Consumer medicine information

Scemblix

Asciminib

BRAND INFORMATION

Brand name

Scemblix

Active ingredient

Asciminib

Schedule

SUMMARY CMI

SCEMBLIX^®

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 Scemblix?

Scemblix contains the active ingredient asciminib. Scemblix is used to treat patients 18 years and over with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in chronic phase (CP) and patients with Ph+ CML in CP who have a certain genetic difference (mutation) called T315I.

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

2. What should I know before I take Scemblix?

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 Scemblix? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Scemblix 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 Scemblix?

The usual total daily dose of Scemblix is 80 mg (2 tablets of Scemblix 40 mg, per day). Do not take Scemblix with food.

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

5. What should I know while taking Scemblix?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Scemblix. Have regular tests to monitor your condition
Things you should not do	Do not stop using this medicine suddenly. Do not take Scemblix with food
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Scemblix affects you.
Drinking alcohol	There are no known interactions between Scemblix and alcohol.
Looking after your medicine	Store below 25°C; protect from moisture

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

6. Are there any side effects?

Common side effects include sudden bleeding or bruising; fever, sore throat, frequent infections; nose and throat infections; tiredness, pale skin; headache, dizziness, chest pain or difficulty breathing; cough; vomiting; diarrhoea; feeling sick; stomach pain; rash; pain in muscles, bones or joints; joint pain; 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

SCEMBLIX^®

Active ingredient(s): asciminib

Consumer Medicine Information (CMI)

This leaflet provides important information about using Scemblix. 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 Scemblix.

Where to find information in this leaflet:

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

1. Why am I taking Scemblix?

Scemblix contains the active ingredient asciminib. Scemblix treats a type of blood cancer (leukaemia) in which the body produces too many abnormal white blood cells. Chronic phase (CP) is the first phase of this blood cancer.

Scemblix is used to treat patients 18 years and over with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in CP who

were previously treated with medicines of a similar type called tyrosine kinase inhibitors.
have a certain genetic difference (mutation) called T315I.

Scemblix blocks the action of a protein (BCR-ABL1) of the abnormal white blood cells and stops them expanding and growing.

2. What should I know before take Scemblix?

Warnings

Do not take Scemblix if:

you are allergic to asciminib, 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 any other medical conditions
take any medicines for any other condition
have or have ever had severe upper stomach pain (inflamed pancreas, pancreatitis).
have or have ever had a hepatitis B infection. This is because during treatment with Scemblix, hepatitis B may become active again. Patients will be carefully checked by their doctor for signs of this infection before starting 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

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss with you the potential risks of taking Scemblix during pregnancy or breast-feeding.

It is not known if Scemblix passes into your breast-milk. Breast-feeding is not recommended during treatment with Scemblix and for at least 3 days after the last dose.

Females of child-bearing potential

Scemblix can harm your unborn baby. If you are a woman of child-bearing age, your doctor, pharmacist or healthcare provider will check if you are pregnant and perform a pregnancy test if necessary before starting treatment with Scemblix.

If you may become pregnant, you should use an effective birth control during treatment with Scemblix and for at least 3 days after the last dose. Ask your doctor about effective birth control options.

Children and adolescents

Scemblix is not to be used in children or adolescents under 18 years of age. It is not known whether Scemblix is safe and effective in children or adolescents.

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 may interfere with Scemblix and affect how it works:

Medicines used to treat bacterial infections such as clarithromycin, telithromycin or troleandomycin.
Medicines used to treat fungal infections such as itraconazole, ketoconazole or voriconazole.
Medicines used to treat human immunodeficiency virus (HIV) such as ritonavir, indinavir, nelfinavir or saquinavir.
An antibiotic used to treat infections caused by bacteria (rifampicin).
Medicines used to treat seizures such as carbamazepine, phenobarbital or phenytoin.
St. John's wort (also known as Hypericum perforatum), a herbal medicine used to treat depression and other conditions.

Food also interferes with Scemblix and affects how it works. Therefore do not take Scemblix with food.

Scemblix may interfere with some medicines and affect how they work:

Medicines used to treat pain or used as sedatives before or during medical or surgical procedures, such as alfentanil, fentanyl or midazolam.
Medicines used to treat migraine or dementia, such as dihydroergotamine or ergotamine.
Medicines used to reduce the blood's ability to clot, such as warfarin or dabigatran.
Medicines used to treat severe inflammation of the bowel or severe rheumatic or painful joint inflammation, such as sulfasalazine or colchicine.
Medicines used to treat cancer, severe rheumatic joint inflammation, or psoriasis, such as methotrexate
Medicines used to reduce blood cholesterol levels, such as pravastatin, atorvastatin, rosuvastatin and simvastatin.
Medicines used to treat high blood pressure or other heart conditions, such as digoxin.

Caution should be used when taking Scemblix with medicines that may have an unwanted effect on the electrical activities of the heart (torsades de pointes), such as bepridil, chloroquine, clarithyromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide.

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

4. How do I take Scemblix?

How much to take

Take Scemblix exactly as your doctor tells you
Do not change your dose or how frequently you take Scemblix or stop taking Scemblix unless your doctor tells you to.

When to take Scemblix

If instructed to take daily dose once a day take dose at the same time each day.
If instructed to take dose twice a day, take each dose at the same times each day, approximately 12 hours apart.

How to take Scemblix

Take Scemblix without food. You should avoid eating for at least 2 hours before and 1 hour after taking Scemblix.
Swallow tablets whole. Do not break, crush or chew Scemblix tablets.

