Consumer medicine information

Tibsovo

Ivosidenib

BRAND INFORMATION

Brand name

Tibsovo

Active ingredient

Ivosidenib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tibsovo.

SUMMARY CMI

TIBSOVO®

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using TIBSOVO?

TIBSOVO contains the active ingredient ivosidenib. TIBSOVO is used to treat specific cancers (bile duct cancer and Acute myeloid leukaemia (AML)) that contain a particular mutated (abnormal) form of the isocitrate dehydrogenase 1 (IDH1) enzyme. For more information, see Section 1. Why am I using TIBSOVO? in the full CMI.

2. What should I know before I use TIBSOVO?

WARNING: DIFFERENTIATION SYNDROME AND QTc INTERVAL PROLONGATION.

TIBSOVO can cause Differentiation Syndrome in patients with AML, which is a severe reaction to medicines used to treat leukaemia. Symptoms may include: fever; cough; trouble breathing; weight gain; rash; decreased urination; dizziness or light-headedness; rapid weight gain; and swelling of the arms, legs, and neck. TIBSOVO can also cause QTc Interval Prolongation, regardless of the type of cancer a person has, which can cause life-threatening irregular heartbeats. Symptoms may include feeling dizzy, light-headed or faint. These conditions can be life-threatening or lead to death if not treated. Seek urgent medical attention or go straight to the Emergency Department at your nearest hospital if you notice any of these symptoms.

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use TIBSOVO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TIBSOVO and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TIBSOVO?

The usual dose of TIBSOVO is two tablets to be taken once daily at approximately the same time each day. In some cases your doctor may tell you to take a reduced dose if you are taking some other medicines or to help you better tolerate some possible side effects. It is important to follow the instructions provided and use TIBSOVO until your doctor tells you to stop. More instructions can be found in Section 4. How do I use TIBSOVO? in the full CMI.

5. What should I know while using TIBSOVO?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are using TIBSOVO.
  • Continue regular monitoring (e.g. echocardiogram and/or blood tests) as directed by your doctor.
Things you should not do
  • Do not take TIBSOVO along with a high-fat meal.
  • Do not have grapefruit or grapefruit juice during treatment with TIBSOVO as it can affect how this medicine works.
  • You should not take TIBSOVO together with certain medications including dabigatran, St.John's wort, rifampicin or certain medicines used to treat epilepsy (e.g. carbamazepine, phenobarbital, phenytoin).
Looking after your medicine
  • Store in a cool dry place away from moisture, heat, and sunlight. Keep out of reach of children.
  • Close the bottle lid tightly to prevent moisture.

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

6. Are there any side effects?

TIBSOVO is usually well tolerated, however all medications may have unwanted effects in some people. Always tell your healthcare provider about any side effects that you experience. 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.

WARNING: DIFFERENTIATION SYNDROME AND QTc INTERVAL PROLONGATION.

TIBSOVO can cause Differentiation Syndrome in patients with AML, which is a severe reaction to medicines used to treat leukaemia. Symptoms may include: fever; cough; trouble breathing; weight gain; rash; decreased urination; dizziness or light-headedness; rapid weight gain; and swelling of the arms, legs, and neck. TIBSOVO can also cause QTc Interval Prolongation, regardless of the type of cancer a person has, which can cause life-threatening irregular heartbeats. Symptoms may include feeling dizzy, light-headed or faint. These conditions can be life-threatening or lead to death if not treated. Seek urgent medical attention or go straight to the Emergency Department at your nearest hospital if you notice any of these symptoms.



FULL CMI

TIBSOVO®

Active ingredient(s): ivosidenib

Consumer Medicine Information (CMI)

This leaflet provides important information about using TIBSOVO. 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 TIBSOVO.

Where to find information in this leaflet:

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

1. Why am I using TIBSOVO?

TIBSOVO contains the active substance ivosidenib.

TIBSOVO is used to treat specific cancers (bile duct cancer and acute myeloid leukaemia) that contain a particular mutated (abnormal) form of the IDH1 enzyme.

When the IDH1 enzyme is mutated, metabolic changes in the cell can lead to the development of cancer. TIBSOVO blocks the effects of the mutated enzyme and helps to slow or stop the cancer from growing.

TIBSOVO can be used to treat adults with bile duct cancer (also known as 'cholangiocarcinoma'). It is used to treat patients whose bile duct cancer has spread to other parts of the body and when therapy with other anti-cancer medicines are no longer working.

TIBSOVO can also be used alone or in combination with another anti-cancer medicine called azacitidine, to treat adults with acute myeloid leukaemia (AML) who are not eligible to receive intensive chemotherapy.

TIBSOVO can also be used alone in adults with AML when the disease has come back or has not improved after previous treatment(s).

TIBSOVO is only used in patients whose cancer is related to a particular mutation (called R132) in the IDH1 enzyme.

Your doctor will have performed a test confirming the cancer contains the R132-mutated IDH1 enzyme before deciding that this medicine is the right treatment for you. Speak to your doctor if you have any questions about this test and the results.

2. What should I know before I use TIBSOVO?

There are some people who shouldn't take TIBSOVO. Please read the list below. If you think any of these situations apply to you or you have any questions, please see your doctor.

Warnings

Do not use TIBSOVO if:

  • you are allergic to ivosidenib or any of the other ingredients of this medicine (listed in section 3); or
  • you are already taking medicines such as dabigatran, St.John's wort, rifampicin or certain medicines used to treat epilepsy (e.g. carbamazepine, phenobarbital, phenytoin).

Precautions when taking TIBSOVO:

  • If you have AML, and if your cancer responds to treatment, TIBSOVO can cause a serious condition known as Differentiation Syndrome, which can be life-threatening if not treated. Seek urgent medical attention if you develop fever; cough; trouble breathing; weight gain; rash; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; or low blood pressure (see "Serious side effects" in Section 6. Are there any side effects?).
  • TIBSOVO can cause a serious condition known as QTc interval prolongation which can cause life-threatening irregular heartbeats. Seek urgent medical attention if you feel dizzy, light-headed or faint (see also Section 6. Are there any side effects?) after taking TIBSOVO.
  • Guillain-Barré syndrome has happened in patients treated with TIBSOVO. Your doctor will monitor you for nervous system problems. Tell your doctor if you develop weakness or tingling feeling in your legs, arms, or upper body, numbness and pain on one side or both sides of your body, any changes in your ability to see, touch, hear, or taste, burning or prickling sensation, or difficulty breathing.

