dermatitis acneiform, headache, stomatitis, pruritus and constipation.
Table 5 presents the adverse events in SPRINT Phase II Stratum 1.

Clinically relevant adverse reactions that occurred < 20% of patients include:
Eye: vision blurred.
Gastrointestinal Disorders: dry mouth.
General Disorders: facial oedema, including periorbital oedema and face oedema.
Respiratory, Thoracic and Mediastinal: dyspnoea, including exertional dyspnoea and dyspnoea at rest.
Table 6 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.

Adverse drug reactions identified in other clinical trials.

Table 7 presents the adverse drug reactions identified from other clinical trial experience in adult patients (N=347), with multiple tumour types, receiving treatment with selumetinib (75 mg twice daily):

In addition, a single event of RPED was reported in a paediatric patient receiving selumetinib monotherapy (25 mg/m² twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study, see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

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 specific treatment for overdose. If overdose occurs, patients should be treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Selumetinib is an orally available, inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) that is not competitive with respect to ATP. MEK1/2 proteins are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. Selumetinib blocks MEK activity and inhibits growth of RAF-MEK-ERK pathway activated cell lines. Therefore, MEK inhibition can block the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway is activated.

Pharmacodynamics.

In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human type 1 neurofibromas, oral dosing of selumetinib inhibits ERK phosphorylation, reduces neurofibroma volume, proliferation, number and growth.

Cardiac electrophysiology.

At a dose 1.5 times the maximum recommended dose, Koselugo does not prolong the QT/QTc interval to any clinically relevant extent.

Clinical trials.

SPRINT.

The efficacy of Koselugo was evaluated in an open-label, multi-centre, single-arm study [SPRINT Phase II Stratum 1 (NCT01362803)] of 50 paediatric patients with NF1 inoperable PN that caused significant morbidity. Inoperable PN was defined as a PN that could not be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients received 25 mg/m² (BSA) twice daily, for 28 days (1 treatment cycle), on a continuous dosing schedule. Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity or PN progression, or at the discretion of the investigator.
The target PN, the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumour response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles.
Patients had target PN MRI volumetric evaluations and clinical outcome assessments, which included functional assessments and patient reported outcomes.
At enrolment, the median age of the patients was 10.2 years (range: 3.5 - 17.4 years), 60% were male, 84% were Caucasian.
Disease characteristics at baseline are provided in Table 8.

The primary efficacy endpoint was Objective Response Rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume, confirmed at a subsequent tumour assessment within 3-6 months), based on National Cancer Institute (NCI) centralised review. Duration of Response (DoR) was also evaluated.
Efficacy results are provided based on a data cut-off of March 2021, unless stated otherwise.
The primary endpoint, ORR was 68% (95% CI, 53.3 - 80.5). Time to onset of response for the majority of patients (24/34 [70.6%]) was within 8 cycles (range 4 - 42 cycles). The median time to onset of response was 7.2 months (range 3.3 months to 3.2 years).
The median DoR from onset of response was not reached; at the time of data cut-off the median follow-up time was 41.3 months from first dose. Of the 34 patients who had confirmed partial responses, 31 (91.2%) remained in response after 12 months; 26 (76.5%) remained in response after 24 months and 21 (61.8%) remained in response after 36 months. The probability to remain in response after 12, 24 and 36 months, estimated using the Kaplan-Meier method, was 100% (95% CI not estimated), 90.0% (95% CI 72.1 - 96.7) and 86.3% (95% CI 67.3 - 94.6), respectively. The median time from treatment initiation to disease progression while on treatment was not reached. See Table 9.

At the time of data cut-off or last scan on treatment for patients who had discontinued treatment, 25 (50%) patients remained in confirmed partial response, 1 (2%) had unconfirmed partial responses, 12 (24%) had stable disease and 10 (20%) had progressive disease.
The median best percentage change in PN volume from baseline was -27.85% (range: -60.3% to 2.2%). Figure 1 shows the best percentage change in target PN volume for each patient.

An independent centralized review of tumor response per REiNS criteria (data cut-off June 2018) resulted in an ORR of 44% (95% CI: 30.0, 58.7).

5.2 Pharmacokinetic Properties

At the recommended dosage of 25 mg/m² twice daily in paediatric patients (3 to ≤ 18 years old), the geometric mean (coefficient of variation [CV%]) maximum plasma concentration (C_max) was 731 (62%) nanogram/mL and that of the area under the plasma drug concentration curve (AUC_0-12) following the first dose was 2009 (35%) nanogram.h/mL. Minimal accumulation of ~1.1 fold was observed at steady state upon twice daily dosing.
In paediatric patients, at a dose level of 25 mg/m², selumetinib has an apparent oral clearance of 8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of ~6.2 hours.

Absorption.

In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%.
Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasma concentrations (t_max) between 1-1.5 hours post-dose.

Effect of gastric acid reducing agents on selumetinib.

Selumetinib capsules do not exhibit pH dependent dissolution. Koselugo can be used concomitantly with gastric pH modifying agents (i.e. H₂-receptor antagonists and proton pump inhibitors) without restrictions, except for omeprazole which is a CYP2C19 inhibitor.

Distribution.

The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m² ranged from 78 to 171 L in paediatric patients, indicating moderate distribution into tissue.
In vitro plasma protein binding is 98.4% in humans. Selumetinib mostly binds to serum albumin (96.1%) than α-1 acid glycoprotein (< 35%).

Metabolism.

In vitro, selumetinib undergoes Phase 1 metabolic reactions including oxidation of the side chain, N-demethylation, and loss of the side chain to form amide and acid metabolites. CYP3A4 is the predominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP1A2, CYP2C9, CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also undergoes direct Phase 2 metabolic reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinib Phase 1 metabolites involving several UGT isoforms.
Following oral dosing of ¹⁴C-selumetinib to healthy male subjects, unchanged selumetinib (~40% of the radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2; 22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethyl carboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in human plasma. The active metabolite, N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity. N-desmethyl selumetinib is mainly generated by CYP2C19 and catabolised by CYP3A4.

Excretion.

In healthy adult volunteers, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of the dose was recovered in faeces (19% unchanged) while 33% of the administered dose (< 1% as parent) was found in urine by 9 days of sample collection.