If you forget to use Scemblix

Scemblix should be used regularly at approximately the same time each day.

If you take Scemblix once daily:

If you miss your dose at the usual time by more than 12 hours, skip the missed dose and take the next one as usual.

If you take Scemblix twice daily:

If you miss your dose at the usual time by more than 6 hours, skip the missed dose and take the next one as usual.

If you take too much Scemblix

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

Things you should do

Keep all doctor's appointments, as your doctor needs to regularly monitor your condition.

Call your doctor straight away if you:

experience rash, itching, hives, difficulty breathing, wheezing or coughing, light-headedness, dizziness, skin reddening, face/throat swelling, blue discoloration of the lips, tongue or skin (signs of allergic reaction).

Remind any doctor, dentist or pharmacist you visit that you are using Scemblix.

Things you should not do

Do not stop taking this medicine suddenly.

Monitoring during your treatment

You will have regular tests including blood tests during treatment. These tests will monitor:

The amount of blood cells (white blood cells, red blood cells and platelets).
The levels of pancreas enzymes (amylase and lipase).
The levels of electrolytes (potassium, magnesium).
Your heart rate (this could include an electrocardiogram/ ECG) and your blood pressure.

Driving or using machines

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

If you experience dizziness or changes to your vision (such as blurred vision), you should not take part in these activities.

Drinking alcohol

Tell your doctor if you drink alcohol.

There are no known interactions between Scemblix and alcohol.

Looking after your medicine

Store below 25°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
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 take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take 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 effects

What to do

Respiratory such as:

Nose, throat or sinus infections
Cough

Stomach side effects such as:

Diarrhoea
Vomiting
Feeling sick, nausea
Stomach pain

Hormone problems:

Tiredness, weight gain, skin and hair changes (underactive thyroid gland)

General such as:

Tiredness, pale skin
Headache
Dizziness
Rash
Pain in muscles, bones or joints
Itching
Loss of appetite
Blurred vision
Dry eyes
Generalised swelling

Speak to your doctor if you have any of these less serious side effects and they worry you.
If these side effects become severe, please tell your doctor, pharmacist or healthcare provider.

Serious side effects

Serious side effects

What to do

Signs of an allergic reaction including trouble breathing or swallowing; swelling of the face, lips or tongue; skin rash or flushing of your skin; feeling dizzy or faint; fever; fast heartbeat
Fever, coughing, difficulty breathing, wheezing (signs of lower respiratory tract infections)
Chest pain or difficulty breathing/shortness of breath, irregular heartbeat, swelling in the ankles or feet, dizziness, weight gain, numbness or weakness on one side of your body, decreased vision/loss of vision, trouble talking, pain in your arms, legs, back, neck or jaw, headache, severe stomach area pain. This could be related to heart problems.
Sudden bleeding or bruising, blood in your urine or stool, fever, or any signs of infection. This could be related to low blood counts.
Fever, sore throat, frequent infections
Influenza
Fever above 38°C
Severe upper stomach pain
Sudden stomach-area pain or discomfort, nausea or vomiting. This could be related to pancreas problems.
Symptoms of elevated blood pressure including confusion, headaches, dizziness, chest pain or shortness of breath.

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 Scemblix contains

Active ingredient (main ingredient)	asciminib
Other ingredients (inactive ingredients)	Lactose monohydrate, microcrystalline cellulose, hyprolose, croscarmellose sodium, polyvinyl alcohol, titanium dioxide, magnesium stearate, purified talc, silicon dioxide, iron oxide (20 mg: yellow and red; 40 mg: black and red), lecithin, xanthan gum
Potential allergens	Sugars as lactose and soybean products

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

What Scemblix looks like

Scemblix is supplied as:

Scemblix 20 mg film coated tablets: The tablets are pale yellow, round, biconvex, film-coated tablets with beveled edges, approximately 6.2 mm diameter, unscored, debossed with “Novartis” logo on one side and “20” on the other side. in Scemblix 20 mg film coated tablets in blister packs containing 20 or 60 tablets (Aust R 371019).

Scemblix 20 mg film coated tablets in bottles containing 20 or 60 tablets (AUST R 407914).*

Scemblix 40 mg film coated tablets: The tablets are violet white, round, biconvex, film-coated tablets with beveled edges, approximately 8.2 mm diameter, unscored, debossed with “Novartis” logo on one side and “40” on the other side. in Scemblix 40 mg film coated tablets in blister packs containing blister packs containing 20 or 60 tablets (Aust R 371018).

Scemblix 40 mg film coated tablets in bottles containing 20, 60 or 300 tablets (AUST R 407913).*

*Not all products may be marketed

Who distributes Scemblix

Scemblix is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
(ABN 18 004 244 160)
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Website: www.novartis.com.au

This leaflet was prepared in November 2024.

(sce221124c based on PI sce221124i)

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Scemblix

Active ingredient

Asciminib

Schedule

1 Name of Medicine

Asciminib hydrochloride.

2 Qualitative and Quantitative Composition

Each 20 mg film-coated tablet contains 21.62 mg asciminib hydrochloride, which is equivalent to 20 mg asciminib.
Each 40 mg film-coated tablet contains 43.24 mg asciminib hydrochloride, which is equivalent to 40 mg asciminib.
Scemblix tablets contain sugars as lactose and soyabean products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

20 mg film-coated tablets.

Pale yellow, round, biconvex, film-coated tablets with beveled edges, approximately 6.2 mm diameter, unscored, debossed with "Novartis" logo on one side and "20" on the other side.

40 mg film-coated tablets.