If you get any of the above serious side effects, your doctor may give you other medicines to treat them and they may tell you to stop taking TIBSOVO for a while or stop taking it altogether.

Check with your doctor if:

  • you have heart problems including a condition called long QT syndrome or have problems with abnormal electrolyte levels (such as sodium, potassium, calcium or magnesium);
  • you are taking certain medicines that can affect the heart (e.g. those used to prevent arrhythmia called anti-arrhythmics, some antibiotics, some antifungals and those used to prevent nausea and vomiting - see also Section 3. What if I am taking other medicines?);
  • you have kidney problems; and/or
  • you have liver problems.

Other side effects that could happen during treatment are described under Section 6. It is important you understand these risks and how to look out for them.

Pregnancy and breastfeeding

It is important to tell your doctor if you are pregnant or intend to become pregnant, or if you are breastfeeding or intend to breastfeed.

Pregnancy

TIBSOVO is not recommended for use during pregnancy as it may harm the unborn baby. People of child-bearing age should have a pregnancy test prior to starting treatment with TIBSOVO and should avoid becoming pregnant during therapy.

If you are pregnant, think you might be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Contact your doctor or nurse immediately if you become pregnant whilst taking TIBSOVO.

As TIBSOVO may affect an unborn developing baby, it is important for women not to become pregnant for at least 1 month after treatment discontinuation.

Contraception

People who might become pregnant, and people who have partners who might become pregnant, should use effective contraception during treatment with TIBSOVO and for at least 1 month after the last dose.

TIBSOVO may stop hormonal contraceptives from working properly. If you or your partner use a hormonal contraceptive (e.g. birth control pills, or contraceptive patches or implants), you should also use a barrier method (e.g. condoms or a diaphragm) to avoid pregnancy. Talk to your doctor or nurse about the right contraceptive method for you.

Breastfeeding

It is not known if TIBSOVO passes into breast milk. Do not breastfeed your baby during treatment with TIBSOVO and for at least 1 month after the last dose.

Fertility

It is not known if TIBSOVO affects fertility. If you are concerned about your fertility whilst taking TIBSOVO talk to your doctor.

Children and adolescents

Do not give this medicine to children and adolescents under 18 years old because there is no information about its use in this age group.

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.

This is because they may reduce how well TIBSOVO works or increase the risk of side effects, or TIBSOVO may affect the way these other medicines work.

In particular, tell your doctor if you are taking any of the following medications:

  • antibiotics used for bacterial infections (e.g. erythromycin, clarithromycin, benzylpenicillin, ciprofloxacin, levofloxacin);
  • warfarin (used to stop blood clots);
  • medicines used for fungal infections (e.g. itraconazole, ketoconazole, fluconazole, isavuconazole, posaconazole, voriconazole);
  • medicines that affect your heartbeat known as anti-arrhythmics (e.g diltiazem, verapamil, quinidine);
  • medicines used to stop nausea and vomiting known as anti-emetics (e.g aprepitant, ondansetron, tropisetron, granisetron);
  • medicines used after organ transplants known as immunosuppressants (e.g. ciclosporin, everolimus, sirolimus, tacrolimus);
  • medicines used for HIV (e.g. raltegravir, ritonavir);
  • alfentanil (used for anaesthesia in surgery);
  • fentanyl (used for severe pain);
  • pimozide (used for schizophrenia);
  • medicines used for cancer (e.g. cyclophosphamide, ifosfamide, paclitaxel);
  • methadone (used for morphine or heroin addiction, or severe pain);
  • medicines used for type 2 diabetes (e.g. pioglitazone, repaglinide);
  • omeprazole (used for stomach ulcers and acid reflux);
  • furosemide (used for fluid build-up known as oedema);
  • medicines used for high cholesterol known as statins (e.g. atorvastatin, pravastatin, rosuvastatin); and/or
  • lamotrigine (used for epilepsy).

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

4. How do I use TIBSOVO?

How much to take / use

Always take this medicine exactly as your doctor has instructed. Check with your doctor if you are unsure.

The recommended dose is 2 tablets (500 mg ivosidenib) to be taken once daily at approximately the same time each day.

Your doctor may tell you to take 1 tablet (250 mg ivosidenib) if you are taking some other medicines or to help you better tolerate some possible side effects. Follow the dosage instructions from your doctor.

The tablets can be taken with or without food, but do not take it with fatty foods (e.g. high fat breakfast).

Swallow the tablets whole with water.

Do not swallow the silica gel desiccant found in the bottle. The silica gel desiccant helps protect the tablets from moisture. (See Section 5. What should I know while using TIBSOVO?.)

If you vomit after taking your usual dose, do not take additional tablets. Take your next dose as usual the following day.

It is important to follow the instructions provided and use TIBSOVO until your doctor tells you to stop.

When to take / use TIBSOVO

TIBSOVO should be taken once daily at approximately the same time each day.

If you forget to take TIBSOVO

If a dose is missed or not taken at the usual time, take the tablets as soon as possible unless the next dose is due within 12 hours.

Do not take two doses within 12 hours.

Take the next dose as usual the following day.

If you use too much TIBSOVO

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

You should immediately do one of the following:

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

You should do one of the above even if there are no signs of discomfort or poisoning.

TIBSOVO with food and drink

  • Do not have grapefruit or grapefruit juice during treatment with TIBSOVO as it can affect how this medicine works.
  • Do not take the tablets with fatty foods (e.g., high fat breakfast), as it can affect how this medicine works

5. What should I know while using TIBSOVO?

Things you should do

Regular Tests

You will be monitored closely by your doctor before and during treatment with TIBSOVO.

You will need to have regular electrocardiograms (ECGs) to monitor your heartbeat, in a hospital. An ECG is a recording of the electrical activity in your heart. You will be given an ECG before you start treatment with TIBSOVO, once a week for the first three weeks of treatment, and then once monthly thereafter.

Call your doctor straight away or go straight to the Emergency Department if you experience any serious side effects.

More information about serious side effects can be found in Section 6. Are there any side effects?.

Things you should not do

Do not stop using this medicine without consulting your doctor.

Driving or using machines

This medicine is not likely to affect your ability to drive or use any tools or machines, but if you feel unwell after taking TIBSOVO, do not drive or use any tools or machines until you feel well again.

Drinking alcohol

Tell your doctor if you drink alcohol.

Drinking alcohol could worsen certain side effects that you may have with TIBSOVO.

Looking after your medicine

Store it in a cool dry place away from moisture, heat or sunlight (e.g. high on a pantry shelf away from the stove).