Violet white, round, biconvex, film-coated tablets with beveled edges, approximately 8.2 mm diameter, unscored, debossed with "Novartis" logo on one side and "40" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Scemblix is indicated for the treatment of patients 18 years of age and above with:
Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors (see Section 5.1, Clinical trials).
Ph+ CML in CP with the T315I mutation.

4.2 Dose and Method of Administration

Treatment with Scemblix should be initiated by a physician experienced in the use of anticancer therapies and should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

Dose regimen.

Ph+ CML-CP.

The recommended total daily dose of Scemblix is 80 mg.
Scemblix can be taken orally either as 80 mg once daily at approximately the same time each day, or as 40 mg twice daily at approximately 12-hour intervals.
Patients changing from 40 mg twice daily to 80 mg once daily should start taking Scemblix once daily approximately 12 hours after the last twice-daily dose, and then continue at 80 mg once daily.
Patients changing from 80 mg once daily to 40 mg twice daily should start taking Scemblix twice daily approximately 24 hours after the last once-daily dose and then continue at 40 mg twice daily at approximately 12-hour intervals.
Any change in the dosage regimen is at the prescriber's discretion, as necessary for the management of the patient.

Ph+ CML CP harbouring the T315I mutation.

The recommended dose of Scemblix is 200 mg taken orally twice daily at approximately 12 hour intervals.

Missed dose.

Once-daily dosage regimen.

If a Scemblix dose is missed by more than approximately 12 hours, it should be skipped and the next dose should be taken as scheduled.

Twice-daily dosage regimen.

If a Scemblix dose is missed by more than approximately 6 hours, it should be skipped and the next dose should be taken as scheduled.

Dose modifications.

Ph+ CML.

For the management of adverse drug reactions, Scemblix dose can be reduced based on individual safety and tolerability, as described in Table 1. If adverse drug reactions are effectively managed, Scemblix may be resumed as described in Table 1.
Scemblix should be permanently discontinued in patients unable to tolerate a total daily dose of 40 mg.

Ph+ CML-CP harbouring the T315I mutation.

The recommended dosage modification for the management of selected adverse drug reactions is shown in Table 2.

Method of administration.

Scemblix should be taken orally without food. Food consumption should be avoided for at least 2 hours before and 1 hour after taking Scemblix (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).
Scemblix film-coated tablets should be swallowed whole and should not be broken, crushed or chewed.

Special populations.

Hepatic impairment.

No dose adjustment is required in patients with mild, moderate or severe hepatic impairment receiving Scemblix. Caution should be exercised in patients with severe hepatic impairment receiving Scemblix 200 mg twice daily dose (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dose adjustment is required in patients with mild, moderate or severe renal impairment receiving Scemblix. Caution should be exercised in patients with severe renal impairment receiving Scemblix 200 mg twice daily dose (see Section 5.2 Pharmacokinetic Properties).

Paediatric patients (below 18 years).

The safety and efficacy of Scemblix in paediatric patients (below 18 years) has not been established.

Elderly patients (65 years of age or above).

No dose adjustment is required in patients 65 years of age or above.

4.3 Contraindications

Known hypersensitivity to the active substance asciminib or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Myelosuppression.

Thrombocytopaenia, neutropaenia and anaemia occurred in patients receiving Scemblix. Severe (NCI CTCAE grade 3 or 4) thrombocytopaenia and neutropaenia reactions were reported during treatment with Scemblix (see Section 4.8 Adverse Effects (Undesirable Effects)).
Myelosuppression was generally reversible and managed by temporarily withholding Scemblix. Complete blood counts should be performed every two weeks for the first 3 months of treatment and monthly thereafter, or as clinically indicated. Patients should be monitored for signs and symptoms of myelosuppression.
Based on the severity of thrombocytopaenia and/or neutropaenia, the Scemblix dose should be reduced, temporarily withheld or permanently discontinued as described in Table 2 (see Section 4.2 Dose and Method of Administration).

Pancreatic toxicity.

Pancreatitis occurred in 9 of 356 (2.5%) patients receiving Scemblix, with grade 3 reactions occurring in 4 (1.1%) patients. All these reactions occurred in the phase I study (X2101). Of the 9 patients with pancreatitis, 2 (0.6%) permanently discontinued Scemblix, while Scemblix was temporarily withheld in 5 (1.4%) patients due to the adverse drug reaction. Asymptomatic elevation of serum lipase and amylase occurred in 82 of 356 (23%) patients receiving Scemblix, with grade 3 and 4 reactions occurring in 37 (10.4%) and 9 (2.5%) patients, respectively. Of the 82 patients with pancreatic enzymes elevation, Scemblix was permanently discontinued in 8 (2.2%) patients due to the adverse drug reaction.
Serum lipase and amylase levels should be assessed monthly during treatment with Scemblix, or as clinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity. More frequent monitoring should be performed in patients with a history of pancreatitis. If serum lipase and amylase elevation are accompanied by abdominal symptoms, treatment should be temporarily withheld and appropriate diagnostic tests should be considered to exclude pancreatitis (see Section 4.2 Dose and Method of Administration).
Based on the severity of serum lipase and amylase elevation, the Scemblix dose should be reduced, temporarily withheld or permanently discontinued as described in Table 2 (see Section 4.2 Dose and Method Administration).

QT prolongation.

Electrocardiogram QT prolongation occurred in 4 of 356 (1.1%) patients receiving Scemblix (see Section 4.8 Adverse Effects (Undesirable Effects)). In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 ms together with more than 60 ms QTcF increase from baseline and one patient had prolonged QTcF with more than 60 ms QTcF increase from baseline.
It is recommended that an electrocardiogram is performed prior to the start of treatment with Scemblix and monitored during treatment as clinically indicated. Hypokalaemia and hypomagnesaemia should be corrected prior to Scemblix administration and monitored during treatment as clinically indicated.
Caution should be exercised when administering Scemblix at a total daily dose of 80 mg concomitantly with medicinal products with a known risk of torsades de pointes. Coadministration of Scemblix at 200 mg twice daily concomitantly with medicinal products with a known risk of torsades de pointes should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 Pharmacodynamic Properties).

Hypertension.

Hypertension occurred in 74 of 356 (20.8%) patients receiving Scemblix, with grade 3 and 4 reactions reported in 39 (11%) and 1 (0.3%) patients, respectively. Among the patients with hypertension ≥ grade 3, the median time to first occurrence of reactions was 29.21 weeks (range: 0.14 to 365 weeks). Of the 74 patients with hypertension, Scemblix was temporarily withheld in 3 (0.8%) patients due to the adverse drug reaction.
Hypertension should be monitored and managed using standard antihypertensive therapy during treatment with Scemblix as clinically indicated.
For grade 3 or higher hypertension, temporarily withhold, reduce dose, or permanently discontinue Scemblix depending on persistence of hypertension (see Section 4.2 Dose and Method of Administration).

Hypersensitivity.

Hypersensitivity events occurred in 119 of 356 (33.4%) patients receiving Scemblix, with ≥ grade 3 events reported in 6 (1.7%) patients. Patients should be monitored for signs and symptoms of hypersensitivity and appropriate treatment should be initiated as clinically indicated.

Hepatitis B reactivation.

Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus following administration of other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection before the start of treatment with Scemblix. HBV carriers who require treatment with Scemblix should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Embryo-fetal toxicity.

Based on findings from animal studies, Scemblix can cause fetal harm when administered to a pregnant woman. Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus if Scemblix is used during pregnancy or if the patient becomes pregnant while taking Scemblix. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Scemblix. Sexually-active females of reproductive potential should use effective contraception during treatment with Scemblix and for at least 3 days after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

The safety and efficacy of Scemblix in paediatric patients (below 18 years) has not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Agents that may increase asciminib plasma concentrations.

Strong CYP3A4 inhibitors.

Physiologically-based pharmacokinetic (PBPK) models predict that co-administration of Scemblix at 200 mg twice daily with a strong CYP3A4 inhibitor (clarithromycin) would increase asciminib AUC_tau and C_max by 77% and 49%, respectively.
Caution should be exercised during concomitant administration of Scemblix 200 mg twice daily with strong CYP3A4 inhibitors including but not limited to clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Dose adjustment of Scemblix is not required.

Agents that may decrease asciminib plasma concentrations.

Strong CYP3A4 inducers.

Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUC_inf by 14.9%, while increasing asciminib C_max by 9% in healthy subjects receiving a single Scemblix dose of 40 mg.
PBPK models predict that co-administration of asciminib at 80 mg once daily with rifampicin would decrease asciminib AUC_tau and C_max by 52% and 23%, respectively, while co-administration of asciminib at 200 mg twice daily with rifampicin would decrease asciminib AUC_tau and C_max by 63% and 47%, respectively.
Caution should be exercised during concomitant administration of Scemblix at all recommended doses with strong CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin or St. John's wort (Hypericum perforatum). Dose adjustment of Scemblix is not required.

Agents that may have their plasma concentrations altered by asciminib.

CYP3A4 substrates with narrow therapeutic index.

Asciminib is a CYP3A4 inhibitor. Concomitant use of Scemblix increases the C_max and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions of these substrates.
Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving Scemblix 40 mg twice daily.
PBPK models predict that co-administration of asciminib at 80 mg once daily would increase midazolam AUC_inf and C_max by 24% and 17%, respectively, while co-administration of asciminib at 200 mg twice daily would increase midazolam AUC_inf and C_max by 88% and 58%, respectively.
Caution should be exercised during concomitant administration of Scemblix at all recommended doses with CYP3A4 substrates known to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substrates fentanyl, alfentanil, dihydroergotamine, or ergotamine. Dose adjustment of Scemblix is not required.

CYP2C9 substrates.

Asciminib is a CYP2C9 inhibitor. Concomitant use of Scemblix increases the C_max and AUC of CYP2C9 substrates, which may increase the risk of adverse reactions of these substrates.
Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving Scemblix 40 mg twice daily.
PBPK models predict that co-administration of asciminib at 80 mg once daily would increase S-warfarin AUC_inf and C_max by 52% and 4%, respectively, while co-administration of asciminib at 200 mg twice daily would increase S-warfarin AUC_inf and C_max by 314% and 7%, respectively.
Caution should be exercised during concomitant administration of Scemblix at 80 mg total daily dose with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to phenytoin or warfarin. Dose adjustment of Scemblix is not required.
Concomitant administration of Scemblix at 200 mg twice daily with CYP2C9 sensitive substrates and CYP2C9 substrates known to have a narrow therapeutic index should be avoided and alternative medications should be considered. If co-administration cannot be avoided, the CYP2C9 substrates dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of international normalized ratio (INR) monitoring should be increased as the anti-coagulant effect of warfarin may be enhanced.

Substrates of OATP1B, of BCRP or of both transporters.