Do not store it in the refrigerator, bathroom, near a sink, in the car, or on windowsills.

Keep the bottle tightly closed in order to protect from moisture.

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

Keep it where young children cannot reach it.

When to discard your medicine

Do not use this medicine after the expiry date which is printed on the bottle label and box after EXP.

The expiry date is the last day of the printed month.

Getting rid of any unwanted medicine

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

6. Are there any side effects?

All medicines can have side effects. Some side effects may need medical attention.

Ask your doctor or pharmacist if you have any further questions about side effects after reading the below information.

Less serious side effects

Less serious side effectsWhat to do
Stomach
  • feeling sick, nausea, vomiting, diarrhoea, abdominal pain.
  • fluid and swelling in your stomach area.
Liver related
  • yellowing of the skin or eyes (jaundice) which is a sign of reduced flow of bile from the liver.
  • changes in liver function tests.
Respiratory
  • cough
Blood
  • lower number of red blood cells (anaemia). Symptoms may include tiredness, headaches, being short of breath when exercising, dizziness and looking pale.
  • abnormal white blood cell counts.
    Symptoms may include chills, fever, sweating or other signs of infection (sore throat).
  • abnormal platelet counts.
    Symptoms may include unusual bruising or bleeding.
Nervous system
  • headache
  • changes to the peripheral nerves (peripheral neuropathy). Symptoms may include weakness, pain, numbness, pins and needles in the fingers and toes (paraesthesia).
  • dizziness.
Skin
  • rash
Musculoskeletal and connective tissue disorders
  • back pain
  • joint pain
General
  • decreased appetite
  • fatigue
  • falls
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you or if you don't understand something in this list.

Serious side effects

Serious side effectsWhat to do
Differentiation Syndrome (see Precautions when taking TIBSOVO):
Differentiation syndrome in adults with AML occurred from one day and up to 3 months after starting treatment with TIBSOVO.
Signs and symptoms of Differentiation Syndrome include fever; cough; trouble breathing; weight gain; rash; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; low blood pressure.
Changes to the interval between the heart contracting and relaxing (called QTc interval prolongation).
Some or all of these symptoms could be due to a serious condition known as QTc interval prolongation, which can be life-threatening:
  • experience a fast or irregular heart rhythm or heartbeat (QTc prolongation) and/or
  • feel dizzy, lightheaded, or faint
If you are taking TIBSOVO, please show this information to all healthcare providers involved in your care, because this is a new type of medicine and not everyone will be familiar with it.
Alternatively, you can scan the QR code below to access a Patient Alert Card which can be saved to your phone or printed.
Keep this information leaflet, or the Patient Alert Card, with you at all times.

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 nurse 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 TIBSOVO contains

Active ingredient
(main ingredient)		Ivosidenib
Other ingredients
(inactive ingredients)		Microcrystalline cellulose
Croscarmellose sodium
Hypromellose acetate succinate
Colloidal anhydrous silica
Magnesium stearate
Sodium lauryl sulfate
Hypromellose
Titanium dioxide
Lactose monohydrate
Triacetin
Indigo carmine aluminium lake

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

What TIBSOVO looks like

TIBSOVO tablets are blue, oval shaped, film-coated tablets approximately 18 mm in length, debossed with 'IVO' on one side and '250' on the other side.

TIBSOVO is available in plastic bottles containing 60 tablets and a silica gel desiccant. The bottles are packaged in a cardboard box; each box contains 1 bottle.

(AUST R 391874).

Who distributes TIBSOVO

Servier Laboratories (Aust.) Pty. Ltd.
www.servier.com.au
Level 4, Building 9
588A Swan Street,
Burnley, 3121, Victoria, Australia

This leaflet was prepared in May 2024

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Tibsovo

Active ingredient

Ivosidenib

Schedule

S4

 

1 Name of Medicine

Ivosidenib.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 250 mg of ivosidenib.

Excipient with known effect.

Contains lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Blue, oval shaped, film-coated tablets approximately 18 mm in length, debossed with 'IVO' on one side and '250' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Cholangiocarcinoma.

Tibsovo is indicated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) R132 mutation after at least one prior line of systemic therapy.

Acute myeloid leukaemia.

Tibsovo is indicated for the treatment of acute myeloid leukaemia (AML) that carries an IDH1 R132 mutation:
as monotherapy, or in combination with azacitidine, in newly diagnosed patients who are not eligible to receive intensive induction chemotherapy; or
as monotherapy in patients whose AML is relapsed and/or refractory to prior therapy.

4.2 Dose and Method of Administration

Treatment should be initiated by a physician experienced in the use of anti-cancer therapies. Before taking Tibsovo, patients must have confirmation of an IDH1 mutation using an appropriate diagnostic test, and an electrocardiogram (ECG) to assess heart rate corrected QT (QTc) interval. Patients with AML without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment or at relapse.

Dose.

The recommended dose of Tibsovo is 500 mg orally once daily until disease progression or unacceptable toxicity.
When Tibsovo is used in combination with azacitidine to treat patients with newly diagnosed AML, the recommended dose of azacitidine is 75 mg/m2 of body surface area, intravenously or subcutaneously, once daily on Days 1-7 (or on Days 1-5, then on Days 8 and 9) of each 28-day cycle. Refer to the full product information for azacitidine for additional dosing information.
Continue treatment for AML (whether monotherapy or in combination with azacitidine) for a minimum of six months to allow time for clinical response.

Method of administration.

Tibsovo should be taken at about the same time each day, with or without food, but not with a high fat meal (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties). Do not split, crush or chew the tablets.
Two doses should not be taken within 12 hours. If a dose of Tibsovo is missed or not taken at the usual time, administer the dose as soon as possible within 12 hours after it was missed. Administer the following day's dose at the usual time. If 12 hours or longer have elapsed since a dose was missed, do not administer the dose; wait until the next scheduled dose is due. If a dose of Tibsovo is vomited, do not administer replacement tablets; wait until the next scheduled dose is due.

Monitoring.

QTc interval prolongation.

Perform an ECG at baseline, at least weekly during the first three weeks of therapy and at least monthly thereafter. Monitor electrolytes at baseline and throughout treatment as clinically indicated. Patients at higher risk of QTc interval prolongation, including due to concomitant medications, may require more frequent monitoring. Promptly manage abnormalities (see Table 1 and see Section 4.4 Special Warnings and Precautions for Use).

Differentiation syndrome in AML.

Assess full blood count and blood chemistry prior to initiating treatment, and then as clinically indicated: including at least weekly for the first month, at least fortnightly for the second month, and at least monthly thereafter. Promptly manage abnormalities (see Table 1 and see Section 4.4 Special Warnings and Precautions for Use).

Dose modification for concomitant administration of strong CYP3A4 inhibitors.

If use of strong CYP3A4 inhibitors is unavoidable, reduce the Tibsovo dose to 250 mg once daily. If the strong CYP3A4 inhibitor is discontinued, increase the Tibsovo dose to 500 mg after at least 5 half-lives of the strong CYP3A4 inhibitor (see above and see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dose modifications for adverse reactions.

Guidelines for management in case of adverse reactions are summarised in Table 1. Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects).

Special populations.

Renal impairment.

No dose adjustment is required in patients with mild (eGFR ≥ 60 to ˂ 90 mL/min/1.73 m2) or moderate (eGFR ≥ 30 to ˂ 60 mL/min/1.73 m2) renal impairment. A recommended dose has not been determined for patients with severe renal impairment (eGFR ˂ 30 mL/min/1.73 m2). See Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties.

Hepatic impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh class C) and a recommended dose has not been determined in this population. See Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties.

Elderly population.

No dose adjustment is required in elderly patients (≥ 65 years old). See Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties.

Paediatric population.

No data are available. See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Differentiation syndrome in patients with acute myeloid leukaemia (AML).

Tibsovo treatment can cause differentiation syndrome in patients with AML (see Section 4.8 Adverse Effects (Undesirable Effects)), in keeping with its mechanism of action. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal.
Symptoms of differentiation syndrome in patients treated with Tibsovo in pivotal studies included noninfectious leukocytosis, peripheral oedema, pyrexia, dyspnoea, pleural effusion, hypotension, hypoxia, pulmonary oedema, pneumonitis, pericardial effusion, rash, fluid overload, tumour lysis syndrome and creatinine increased. The timing of onset of differentiation syndrome follows that of AML response to treatment: it can occur within a day or after many months of treatment.
If differentiation syndrome is suspected, commence systemic corticosteroids (dexamethasone 10 mg IV every 12 hours or an equivalent dose of an alternative oral or IV corticosteroid) and initiate haemodynamic monitoring. If noninfectious leukocytosis is also observed, initiate treatment with hydroxycarbamide or leukapheresis as clinically indicated.
Continue corticosteroids for a minimum of three days, and taper corticosteroids and hydroxycarbamide only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxycarbamide treatment.
If severe (Grade 3 or higher) signs/symptoms persist for more than 48 hours after the initiation of systemic corticosteroids, interrupt Tibsovo until signs/symptoms are no longer severe (see Section 4.2 Dose and Method of Administration).

QTc interval prolongation.

Tibsovo causes prolongation of the QTc interval, and ventricular arrhythmias have been reported following treatment with Tibsovo in patients with haematological malignancies (see Section 5.1 Pharmacodynamic Properties; Section 4.8 Adverse Effects (Undesirable Effects)). Perform an ECG prior to treatment initiation, at least weekly during the first 3 weeks of therapy and at least monthly thereafter and monitor electrolytes. Manage any abnormalities promptly (see Section 4.2 Dose and Method of Administration).
Avoid concomitant administration of medicines known to prolong the QTc interval (e.g. antiarrhythmics, fluoroquinolones, 5-HT3 receptor antagonists, triazole antifungals), or moderate or strong CYP3A4 inhibitors, as these may increase the risk of QTc interval prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If concomitant use is unavoidable, or for patients with other risk factors (such as congenital long QTc syndrome, congestive heart failure or electrolyte abnormalities), monitor closely, with more frequent ECGs and regular monitoring of electrolytes as required. Adjust dosing if concomitant use of a strong CYP3A4 inhibitor is unavoidable (see Section 4.2 Dose and Method of Administration).
Interrupt Tibsovo for QTc interval over 480 msec, and permanently discontinue Tibsovo in patients with QTc interval prolongation and signs or symptoms of life-threatening arrhythmia (see Section 4.2 Dose and Method of Administration).

Guillain-Barré syndrome.

Guillain-Barré syndrome has occurred uncommonly in patients with haematological malignancies treated with Tibsovo. A causal mechanism is not known, and preclinical studies did not identify the CNS as a target organ for ivosidenib toxicity. No cases of Guillain-Barré syndrome have been reported in patients with solid tumours, though peripheral neuropathy is common (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor patients taking Tibsovo for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paraesthesias, or difficulty breathing. Permanently discontinue Tibsovo in patients who are diagnosed with Guillain-Barré syndrome.

Use in renal impairment.

The safety and efficacy of Tibsovo have not been established in patients with severe renal impairment (eGFR ˂ 30 mL/min/1.73 m2), including those requiring dialysis. Use Tibsovo with caution and monitor closely in this population (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

The safety and efficacy of Tibsovo have not been established in patients with severe hepatic impairment (Child-Pugh class C). Use Tibsovo with caution and monitor closely in this population (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No overall differences in effectiveness or safety were observed in patients ≥ 65 years of age (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

The safety and efficacy of Tibsovo in children and adolescents ˂ 18 years old have not been established. No data are available.

Effects on laboratory tests.

See Table 4, Table 6, Table 8 and Table 10 in Section 4.8 Adverse Effects (Undesirable Effects).

Reproductive toxicity.

Tibsovo may cause fetal harm if administered during pregnancy. Verify pregnancy status prior to starting treatment and advise the use of barrier contraception as ivosidenib may decrease systemic concentrations of hormonal contraceptives (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.6 Fertility, Pregnancy and Lactation).

Interactions.

Clinically significant interactions are predicted with Tibsovo. Give advice regarding potential for food interactions and review concomitant medications (see QTc interval prolongation and Reproductive toxicity, above; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Summary of interactions.

Co-administration of Tibsovo with certain medicines and foods is likely to lead to clinically significant interactions. Categories of substances that interact (or may interact) with ivosidenib are summarised in Table 2 though the included examples are not an exhaustive list.

Effect of other medicines on Tibsovo.

Strong CYP3A4 inducers.

Ivosidenib is a CYP3A4 substrate. Physiologically based pharmacokinetic (PBPK) modelling predicted a 33% decrease in ivosidenib steady-state AUC (AUCss) when given at the recommended dose in the presence of co-administered 600 mg rifampin once daily for 15 days. Avoid co-administration of strong CYP3A4 inducers (see Table 2).

Moderate or strong CYP3A4 inhibitors.