Asciminib is an OATP1B and BCRP inhibitor. The effect of concomitant use of Scemblix with OATP1B and BCRP substrates has not been established in clinical studies. However, based upon a mechanistic understanding of the elimination of asciminib and its in vitro inhibitory potential, concomitant use of Scemblix increases the C_max and AUC of OATP1B and BCRP substrates, which may increase the risk of adverse reactions of these substrates (see Section 5.1 Pharmacodynamic Properties).
Avoid concomitant administration of Scemblix at all recommended doses with rosuvastatin and consider alternative statins. If co-administration cannot be avoided, rosuvastatin dose should be reduced, as recommended in its product information.
Caution should be exercised during concomitant administration of Scemblix at all recommended doses with substrates of OATP1B, BCRP or both transporters, including, but not limited to sulfasalazine, methotrexate, pravastatin, atorvastatin, and simvastatin. Refer to OATP1B and BCRP substrates' dose reductions, as recommended in their prescribing information. Closely monitor for adverse reactions during concomitant use of Scemblix at all recommended doses.

P-gp substrates of narrow therapeutic index.

PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a P-gp substrate (digoxin) would increase digoxin C_max by 30% and 38% and AUC_inf by 20% and 22%, respectively, while co-administration of asciminib at 200 mg twice daily would increase digoxin C_max and AUC_inf by 62% and 40%, respectively.
Caution should be exercised during concomitant administration of Scemblix at all recommended doses with P-gp substrates known to have a narrow therapeutic index, including but not limited to digoxin, dabigatran, and colchicine.

In vitro evaluation of drug interaction potential.

In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9, CYP2C8, CYP2B6, CYP2C19, UGT1A1 and UGT2B7.

Transporters.

Asciminib is a substrate of BCRP and P-gp. In vitro, asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2. Based on PBPK models, asciminib increased the exposure of P-gp, OATP1B and BCRP substrates (see ''Substrates of OATP1B, of BCRP or of both transporters''). The clinical relevance of the interaction with OCT1 is currently unknown at Scemblix 200 mg twice daily dosing.

Multiple pathways.

Asciminib is metabolised by several pathways including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secreted by the transporter BCRP.
Medicinal products inhibiting or inducing multiple pathways may alter Scemblix exposure.
Asciminib inhibits several pathways including CYP3A4, CYP2C9, OATP1B, P-gp and BCRP. Scemblix may increase the exposure of medicinal products, which are substrates of these pathways (see subsection ''Substrates of OATP1B, of BCRP or of both transporters'').

QT prolonging agents.

Caution should be exercised during concomitant administration of Scemblix at 80 mg total daily dose and medicinal products with a known risk of torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide (see Section 5.2 Pharmacokinetic Properties).
Concomitant administration of Scemblix at 200 mg twice daily dose and medicinal products with a known risk of torsades de pointes should be avoided (see Section 5.2 Pharmacokinetic Properties).

Drug-food interactions.

The bioavailability of asciminib decreases on consumption of food (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of Scemblix on human fertility.
In the rat fertility study, asciminib administered via the oral route at doses of 200 mg/kg/day did not affect reproductive function in male and female rats. A slight effect on male sperm motility and sperm count was observed at doses of 200 mg/kg/day, likely at AUC exposures 19-fold, 13-fold or 2-fold higher than those achieved in patients at the 40 mg twice-daily, 80 mg once-daily or 200 mg twice daily doses, respectively.
(Category D)

Risk summary.

Based on findings from animal studies, Scemblix can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women to inform a product-associated risk.
Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and teratogenicity. In embryofetal development studies, pregnant animals received oral doses of asciminib at 25, 150 and 600 mg/kg/day in rats and at 15, 50 and 300 mg/kg/day in rabbits during the period of organogenesis.
In rats, increases in fetal malformations (anasarca, cleft palate, cardiomegaly, pericardium filled with fluid and stenosis of the aortic arch) were noted at 150 mg/kg/day (AUC exposures 13-fold higher than those achieved in patients at the 40 mg twice daily or 80 mg once-daily doses) and increased fetal weights at 25 mg/kg/day (AUC exposures equal to those achieved in patients at the 40 mg twice daily or 80 mg once daily doses) in the absence of adverse maternal effects. At the fetal maternal no-observed-adverse-effect level of 25 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose.
In rabbits, dosed at 50 mg/kg/day (AUC exposures 4-fold higher than those achieved in patients at the 40 mg twice daily or 80 mg once daily doses), increased incidence of resorptions, indicative of embryofetal mortality and incidence of cardiac malformations (including dilated aorta/aortic arch, truncus arteriosus, valve absent, ventricular septum defect and/or atretic pulmonary artery, indicative of dysmorphogenesis) were observed. At the fetal maternal no-observed-adverse-effect level of 15 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose.
All these effects were in absence of adverse maternal effects and were considered to be drug related.
Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus if Scemblix is used during pregnancy or if the patient becomes pregnant while taking Scemblix (see Section 4.4 Special Warnings and Precautions for Use).

Pregnancy testing.

The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Scemblix.

Contraception.

Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Scemblix and for at least 3 days after the last dose.
It is not known if asciminib is transferred into human milk after administration of Scemblix. There are no data on the effects of asciminib on the breastfed child or on milk production.
Because of the potential for serious adverse drug reactions in the breastfed child, breast-feeding is not recommended during treatment with Scemblix and for at least 3 days after the last dose.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The overall safety profile of Scemblix has been evaluated in 356 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases receiving Scemblix as monotherapy. It is based on the safety pool of the pivotal phase III study A2301 (ASCEMBL) (N=156 Ph+ CML-CP patients) and the phase I study X2101, including patients with: Ph+ CML-CP (N=115), Ph+ CML-CP harbouring the T315I mutation (N=70), Ph+ CML-AP (N=15).
The safety pool (N=356) includes patients receiving Scemblix at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily. In the pooled dataset, the median duration of exposure to Scemblix was 167 weeks (range: 0.1 to 439 weeks).
The most common adverse drug reactions of any grade (incidence ≥ 20%) in patients receiving Scemblix were musculoskeletal pain (38.8%), upper respiratory tract infections (29.5%), thrombocytopaenia (28.1%), headache (26.4%), arthralgia (24.4%), increased pancreatic enzymes (23%), diarrhoea (22.5%), abdominal pain (22.2%), rash (21.6%), hypertension (20.8%) and nausea (20.8%). The most common adverse drug reactions of ≥ grade 3 (incidence ≥ 5%) in patients receiving Scemblix were thrombocytopaenia (18.5%), neutropaenia (15.7%), increased pancreatic enzymes (12.9%), hypertension (11.2%) and anaemia (5.3%).
Serious adverse drug reactions occurred in 13.2% of patients receiving Scemblix. The most frequent serious adverse drug reactions (incidence ≥1%) were pleural effusion (2.5%), lower respiratory tract infections (2.2%), thrombocytopaenia (1.7%), pyrexia (1.4%), pancreatitis (1.1%), abdominal pain (1.1%), non-cardiac chest pain (1.1%) and vomiting (1.1%).
The predicted safety profile of Scemblix at the 80 mg once daily dose is similar to the 40 mg twice-daily dose, based on exposure-safety analysis.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions from clinical studies (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 7.1% (grade 3/4) of 156 patients receiving Scemblix at 40 mg twice daily.

Description of selected adverse drug reactions.

Myelosuppression.

Thrombocytopaenia occurred in 100 of 356 (28.1%) patients receiving Scemblix, with grade 3 and 4 reactions reported in 24 (6.7%) and 42 (11.8%) of patients, respectively. Among the patients with thrombocytopaenia ≥ grade 3, the median time to first occurrence of reactions was 6.14 weeks (range: 0.14 to 64.14 weeks) with median duration of any occurring reaction of 2 weeks (95% CI, range: 1.43 to 2 weeks). Of the 100 patients with thrombocytopaenia, 9 (2.5%) permanently discontinued Scemblix, while Scemblix was temporarily withheld in 44 (12.4%) patients due to the adverse drug reaction.
Neutropaenia occurred in 70 of 356 (19.7%) patients receiving Scemblix, with grade 3 and 4 reactions reported in 26 (7.3%) and 30 (8.4%) patients, respectively. Among the patients with neutropaenia ≥ grade 3, the median time to first occurrence of reactions was 6.14 weeks (range: 0.14 to 180.1 weeks) with median duration of any occurring reaction of 2 weeks (95% CI, range: 1.43 to 2.14 weeks). Of the 70 patients with neutropaenia, 6 (1.7%) permanently discontinued Scemblix, while Scemblix was temporarily withheld in 33 (9.3%) patients due to the adverse drug reaction.
Anaemia occurred in 47 of 356 (13.2%) patients receiving Scemblix, with grade 3 reactions occurring in 19 (5.3%) patients. Among the patients with anaemia grade 3, the median time to first occurrence of reactions was 30.43 weeks (range: 0.43 to 207 weeks) with median duration of any occurring reaction of 0.86 weeks (95% CI, range: 0.29 to 1.71 weeks). Of the 47 patients with anaemia, Scemblix was temporarily withheld in 2 (0.6%) patients due to adverse drug reaction.

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 limited experience of Scemblix overdose. In clinical studies, Scemblix has been administered at doses up to 280 mg twice daily with no evidence of increased toxicity. General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors. ATC code: L01EA06.

Mechanism of action.

Asciminib is an oral and potent inhibitor of ABL/BCR::ABL1 tyrosine kinases. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein, by specifically targeting the ABL myristoyl pocket.

Pharmacodynamics (PD).

In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC₅₀ values below 3 nanomolar. In patient-derived cancer cells, asciminib specifically inhibits the proliferation of cells harbouring BCR::ABL1 with IC₅₀ values between 1 and 25 nanomolar. In cells engineered to express the wild-type or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC₅₀ value of 0.61 ± 0.21 and 7.64 ± 3.22 nanomolar, respectively.
In mouse xenograft models of CML, asciminib dose-dependently inhibited the growth of tumours harbouring either the wild-type or the T315I mutant form of BCR::ABL1, with tumour regression being observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.

Cardiac electrophysiology.

Scemblix treatment is associated with an exposure-related prolongation of the QT interval. The correlation between asciminib concentration and the estimated maximum mean change from baseline of the QT interval with Fridericia's correction (ΔQTcF) was evaluated in 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukaemia (ALL) receiving Scemblix at doses ranging from 10 to 280 mg twice daily and 80 to 200 mg once daily. The estimated mean ΔQTcF was 3.35 ms (upper bound of 90% CI: 4.43 ms) for Scemblix 40 mg twice-daily dose and 3.64 ms (upper bound of 90% CI: 4.68 ms), for the 80 mg once-daily dose and 5.37 ms (upper bound of 90% CI: 6.77 ms) for the 200 mg twice daily dose.

Clinical trials.

Ph+ CML-CP.