Co-administration of a single dose of Tibsovo 250 mg with a strong CYP3A4 inhibitor (200 mg itraconazole daily for 18 days) increased the ivosidenib AUC by 2.7-fold (with no change in Cmax) in healthy volunteers. PBPK modelling predicted an increase in ivosidenib AUCss in the presence of a co-administered strong (ketoconazole: 3.2-fold) or moderate (fluconazole: 1.9-fold) CYP3A4 inhibitor. Avoid co-administration of moderate or strong CYP3A4 inhibitors (see Table 2): consider alternative therapies. If co-administration is unavoidable, treat with caution and monitored closely for QTc interval prolongation (see Section 4.4 Special Warnings and Precautions for Use). If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce the ivosidenib dose (see Section 4.2 Dose and Method of Administration).

Interactions with transporters.

Ivosidenib is a P-glycoprotein (P-gp) substrate. However, data from study in healthy subjects suggest that the potential for clinically relevant interactions with ivosidenib and P-gp inhibitors is low.

Effect of Tibsovo on other medicines.

Enzyme induction.

Ivosidenib induces CYP3A4 (including its own metabolism), CYP2B6, CYP2C8, CYP2C9 and may induce CYP2C19 and UGT (see Section 5.2 Pharmacokinetic Properties). Therefore, it may decrease systemic exposure to substrates of these enzymes. This is of particular importance for substrates with a narrow therapeutic index or with significant clinical consequence of inefficacy (such as hormonal contraceptives and antifungals: see Table 2). Consider suitable alternatives, recommend barrier contraception (see Section 4.6 Fertility, Pregnancy and Lactation), and if concomitant use can't be avoided, monitor for loss of substrate efficacy.

Interactions with transporters.

Ivosidenib inhibits P-gp and OAT3 and has the potential to induce P-gp. Therefore, it may alter systemic exposure to active substances that are predominantly transported by P-gp and may increase systemic exposure to OAT3 substrates (see Table 2). Consider suitable alternatives, and if concomitant use can't be avoided, monitor for loss of substrate efficacy or P-gp substrate toxicity. Avoid co-administration of dabigatran due to risk of dabigatran toxicity (haemorrhage).

Other interactions.

Medicines known to prolong the QTc interval.

Co-administration of other medicines known to prolong the QTc interval (see Table 2) may increase the risk of QTc interval prolongation. Avoid co-administration of medicines known to prolong the QTc interval (see Table 2): consider alternative therapies. If co-administration is unavoidable, treat with caution and monitored closely for QTc interval prolongation (see Section 4.4 Special Warnings and Precautions for Use).

Food interactions.

Administration of Tibsovo with a high-fat meal should be avoided, as it has a significant effect on the absorption of ivosidenib and leads to increased exposure (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Grapefruit and grapefruit juice moderately inhibit CYP3A4 (see Moderate or strong CYP3A4 inhibitors).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of ivosidenib on fertility. No specific fertility studies have been conducted in animals, but undesirable effects on reproductive organs were observed in a 28-day repeat-dose toxicity study in rats. Uterine atrophy was observed in females at non-tolerated dose levels approximately 1.7-fold the clinical exposure (based on AUC) and was reversible after a 14-day recovery period. Testicular degeneration was observed in males at non-tolerated dose levels approximately 1.2-fold the clinical exposure (based on AUC) and reversibility of this finding has not been assessed. The clinical relevance of these effects is unknown.
(Category D)
There are no human data, but based on animal data, Tibsovo may cause fetal harm if administered during pregnancy. Reproductive toxicity (embryofetal mortality and growth alteration) was seen in animal studies, starting at 2-fold the steady-state clinical exposure (based on AUC) at the recommended human dose (see Preclinical data).
Advise patients of the risk to the fetus if Tibsovo is used during pregnancy. Assess pregnancy status prior to starting treatment with Tibsovo. Advise patients to use effective contraception during treatment with Tibsovo and for at least 1 month after the last dose.
As ivosidenib may decrease systemic concentrations of hormonal contraceptives, concomitant use of an alternative contraceptive method such as barrier contraceptives is recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Preclinical data.

In embryofetal development studies in rats, lower fetal body weights, delayed skeletal ossification and development variation of major blood vessels occurred in the absence of maternal toxicity. In rabbits, maternal toxicity, spontaneous abortions, decreased fetal body weights, increased post-implantation loss, delayed skeletal ossification and visceral development variation (small spleen) were observed. In rats and rabbits, the no-adverse-effect levels for embryofetal development were 0.4-fold and 1.4-fold the clinical exposure (based on AUC), respectively. Animal studies indicate that ivosidenib crosses the placenta and is found in fetal plasma. It is not known whether ivosidenib or its metabolites are excreted in milk.
 There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Due to the potential risk to a breastfed child, breastfeeding should be discontinued during treatment with Tibsovo and for at least one month after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Tibsovo does not have sedating properties and does not specifically change the ability to drive and use machines. However, any adverse effects of Tibsovo which a patient experiences (which could include fatigue, dizziness and QTc interval prolongation - see Section 4.8 Adverse Effects (Undesirable Effects)) should be considered when assessing ability to drive or operate machines.

4.8 Adverse Effects (Undesirable Effects)

Safety profile in cholangiocarcinoma.

The safety profile of Tibsovo was studied in 123 patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005. Patients received at least one dose of either Tibsovo 500 mg daily (n=123) or placebo (n=59).
The median (range) and mean (standard deviation, SD) duration of treatment with Tibsovo were 2.8 (0.1 to 45.1) months and 6.7 (8.2) months, respectively.
Serious adverse events occurred in 35% of patients receiving Tibsovo. Serious adverse events that occurred in ≥ 2% of patients in the Tibsovo arm were pneumonia, ascites, hyperbilirubinaemia, and jaundice cholestatic. Fatal adverse events occurred in 4.9% of patients receiving Tibsovo, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%).
Tibsovo was permanently discontinued in 7% of patients. The most common adverse event leading to permanent discontinuation was acute kidney injury (1.6%).
Dose interruptions due to adverse events occurred in 30% of patients treated with Tibsovo. The most common (> 2%) adverse events leading to dose interruption were hyperbilirubinaemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue.
Dose reductions of Tibsovo due to an adverse event occurred in 4% of patients. Adverse events leading to dose reduction were electrocardiogram QTc interval prolongation (3.3%) and neuropathy peripheral (0.8%).
The most common adverse events and laboratory abnormalities in patients who received Tibsovo in Study AG120-C-005 are presented in Table 3 and Table 4, respectively.

Safety profile in acute myeloid leukaemia (AML).

Summary of the safety profile in AML across studies. Tibsovo 500 mg daily has been studied in combination with azacitidine in newly diagnosed AML (Study AG120-C-009 [N=71]) and as monotherapy in patients with newly diagnosed or with relapsed/refractory AML (Study AG120-C-001 [N=213]). These studies are described further in Section 5.1 Pharmacodynamic Properties. In patients with AML across both of these studies, the most common adverse events including laboratory abnormalities (≥ 25% in either trial) were leukocytes decreased, diarrhoea, haemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, oedema, potassium decreased, nausea, vomiting, phosphatase decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnoea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QTc interval prolongation, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia.

Safety profile in the treatment of newly diagnosed AML (Tibsovo in combination with azacitidine).

In the randomised, phase 3 Study AG120-C-009, patients with newly diagnosed AML received azacitidine in combination with either Tibsovo (500 mg daily, n=72) or matching placebo (n=74). The median duration of treatment with Tibsovo was 7.8 months (range: 0.1 to 40.0 months). Forty patients (55.6%) were exposed to Tibsovo for at least six months and twenty-nine patients (40.3%) were exposed for at least one year.
The most common adverse events and laboratory abnormalities reported in patients who received Tibsovo and azacitidine are shown in Table 5 and Table 6, respectively.
The most common (≥ 5%) serious adverse event to Tibsovo was differentiation syndrome (8%). There were eleven fatal adverse events in patients who received Tibsovo (15%) - most common (≥ 2%) included pneumonia (3%) and haemorrhage intracranial (3%).
The frequency of discontinuation of Tibsovo due to adverse events was 29%. Adverse event leading to discontinuation of Tibsovo in ≥ 2% of patients was pulmonary embolism (3%).
The frequency of dose interruption of Tibsovo due to adverse events was 67%. The most common (≥ 5%) adverse events leading to dose interruption of Tibsovo were neutropenia (24%), febrile neutropenia (13%), pneumonia (13%), thrombocytopenia (7%) and electrocardiogram QTc interval prolongation (7%).
The frequency of dose reduction of Tibsovo due to adverse events was 22%. The most common (≥ 5%) adverse events leading to dose reduction were electrocardiogram QTc interval prolongation (10%) and neutropenia (8%).

Safety profile in the treatment of newly diagnosed AML (Tibsovo monotherapy).

The safety profile of single-agent Tibsovo at a dose of 500 mg daily was studied in 28 adults with newly diagnosed AML in a single-arm, open-label, multicenter clinical trial (Study AG120-C-001).
The median duration of exposure to Tibsovo amongst this group was 4.3 months (range: 0.3 to 40.9 months). Ten patients (36%) were exposed to Tibsovo for at least six months and six patients (21%) were exposed for at least one year.
Common (≥ 5%) serious adverse events included differentiation syndrome (18%), electrocardiogram QTc interval prolongation (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
Common (≥ 10%) adverse events leading to dose interruption included electrocardiogram QTc interval prolongation (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QTc interval prolongation. One patient each required permanent discontinuation due to diarrhoea and PRES.
The most common adverse events and changes in selected post-baseline laboratory values reported in Study AG120-C-001 amongst these patients with newly diagnosed AML are shown in Table 7 and Table 8, respectively.

Safety profile in the treatment of relapsed or refractory AML (Tibsovo monotherapy).

The safety profile of single-agent Tibsovo was studied in 179 adults with relapsed or refractory AML who received Tibsovo 500 mg daily in Study AG120-C-001 (see Section 5.1 Pharmacodynamic Properties).
The median duration of exposure to Tibsovo was 3.9 months (range: 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to Tibsovo for at least six months and 16 patients (9%) were exposed for at least 1 year.
Serious treatment emergent adverse events (TEAEs) (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QTc interval prolongation (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
The most common adverse events leading to dose interruption were electrocardiogram QTc interval prolongation (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnoea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse events leading to a dose reduction included electrocardiogram QTc interval prolongation (1%), diarrhoea (1%), nausea (1%), decreased haemoglobin (1%), and increased transaminases (1%). Adverse events leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).
The most common adverse events and changes in selected post-baseline laboratory values reported in this group of patients with relapsed or refractory AML are shown in Table 9 and Table 10, respectively.

Description of selected adverse events.

Differentiation syndrome in patients with AML.

Differentiation syndrome is a known risk associated with Tibsovo treatment in patients with AML (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with Tibsovo experienced differentiation syndrome. Of the seven patients with newly diagnosed AML who experienced differentiation syndrome, six (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of Tibsovo. Differentiation syndrome occurred as early as one day and up to three months after initiation with Tibsovo and has been observed with or without concomitant leukocytosis.
In Study AG120-C-009, 14% (10/71) of patients with newly diagnosed AML treated with Tibsovo in combination with azacitidine experienced differentiation syndrome. Of these ten patients, two required dose interruptions to manage signs/symptoms and zero patients permanently discontinued Tibsovo treatment due to differentiation syndrome. The median time to onset of differentiation syndrome after initiation of combination therapy was 20 days, with a range of three to 46 days.

QTc interval prolongation.

Prolongation of the electrocardiogram QTc interval is a known risk associated with Tibsovo treatment and may occur at any time during treatment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In Study AG120-C-005, in the 123 patients with locally advanced or metastatic cholangiocarcinoma treated with Tibsovo monotherapy, QTc prolongation was reported in 10%; 2% experienced Grade 3 or higher reactions. Based on the analysis of the ECGs, 2% of patients had a QTc interval ˃ 500 msec and 5% had QTc interval prolongation ˃ 60 msec from baseline. No patient discontinued treatment due to QTc prolongation, and dose reduction to manage signs/symptoms was required in (3% of patients). The median time to onset after treatment initiation was 28 days (range: one day to 698 days [23 months]).
Of the 258 patients with hematological malignancies treated with Tibsovo monotherapy in the clinical trial AG120-C-001, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec (see Section 4.8 Adverse Effects (Undesirable Effects)). One patient developed ventricular fibrillation attributed to Tibsovo. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.
In Study AG120-C-009, in the 71 patients with newly diagnosed AML treated with Tibsovo in combination with azacitidine, electrocardiogram QT prolonged was reported in 20%; 10% experienced Grade 3 or higher reactions. Based on the analysis of the ECGs, 14% of patients treated with Tibsovo in combination with azacitidine, who had at least one post-baseline ECG assessment, were found to have a QTc interval ˃ 500 msec, 22% had an increase from baseline QTc ˃ 60 msec. One patient discontinued Tibsovo treatment due to electrocardiogram QT prolongation. Dose interruption and reduction were required in 6% and 9% of patients, respectively. The median time to onset of QT prolongation in patients treated with Tibsovo was 29 days. Electrocardiogram QT prolongation occurred as early as 1 day and up to 5 months after treatment initiation.