The clinical efficacy of Scemblix in the treatment of patients with Philadelphia chromosome-positive myeloid leukaemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine kinase inhibitors were demonstrated in the multi-centre, randomised, active-controlled and open-label phase III study ASCEMBL.
In this study, a total of 233 patients were randomised in a 2:1 ratio and stratified according to major cytogenetic response (MCyR) status at baseline to receive either Scemblix 40 mg twice daily (N=157) or bosutinib 500 mg once daily (N=76). Patients continued treatment until unacceptable toxicity or treatment failure occurred.
Patients with Ph+ CML-CP were 51.5% female and 48.5% male with median age 52 years (range: 19 to 83 years). Of the 233 patients, 18.9% were 65 years or older, while 2.6% were 75 years or older. Patients were Caucasian (74.7%), Asian (14.2%) and Black (4.3%). Of the 233 patients, 80.7% and 18% had Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, respectively. Patients who had previously received 2, 3, 4, 5 or more prior lines of TKIs were 48.1%, 31.3%, 14.6% and 6%, respectively. The median duration of treatment was 156 weeks (range: 0.1 to 256.3 weeks) for patients receiving Scemblix and 30.5 weeks (range: 1 to 293.3 weeks) for patients receiving bosutinib.
The primary endpoint of the study was major molecular response rate (MMR) at 24 weeks and the key secondary endpoint was MMR rate at 96 weeks. MMR is defined as BCR::ABL1 ratio ≤ 0.1% by International Scale [IS]. Secondary endpoints were complete cytogenetic response rate (CCyR) at 24 and 96 weeks, defined as no Philadelphia-positive metaphases in bone marrow with a minimum of 20 metaphases examined.
The main efficacy outcomes from ASCEMBL are summarised in Table 4.

The Kaplan-Meier estimated OS rate at 2 years was 97.3% (95% CI: 92.9, 99.0) for the asciminib arm and 98.6% for the bosutinib arm (95% CI: 90.2, 99.8).
The MMR rate at 24 weeks in patients in whom the randomised treatment represented the third, fourth, fifth or more line of TKI was 29.3%, 25%, and 16.1% in patients treated with Scemblix and 20%, 13.8%, and 0% in patients receiving bosutinib, respectively.
The MMR rate at 48 weeks was 29.3% (95% CI: 22.32, 37.08) in patients receiving Scemblix and 13.2% (95% CI: 6.49, 22.87) in patients receiving bosutinib. The Kaplan-Meier estimated proportion of patients receiving Scemblix and maintaining MMR for at least 120 weeks was 97% (95% CI: 88.6, 99.2).

Ph+ CML-CP harbouring the T315I mutation.

The clinical efficacy of Scemblix in the treatment of patients with Ph+ CML-CP with the T315I mutation was evaluated in a multi-centre open-label study CABL001X2101 (NCT02081378). Testing for T315I mutation utilised a qualitative p210 BCR::ABL1 mutation test using Sanger Sequencing.
Efficacy was based on 48 patients with Ph+ CML-CP with the T315I mutation who received Scemblix at a dose of 200 mg twice daily. Patients continued treatment until unacceptable toxicity or treatment failure occurred.
Of the 48 patients, 77.1% were male and 22.9% female; 33.3% were 65 years or older, while 8.3% were 75 years or older with a median age of 56.5 years (range, 26 to 86 years). The patients were White (47.9%), Asian (25%), and Black or African American (2.1%), and 25% were unreported or unknown. Seventy-five percent and 25% of patients had ECOG performance status 0 and 1, respectively. Patients who had previously received 1, 2, 3, 4, and 5 or more TKIs were 16.7%, 31.3%, 35.4%, 14.6%, and 2%, respectively.
MMR was achieved by 24 weeks in 42% (19/45, 95% CI: 27.7-57.8) of the 45 patients treated with Scemblix. MMR was achieved by 96 weeks in 49% (22/45, 95% CI: 34% to 64%) of the 45 patients treated with Scemblix. The median duration of treatment was 108 weeks (range, 2 to 215 weeks).

5.2 Pharmacokinetic Properties

Absorption.

Asciminib is rapidly absorbed, with median maximum plasma levels (T_max) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of C_max at steady state is 1781 nanogram/mL (23%) and 793 nanogram/mL (49%) following administration of Scemblix at 80 mg once-daily and 40 mg twice-daily doses, respectively. The geometric mean (geoCV%) of C_max at steady state is 5642 nanogram/mL (40%) following administration of Scemblix at 200 mg twice daily dose. The geometric mean (geoCV%) of AUC_tau is 5262 nanogram*h/mL (48%) following administration of Scemblix at 40 mg twice-daily dose.
PBPK models predict that the asciminib absorption is approximately 100%, while bioavailability is approximately 73%.
Asciminib bioavailability may be reduced by co-administration of oral medicinal products containing hydroxypropyl-β-cyclodextrin as an excipient. Co-administration of multiple doses of itraconazole oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib, decreased asciminib AUC_inf by 40.2% in healthy subjects.

Food effect.

Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact on asciminib pharmacokinetics than a low-fat meal. Asciminib AUC is decreased by 62.3% with a high-fat meal and by 30% with a low-fat meal compared to the fasted state, independent of the dose (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Distribution.

Asciminib apparent volume of distribution at steady state is 111 L, based on population pharmacokinetic analysis. Asciminib is mainly distributed to plasma, with a mean blood-to-plasma ratio of 0.58, independent of the dose. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.

Metabolism.

Asciminib is primarily metabolised via CYP3A4-mediated oxidation (36%), UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively). Asciminib is the main circulating component in plasma (92.7% of the administered dose).

Excretion.

Asciminib is mainly eliminated via fecal excretion, with a minor contribution of the renal route. Eighty and 11% of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of [¹⁴C]-labelled asciminib. Fecal elimination of unchanged asciminib accounts for 56.7% of the administered dose.
The oral total clearance (CL/F) of asciminib is 6.31 L/hour, based on population pharmacokinetic analysis. The accumulation half-life of asciminib is 5.2 hours at 40 mg twice daily and 80 mg once daily.
PBPK models predict that asciminib biliary secretion via BCRP accounts for 31.1% of its total systemic clearance.

Linearity/non-linearity.

Asciminib exhibits a slight dose over-proportional increase in steady-state exposure (AUC and C_max) across the dose range of 10 to 200 mg administered once or twice daily.
The geometric mean average accumulation ratio is approximately 2-fold, independent of the dose. Steady-state conditions are achieved within 3 days at the 40 mg twice-daily dose.

Special populations.

Use in elderly patients (65 years of age or above).

In ASCEMBL, 44 of the 233 (18.9%) patients were 65 years or older, while 6 (2.6%) were 75 years or older. In study X2101, 16 of the 48 (33.3%) patients were 65 years or older, while 4 (8.3%) were 75 years or older.
No overall differences in the safety or efficacy of Scemblix were observed between patients of 65 years of age or above and younger patients. There is an insufficient number of patients of 75 years of age or above to assess whether there are differences in safety or efficacy.

Gender/race/body weight.

Asciminib systemic exposure is not affected by gender, race or body weight to any clinically relevant extent.

Renal impairment.

A dedicated renal impairment study including 6 subjects with normal renal function (absolute glomerular filtration rate [aGFR] ≥ 90 mL/min) and 8 subjects with severe renal impairment not requiring dialysis (aGFR 15 to < 30 mL/min) has been conducted. Asciminib AUC_inf and C_max are increased by 56% and 8%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function, following oral administration of a single 40 mg dose of Scemblix (see Section 4.2 Dose and Method of Administration).
Population pharmacokinetics models indicate an increase in asciminib median steady state AUC_0-24h by 11.5% in subjects with mild to moderate renal impairment, compared to subjects with normal renal function.

Hepatic impairment.

A dedicated hepatic impairment study including 8 subjects each with normal hepatic function, mild hepatic impairment (Child-Pugh A score 5 to 6), moderate hepatic impairment (Child-Pugh B score 7 to 9) or severe hepatic impairment (Child-Pugh C score 10 to 15) was conducted. Asciminib AUC_inf is increased by 22%, 3% and 66% in subjects with mild, moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function, following oral administration of a single 40 mg dose of Scemblix (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Asciminib was evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity and phototoxicity studies.

Genotoxicity.

Asciminib was negative for genotoxicity in a bacterial reverse mutation assay, in vitro micronucleus assays in lymphocytes and TK6 cells and in vivo, in a rat micronucleus assay at PO doses up to 600 mg/kg/day.

Carcinogenicity.

The carcinogenic potential of asciminib was investigated in a 2-year study by the oral route in rats. Benign ovarian Sertoli cell tumours were observed in female animals at 66 mg/kg/day (yielding exposure to asciminib 8- and 6-fold higher than in patients at 40 mg twice daily and 80 mg once daily, respectively, and comparable to that in patients with dosing at 200 mg twice daily, based on plasma AUC). This occurred in conjunction with increased ovarian Sertoli cell hyperplasia (observed with treatment at ≥ 30 mg/kg/day). The clinical relevance of the finding is currently unknown. No treatment-related neoplastic or hyperplastic findings were observed in male rats up to the highest dose tested (200 mg/kg/day; yielding exposure 18, 12 and 2.5 times higher, respectively, than in patients treated at 40 mg twice daily, 80 mg once daily and 200 mg twice daily).

6 Pharmaceutical Particulars

6.1 List of Excipients

Scemblix tablets contain the following inactive ingredients:

20 mg film-coated tablets.

Lactose monohydrate, microcrystalline cellulose (E460i), hydroxypropylcellulose (E463), croscarmellose sodium (E468), polyvinyl alcohol (E1203), titanium dioxide (E171), magnesium stearate, talc (E553b), colloidal silicon dioxide, iron oxide (E172, yellow and red), lecithin (E322), xanthan gum (E415).

40 mg film-coated tablets.

Lactose monohydrate, microcrystalline cellulose (E460i), hydroxypropylcellulose (E463), croscarmellose sodium (E468), polyvinyl alcohol (E1203), titanium dioxide (E171), magnesium stearate, talc (E553b), colloidal silicon dioxide, iron oxide (E172, black and red), lecithin (E322), xanthan gum (E415).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C - blister packs.
Store below 30°C - bottles.
Store in the original package in order to protect from moisture.

6.5 Nature and Contents of Container

Scemblix tablets are supplied in HDPE bottles or PCTFE/PVC/Alu blisters.*

Scemblix 20 mg tablets.

Supplied in blister packs or bottles containing 20 or 60 tablets.*

Scemblix 40 mg tablets.

Supplied in blister packs or bottles containing 20 or 60 tablets or in bottles containing 300 tablets.*
*Not all pack sizes and container types may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Asciminib hydrochloride has a molecular formula C₂₀H₁₈ClF₂N₅O₃.HCl; the free base has a molecular weight of 449.8. Asciminib HCl is a crystalline powder with pKa 3.9 and pH-dependent solubility.

Chemical structure.

CAS number.

2119669-71-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Scemblix 20 mg Tablets

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