Guillain-Barré syndrome.

Two cases of Guillain-Barré syndrome (< 1%) occurred in patients with haematological malignancies receiving Tibsovo in Study AG120-C-001. There were no cases in Study AG120-C-009 or Study AG120-C005.

Special populations.

Elderly.

Of the 72 patients with newly diagnosed AML treated with Tibsovo in combination with azacitidine, 94% were 65 years of age or older, and 54% were 75 years or older. Of the 34 patients with newly diagnosed AML treated with Tibsovo monotherapy, 97% were 65 years of age or older, and 56% were 75 years or older. Of the 179 patients with relapsed or refractory AML treated with Tibsovo monotherapy, 63% were 65 years of age or older and 22% were 75 years or older. Of 123 patients with cholangiocarcinoma treated with Tibsovo in Study AG120-C-005, 36% were ≥ 65 years of age and 11% were ≥ 75 years of age. No overall difference in safety was observed between patients ≥ 65 years old and younger patients.

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

In the event of overdose, toxicity may manifest as QTc interval prolongation or ventricular arrhythmia, or exacerbation of other adverse reactions (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored and provided with appropriate supportive care (see Section 4.2 Dose and Method of Administration). There is no specific antidote for Tibsovo overdose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents. ATC code: L01XX62.

Mechanism of action.

Ivosidenib is a small molecule inhibitor of certain mutant isocitrate dehydrogenase 1 (IDH1) enzymes. Through a gain of neomorphic function, the mutant IDH1 converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As 2-HG competitively inhibits α-KG-dependent enzymes, including histone and DNA demethylases, its accumulation leads to widespread epigenetic dysregulation.
Ivosidenib inhibited selected IDH1 mutants (R132C, R132L, R132G, R132H and R132S) at much lower concentrations than wild-type IDH1 in vitro.

Cholangiocarcinoma.

In a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C, ivosidenib reduced 2-HG levels.

Acute myeloid leukaemia.

Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels, reduced blast counts, and increased percentages of mature myeloid cells.

Pharmacodynamic effects.

Multiple doses of ivosidenib 500 mg daily decreased plasma concentrations of 2-HG in patients with haematological malignancies and cholangiocarcinoma with mutated IDH1 to levels approximating those observed in healthy subjects. In tumour biopsies from patients with cholangiocarcinoma who received ivosidenib, the mean (coefficient of variation [CV]) reduction in 2-HG concentrations was 82% (32%). In bone marrow biopsies from patients with haematological malignancies who received ivosidenib, the mean (CV) reduction in 2-HG concentrations was 93% (11%).
Concentration-dependent prolongation of the QTc interval was observed following administration of ivosidenib at the recommended dose in patients with haematological malignancies and solid tumours. The mean maximal prolongation in both settings was 17 msec, with an upper confidence interval of 20 msec. Co-administration of moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

Clinical trials (efficacy).

Efficacy in previously treated, locally advanced or metastatic cholangiocarcinoma.

The efficacy of Tibsovo was evaluated in a randomised (2:1), multicentre, double-blind, placebo-controlled, phase 3 clinical trial (Study AG120-C-005, also known as 'ClarIDHy') of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following at least 1 but not more than 2 prior treatment regimens, including at least 1 gemcitabine- or 5-FU-containing regimen. Patients with certain IDH1 mutations (R132C, R132CL, R132G, R132H or R132S) were selected using a central diagnostic next generation sequencing assay (the Oncomine Focus Assay).
Patients were randomised to receive either Tibsovo 500 mg orally once daily or matched placebo until disease progression or development of unacceptable toxicity. Randomisation was stratified by number of prior therapies (1 or 2). Eligible patients who were randomised to placebo were allowed to cross over to receive Tibsovo after documented radiographic disease progression as assessed by the Investigator.
Tumour imaging assessments were performed every 6 weeks for the first 8 assessments and every 8 weeks thereafter. The primary efficacy outcome was progression-free survival (PFS) assessed by an independent review committed (IRC) according to response evaluation criteria in solid tumors (RECIST) v1.1.
The median age was 62 years (range: 33 to 83). Most patients were female (63%), 57% were Caucasian, all patients had an ECOG performance status of 0 (37%) or 1 (62%), and 47% had received two prior lines of systemic therapy. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Across both arms, 70% of patients had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.6% had an R132S mutation, and 1.1% had an R132H mutation. No patients with R132H-mutant IDH1 were randomised to Tibsovo.
The study demonstrated a statistically significant improvement in PFS. The efficacy results for Study AG120-C-005 are summarised in Table 11 and Figure 1.

Efficacy in newly diagnosed AML - Tibsovo in combination with azacitidine.

The efficacy and safety of Tibsovo was evaluated in a randomised, multicentre, double-blind, placebo-controlled clinical trial (Study AG120-C-009) of 146 adult patients with newly diagnosed AML with an IDH1 mutation who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, creatinine clearance < 45 mL/min, or other comorbidity. IDH1 mutations were confirmed centrally using the Abbott RealTime IDH1 Assay. Local diagnostic tests were permitted for screening and randomisation, provided a bone marrow or peripheral blood sample was sent for central confirmation. Gene mutation analysis to document IDH1 mutated disease from a bone marrow or peripheral blood sample was conducted for all patients. Patients were randomised to receive either Tibsovo 500 mg, or matched placebo, orally once daily on Days 1-28, in combination with azacitidine 75 mg/m2/day subcutaneously or intravenously on Days 1-7 or Days 1-5 and 8-9 of each 28-day cycle. Treatment was continued for a minimum of 6 cycles unless they experienced disease progression or unacceptable toxicity or underwent haematopoietic stem cell transplantation.
The primary efficacy outcome was event-free survival (EFS), measured from the date of randomisation until treatment failure, relapse from remission, or death by any cause. Treatment failure was defined as failure to achieve complete remission (CR) by week 24. Overall Survival (OS), CR rate, CR + CR with partial hematologic recovery (CR + CRh) rate and objective response rate (ORR) were key secondary efficacy endpoints.
Amongst patients randomised to receive Tibsovo, the median age was 76 years (range: 58 to 84); 58% were male; 21% Asian and 17% were Caucasian, whilst ethnicity was not reported for 61%. ECOG performance status was 0 (19%), 1 (44%), or 2 (36%), and most patients (75%) had de novo AML. Cytogenetic risk (per National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology, 2017), was intermediate for most patients (67%), with 4% having favourable and 26% having poor/other cytogenetic risk. According to the central testing, 63% of patients had an R132C mutation, 19% had an R132H mutation, 8% had an R132G mutation, 4% had an R132L mutation, and 3% had an R132H mutation.
The key efficacy findings of Study AG120-C-009 are summarised in Table 12 and Figure 2.
The median time to first CR for Tibsovo with azacitidine was four months (range: 1.7 to 9.2 months). The median time to first CR + CRh for Tibsovo with azacitidine was four months (range: 1.7 to 8.6 months). The median time to first objective response (defined as CR, CRi (including CRp), PR or MLFS) was two months (range: 1.7 to 7.5 months) for Tibsovo with azacitidine.

Efficacy in newly diagnosed AML - Tibsovo monotherapy.

The efficacy of Tibsovo was evaluated in an open-label, single-arm, multicentre clinical trial (Study AG120C-001) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance 45 mL/min. Tibsovo was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing haematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following Tibsovo treatment.
Amongst this group of patients, the median age was 77 years (range: 64 to 87). Most patients were male (54%), 87% were Caucasian, ECOG performance status was 0 in 37%, 1 in 62%, two in five patients (18%) and 3 in one patient (4%). Just under half (46%) had received a hypomethylating agent previously for an antecedent haematological disorder. Most patients (61%) were transfusion dependent at baseline, defined as receipt of any transfusion within 56 days prior to the first dose of Tibsovo. Most patients had AML with myelodysplasia-related changes (68%), whilst 21% had de novo AML and 11% had therapy-related AML. European Leukaemia Net risk category was adverse for most patients (68%) and intermediate for the remaining 32%. According to the central retrospective confirmatory testing, 86% of patients had an R132C mutation, 7% had an R132H mutation, there was 1 patient each with an R132G or R132L mutation, and no patients with an R132S mutation.
Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR + CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 13. The median follow-up was 8.1 months (range: 0.6 to 40.9 months) and median treatment duration was 4.3 months (range: 0.3 to 40.9 months).
For patients who achieved a CR or CRh, the median time to CR or CRh was 2.8 months (range: 1.9 to 12.9 months). Of the 12 patients who achieved a best response of CR or CRh, 11 (92%) achieved a first response of CR or CRh within six months of initiating Tibsovo.
Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, seven (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, six (54.5%) remained transfusion independent during any 56-day post-baseline period.

Efficacy in relapsed or refractory AML.

The efficacy of Tibsovo was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120C-001) in 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime IDH1 Assay. Tibsovo was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing haematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following Tibsovo treatment.
Amongst this group of patients, the median age was 67 years (range: 18 to 87). Half of the group were male (51%), 62% were Caucasian, ECOG performance status was 0 in 21%; 1 in 56%; 2 in 22% and 3 in two patients (1%). Most patients had de novo AML (67%) and 33% had secondary AML. Relapse was primary refractory for 37%, untreated relapse for 37% and refractory relapse for 26% of patients. Most patients (63%) were transfusion dependent at baseline (defined as receipt of any transfusion within 56 days prior to the first dose of Tibsovo), and the median number of prior therapies was 2 (range: 1-6): 23% had received prior stem cell transplantation for AML. Cytogenetic risk was intermediate for most patients (60%), with 27% having poor cytogenetic risk and the remainder unknown. According to the central retrospective confirmatory testing, 59% of patients had an R132C mutation, 25% had R132H, 7% had R132G, 6% had R132S, and 4% had an R132L mutation.
Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial haematologic recovery (CRh), the duration of CR + CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 14. The median follow-up was 8.3 months (range: 0.2 to 39.5 months) and median treatment duration was 4.1 months (range: 0.1 to 39.5 months).
For patients who achieved a CR or CRh, the median time to CR or CRh was two months (range: 0.9 to 5.6 months). Of the 57 patients who achieved a best response of CR or CRh, all achieved a first response of CR or CRh within six months of initiating Tibsovo.
Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59%) remained transfusion independent during any 56-day post-baseline period.

5.2 Pharmacokinetic Properties

A summary of ivosidenib pharmacokinetic (PK) parameters following administration of ivosidenib 500 mg as a single or daily dose (for steady state) is provided in Table 15. The AUC and Cmax of ivosidenib increase in a less than dose proportional manner from 200 mg to 1,200 mg once daily (0.4 to 2.4 times the recommended dose). Steady-state PK is reached within 14 days with daily dosing.

Metabolism.

Ivosidenib was the predominant component (> 92%) of total radioactivity in plasma from healthy subjects. It is primarily metabolised by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.

Special populations.

No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 to 89 years), sex, race, body weight (38 to 150 kg), ECOG performance status, mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2), and mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), including patients requiring dialysis, and in patients with severe hepatic impairment (Child-Pugh class C) are unknown.

5.3 Preclinical Safety Data

Genotoxicity.

Ivosidenib was not mutagenic in a bacterial reverse mutation assay or clastogenic in vitro in human lymphocytes or in vivo in a rat micronucleus assay.

Carcinogenicity.

Carcinogenicity studies have not been conducted with ivosidenib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, croscarmellose sodium, hypromellose acetate succinate, colloidal anhydrous silica, magnesium stearate, sodium lauryl sulfate, hypromellose, titanium dioxide, lactose monohydrate, triacetin, indigo carmine aluminium lake.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store in a dry place below 30°C. Keep the bottle tightly closed to protect from moisture.

6.5 Nature and Contents of Container

White, high-density polyethylene (HDPE) bottle with polypropylene (PP) child resistant closure and polyethylene (PE) faced induction heat seal liner. Each bottle contains 60 film-coated tablets and a silica gel desiccant in a HDPE canister. The bottles are packaged in a cardboard box; each box contains 1 bottle.

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

The active component of Tibsovo is ivosidenib which is a white to light yellow solid and has the chemical name: Glycinamide, 1-(4-cyano-2-pyridinyl)-5-oxo-L-prolyl-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-N2-(5-fluoro-3-pyridinyl)-, (2S)- and molecular formula: C28H22ClF3N6O3 (MW = 583.0). Ivosidenib is practically insoluble in aqueous solutions and is variably soluble in various organic solvents.

Chemical structure.

The chemical structure of ivosidenib free form drug substance:

CAS number.

1448347-49-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes