Consumer medicine information

Iclusig

Ponatinib

BRAND INFORMATION

Brand name

Iclusig

Active ingredient

Ponatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Iclusig.

SUMMARY CMI

ICLUSIG®

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 ICLUSIG?

ICLUSIG contains the active ingredient ponatinib hydrochloride. ICLUSIG is used to treat adults with certain types of leukaemia.

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

2. What should I know before I use ICLUSIG?

Do not use if you have ever had an allergic reaction to ICLUSIG 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 ICLUSIG? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ICLUSIG 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 ICLUSIG?

  • You should follow all directions on how to use ICLUSIG given by your doctor or pharmacist

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

5. What should I know while using ICLUSIG?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ICLUSIG. If you are pregnant, intending to get pregnant or to father a child, tell your doctor immediately.
Things you should not do
  • Do not stop using this medicine without talking to your doctor first.
Driving or using machines
  • Be careful driving or operating machinery until you know how ICLUSIG affects you.
Drinking alcohol
  • Tell your doctor if you have a history of alcohol abuse.
Looking after your medicine
  • Store the tablets in the original container to protect from light.
  • Keep the medicine in a cool, dry place where temperature stays below 30°C.

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

6. Are there any side effects?

Severe side effects include chest pain, shortness of breath, weakness in one side, fast or irregular heartbeats, leg or abdominal swelling, sudden weigh gain, jaundice, loss of appetite, elevated blood pressure, severe headache, nausea, vomiting, severe abdominal pain, unusual bleeding or easy bruising, low blood cell counts, fever, chills. Common side effects include upper respiratory tract infection, pneumonia, skin rash, sleeplessness, dry or blurred eye, conjunctivitis, rash, dry skin, pruritus.

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: The following adverse effects have been observed in some ICLUSIG-treated patients in the main clinical trial. Therefore, your medical condition will be monitored during ICLUSIG treatment with interruption or stoppage of the treatment if decided necessary by your doctor:
• Complete or partial blockage of a blood artery: occurred in ICLUSIG-treated patients in the main clinical trial, resulting in heart attack or chest pain, stroke, narrowing of blood vessels, vision loss, severe blood circulation disorder (sometimes resulting in amputation), and the need for urgent surgical procedure to widen the blocked or narrowed arteries.
• Blockage of blood vein due to a blood clot
• Heart failure
• High blood pressure including a marked proportion graded as severe
• Liver toxicities including fatal liver failure.



FULL CMI

ICLUSIG®

Active ingredient(s): ponatinib (pon-a-tin-ib) hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using ICLUSIG. 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 ICLUSIG. The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.takeda.com/en-au. Those updates may contain important information about the medicine and its use of which you should be aware.

Where to find information in this leaflet:

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

1. Why am I using ICLUSIG?

ICLUSIG contains the active ingredient ponatinib hydrochloride. ICLUSIG belongs to a group of medicines called tyrosine kinase inhibitors. In patients with CML and Ph+ ALL, changes in the DNA trigger a signal that tells the body to produce abnormal white blood cells. ICLUSIG blocks this signal, thereby stopping the production of these cells.

ICLUSIG is used to treat adults with the following types of leukaemia who are no longer benefiting from treatment with other medicines:

Chronic myeloid leukaemia (CML): a blood cancer (leukaemia) involving too many abnormal white blood cells (granulocytes), in the blood and the bone marrow (where blood cells are formed)

Philadelphia-chromosome positive acute lymphoblastic leukaemia (Ph+ ALL): another type of leukaemia involving too many immature white blood cells (lymphocytes or lymphoblasts), in the blood and blood-forming bone marrow.

In both types of leukaemia, some of the DNA (genetic material) has become rearranged to form an abnormal chromosome, called the Philadelphia chromosome.

This medicine is only available with a prescription from a doctor experienced with leukaemia treatment.

2. What should I know before I use ICLUSIG?

Warnings

Do not use ICLUSIG if:

  • you are allergic to ponatinib, 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:

  • a history of blood clots in your blood vessels (arteries or veins)
  • heart problems, for example heart failure, irregular heartbeats, a condition called QT prolongation or a prior heart attack
  • a history of stroke
  • high blood pressure
  • diabetes
  • high cholesterol
  • bleeding problems
  • liver or kidney problems
  • a pancreas disorder
  • a history of alcohol abuse
  • hepatitis B
  • take any medicines for any other condition

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant, intending to become pregnant or to father a child.

You and your partner must use effective contraception during your treatment with this medicine.

Women of childbearing age being treated with ICLUSIG should avoid becoming pregnant, as potential risks exist for the unborn child.

Men being treated with ICLUSIG should avoid fathering a child during treatment.

You must not breastfeed during treatment with ICLUSIG. It is not known if ICLUSIG passes into breast milk.

Your doctor can discuss with you the risks involved.

Tell your doctor if you are lactose intolerant. ICLUSIG tablets contain lactose.

If you have not told your doctor or pharmacist about any of the above, tell them before you take ICLUSIG.

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 and ICLUSIG may interfere with each other. These include:

  • ketoconazole, itraconazole, voriconazole: medicines used to treat fungal infections
  • atazanavir, indinavir, nelfinavir, ritonavir, saquinavir: medicines used to treat HIV infection
  • clarithromycin, telithromycin, troleandomycin: medicines used to treat bacterial infections
  • nefazodone, a medicine to treat depression
  • St. John's Wort, a herbal product used to treat depression
  • carbamazepine, a medicine to treat epilepsy, euphoric/depressive stages and certain pain conditions
  • phenobarbital, phenytoin: medicines used to treat epilepsy
  • rifabutin, rifampicin: medicines used to treat tuberculosis or other infections
  • medicines which decrease stomach acid such as omeprazole, pantoprazole, ranitidine, cimetidine, famotidine, aluminum, and magnesium hydroxides
  • digoxin: a medicine used to treat heart weakness
  • dabigatran: a medicine used to prevent the formation of blood clots
  • colchicine: a medicine used to treat gout attacks
  • pravastatin, rosuvastatin, medicines used to lower cholesterol
  • methotrexate, a medicine used to treat arthritis, cancer and some skin diseases
  • sulfasalazine, a medicine used to treat severe bowel and rheumatic joint inflammation.

These medicines may be affected by ICLUSIG or may affect how well it works. You may need to use different amounts of your medicine or take different medicines.

Avoid grapefruit products such as grapefruit juice, or Seville orange-based products such as marmalade.

These products may contain components that alter the metabolism of some medicines, including ICLUSIG.

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

4. How do I use ICLUSIG?

ICLUSIG should only be prescribed by a doctor experienced in leukaemia treatment.

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

They may differ from the information contained in this leaflet.

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

How much to take

The recommended starting dose is one 45 mg tablet once daily.

Your doctor may reduce your dose or tell you to temporarily stop taking ICLUSIG if:

  • the number of white blood cells called neutrophils is reduced
  • the number of blood platelets is reduced
  • a severe side effect occurs, not affecting the blood, for example if you develop:
    - pancreas inflammation
    - increased levels of serum protein lipase or amylase
    - liver inflammation and/or increased levels of liver enzymes, such as liver transaminase or bilirubin
  • you develop heart or blood vessel problems.

ICLUSIG may be resumed at the same, or at a reduced dose, after the event is resolved or controlled.

Your doctor may reduce your dose of ICLUSIG if your condition has responded well to ICLUSIG.

Your doctor may recommend you discontinue ICLUSIG if your condition has not responded to the treatment at all or you cannot tolerate the treatment.

When to take ICLUSIG

Take ICLUSIG at about the same time each day.

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

It does not matter if you take this medicine before or after food.

How to take ICLUSIG

Swallow the tablets whole with a glass of water.

Do not crush or dissolve the tablets.

How long to take it

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

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

Do not stop taking ICLUSIG without talking to your doctor first.

If you forget to use ICLUSIG

ICLUSIG should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your medicine as you would normally.

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

If you use too much ICLUSIG

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

You should immediately:

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

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

5. What should I know while using ICLUSIG?

Things you should do

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

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

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

If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.

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

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects. These may include:

  • checking your heart function and the condition of your arteries and veins
  • checking your blood count
  • measuring your serum protein known as lipase
  • testing your liver function
  • checking your blood pressure
  • checking for hepatitis B infection.

A Patient Alert Card (PAC) is provided in the pack with your ICLUSIG tablets and should be carried with you at all times. The PAC provides important and readily accessible information for your Healthcare Practitioners on important risks, their treatment and contact details of your haematologist. If you require additional copies, please contact the supplier whose details can be found at the end of this leaflet.

Things you should not do

  • Do not stop using this medicine or lower the dosage, without checking with your doctor.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful driving or operating machinery until you know how ICLUSIG affects you.

This medicine may cause dizziness, tiredness, visual impairment, mental status changes, confusion, or blurred vision in some people.

Looking after your medicine

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

Store the tablets in the original container to protect from light.

Keep the medicine in a cool, dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill. Do not leave it in the car.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

If you are over 65 years of age you may have an increased chance of getting side effects.

Less serious side effects

Less serious side effectsWhat to do
  • nausea, vomiting, constipation, diarrhoea
  • abdominal distension, discomfort, indigestion, pain
  • stomach acid reflux
  • rash, dry skin, itching, peeling of the skin, skin pain, infection of the skin
  • inflammation of hair follicles, hair loss
  • fatigue, sleeplessness, weakness
  • muscle spasms and pain, muscle weakness
  • hot flush/flushing, night sweats, increased sweating
  • decreased appetite, weight loss
  • dehydration
  • dry mouth, inflammation in the mouth, bleeding gums
  • pins and needles, tingling or burning sensation in feet, legs, hands or arms
  • inability to develop or maintain an erection.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • sudden severe headache
  • eye or sight changes (blurred vision, loss of vision, dry eye, eye pain)
  • eyelid or face swelling, conjunctivitis
  • changes in speech or difficulty talking
  • dizziness or feeling faint
  • decreased alertness, lethargy or confusion
  • chest pain or pressure
  • pain in your arms, legs, back, neck or jaw
  • changes in heart rate (abnormally slow, fast, or irregular heart rate), bruise or blood clot
  • breathing difficulties (shortness of breath, cough, rapid breathing)
  • weakness on one side of the body
  • numbness or loss of fine motor skills
  • trouble talking
  • unusual bleeding, including blood in your stool/bowel motions or dark or tarry stool, vomiting blood, bruising easily, nose bleeding
  • fever in association with other signs of infection, chills
  • yellow skin and/or eyes
  • severe stomach area pain, swelling due to build-up of fluid around the stomach
  • dark-coloured urine
  • swelling of the leg, ankle or foot.
  • painful rash, blistering, and mouth sores
  • signs of Posterior Reversible Encephalopathy Syndrome (PRES): ICLUSIG may trigger a condition called PRES. Call your healthcare provider right away if you experience headaches, seizures, confusion, changes in vision, problems thinking
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 affects 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 ICLUSIG contains

Active ingredient
(main ingredient)		Ponatinib hydrochloride
Other ingredients
(inactive ingredients)		lactose
microcrystalline cellulose
sodium starch glycollate
silica - colloidal anhydrous
magnesium stearate
talc
Macrogol 4000
poly vinyl alcohol
titanium dioxide
Potential allergensICLUSIG does not contain gluten, sucrose, tartrazine or any other azo dyes.

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

What ICLUSIG looks like

ICLUSIG 10 mg (AUST R 374484): white to off-white, biconvex, oval film-coated tablet, marked with "NZ" on one side. Available in bottles of 30 tablets.

ICLUSIG 15 mg (AUST R 212583): white, round film-coated tablet, marked "A5" on one side. Available in bottles of 36 or 60 tablets.

ICLUSIG 30 mg (AUST R 374492): white, biconvex, round film-coated tablet, marked with "C7" on one side. Available in bottles of 30 tablets.

ICLUSIG 45 mg (AUST R 212584): white, round film-coated tablet, marked "AP4" on one side. Available in bottles of 30 tablets.

Not all strengths may be marketed.

Who distributes ICLUSIG

Takeda Pharmaceuticals
Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Phone: 1800 012 612
www.takeda.com/en-au

This leaflet was prepared in September 2022.

ICLUSIG® and the ICLUSIG Logo® are registered trademarks of Ariad Pharmaceuticals, Inc. TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Iclusig

Active ingredient

Ponatinib

Schedule

S4

 

1 Name of Medicine

Ponatinib (as hydrochloride).

2 Qualitative and Quantitative Composition

Each tablet contains ponatinib hydrochloride equivalent to 10, 15, 30, or 45 mg ponatinib.

Excipients with known effect.

Lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Iclusig tablets are available for oral administration.

10 mg tablet.

White to off-white, biconvex, oval film-coated tablet with "NZ" debossed on one side.

15 mg tablet.

White, biconvex, round film-coated tablet with "A5" debossed on one side.

30 mg tablet.

White, biconvex, round film-coated tablet with "C7" debossed on one side.

45 mg tablet.

White, biconvex, round film-coated tablet with "AP4" debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Iclusig is indicated for the treatment of adult patients with:
Chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukaemia (CML) whose disease is resistant to, or who are intolerant of at least two prior tyrosine kinase inhibitors; or where there is a T315I mutation.
Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) whose disease is resistant to, or who are intolerant of dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or where there is a T315I mutation.
Therapy with Iclusig should be initiated and monitored by a haematologist with expertise in managing adult leukaemias.

4.2 Dose and Method of Administration

The following laboratory tests and observations are recommended to monitor for haematologic and non-haematologic adverse reactions that would require dose modifications while taking Iclusig. See Table 1.
Before starting treatment with Iclusig, the cardiovascular status of the patient should be assessed and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and therapy optimised during treatment with Iclusig.

Dosage.

Iclusig may be taken with or without food.
For dose adjustments to lower strengths, 10 mg or 15 mg film-coated tablets are available.

CP-CML.

The recommended starting dosage of Iclusig is 45 mg once daily taken at the same approximate time each day with a reduction to 15 mg orally once daily upon achievement of molecular response (≤ 1% BCR-ABL1IS). Patients with loss of molecular response can re-escalate the dose of Iclusig to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue Iclusig until loss of response at the re-escalated dose or unacceptable toxicity.
Consider discontinuing Iclusig if haematologic response has not occurred by 3 months.

AP-CML, BP-CML, and Ph+ ALL.

The recommended starting dose of Iclusig is 45 mg once daily, taken at the same approximate time each day. Consider reducing the dose of Iclusig for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity.
Consider discontinuing Iclusig if response has not occurred by 3 months.

Dose adjustments or modifications for adverse reactions.

Dose modifications should be considered for the management of treatment toxicity. For patients whose adverse reactions are resolved, escalation of the dose back to the patient's former dose should be considered, if clinically appropriate.
For a dose of 30 mg, 15 mg or 10 mg once daily, 15 mg and 10 mg film-coated tablets are available.
Recommendations for dose modifications of Iclusig for the management of adverse reactions are summarised in Table 2 and recommended dose reductions of Iclusig for adverse reactions are presented in Table 3.

Patients with hypertension.

Hypertension may contribute to risk of arterial thrombosis and occlusions, including renal artery stenosis. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled. In the event of significant worsening, labile or treatment resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Patients with hepatic impairment.

Caution is recommended when administering Iclusig to patients with moderate to severe hepatic impairment. Doses above 30 mg have not been tested in patients with hepatic impairment. Therefore, a starting dose of 30 mg is recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Patients with renal impairment.

Iclusig has not been studied in patients with severe renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for severe renal impairment to affect the pharmacokinetics of ponatinib has not been determined. No dose adjustment of Iclusig is recommended for patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/min). Caution is recommended when administering Iclusig to patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease.

Concomitant treatment.

Avoid concurrent use of Iclusig and strong CYP3A inhibitors. If co-administration of a strong CYP3A inhibitors cannot be avoided, reduction of the starting dose of Iclusig to 30 mg should be considered with concurrent use of Iclusig and strong CYP3A inhibitors. Avoid concurrent use of Iclusig and strong CYP3A inducers unless the benefit outweighs the possible risk of decreased ponatinib exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Substances that may increase ponatinib serum concentrations).
Concomitant use of Iclusig with anticoagulants and/or anti-platelet agents should be approached with caution in patients who may be at risk of bleeding. Formal clinical studies evaluating the co-administration of Iclusig with these medications have not been conducted.

Missed dose.

If a dose is missed, the patient should not take an additional dose. In this case, the patient should take the usual dose at the next scheduled time.

Method of administration.

The tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Iclusig may be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Arterial occlusive events.

Arterial occlusive events (AOEs), including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease (sometimes resulting in amputation), and the need for urgent revascularisation procedures, have occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Some patients experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients aged 50 years or younger, experienced AOEs. Arterial occlusion and occlusive events were more frequent with increasing age and in patients with prior history of ischaemia, hypertension, diabetes, or hyperlipidaemia. The dose intensity-safety relationship indicated that there are significant increases in adverse events over the dose range of 15 to 45 mg once daily, including vascular occlusion and arterial thrombosis.
Ocular toxicities, including retinal arterial occlusions leading to vision loss have occurred in Iclusig-treated patients. If decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed and Iclusig should be interrupted if vascular occlusion is suspected.
Iclusig should not be used in patients with a history of myocardial infarction, prior revascularisation or stroke, unless the potential benefit of treatment outweighs the potential risk.
Before starting treatment with Iclusig, the cardiovascular status of the patient should be assessed and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and any cardiovascular therapy optimised during treatment with Iclusig.
Monitoring for evidence of arterial occlusion should be performed and Iclusig should be interrupted immediately in case of an AOE (see Section 4.2 Dose and Method of Administration). A benefit-risk consideration should guide a decision to restart Iclusig therapy after the occurrence of an AOE.

Venous thromboembolism events.

Venous thromboembolism events (VTEs) have occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
Events reported include retinal venous occlusion and retinal vein thrombosis with vision loss, deep vein thrombosis, and pulmonary embolus, and superficial thrombophlebitis. The incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with AP-CML or CP-CML.
Monitoring for evidence of thromboembolism and vascular occlusion should be performed and Iclusig should be interrupted immediately in case of a VTE (see Section 4.2 Dose and Method of Administration). A benefit-risk consideration should guide a decision to restart Iclusig therapy after the occurrence of a VTE.

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating ponatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysms.

Heart failure.

Fatal and serious heart failure or left ventricular dysfunction occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider dose modification of Iclusig in patients who develop heart failure (see Section 4.2 Dose and Method of Administration). Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hypertension.

Hypertension (including hypertensive crisis) has occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
During Iclusig treatment, all patients should be monitored for blood pressure elevations at each clinic visit and managed as clinically indicated. Hypertension should be treated to normalise blood pressure. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled. Hypertension may also contribute to renovascular disorders, most commonly observed as renal artery stenosis. Monitoring for significant or unexplained hypertension is recommended as it may contribute to renal vascular disease.
Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Hypertension may contribute to the development of AOEs.

QT prolongation.

The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and no clinically significant QT prolongation was observed (see Section 5.1 Pharmacodynamic Properties). However, due to design limitations of this study a clinically significant effect on QT cannot be excluded. The pivotal clinical study excluded subjects with a prolonged QT interval at baseline, and those receiving medicines known to be associated with torsades de pointes. QT prolongation has been observed with some other BCR-ABL1 inhibitors. Measurement of baseline QT is recommended prior to commencing Iclusig.

Haemorrhage.

Haemorrhage and bleeding events have occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Some fatal haemorrhage events have been reported. The incidence of severe bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal haemorrhage and subdural hematoma were the most commonly reported grade 3 or 4 bleeding events. Most haemorrhagic events, but not all, occurred in patients with grade 3 or grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe haemorrhage and evaluate; discontinuation may be required (see Section 4.2 Dose and Method of Administration, Table 2, Myelosuppression).
Concomitant use of Iclusig with anticoagulants and/or antiplatelet agents should be approached with caution in patients who may be at risk of bleeding. Formal clinical studies evaluating the coadministration of Iclusig with these medications have not been conducted.

Myelosuppression.

Iclusig is associated with ≥ grade 3 thrombocytopenia, neutropenia, and anaemia. Most commonly reported events included neutropenia, thrombocytopenia, and anaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). Of the patients who developed grade 3 or 4 myelosuppression, most developed it within the first 3 months of treatment. The frequency of these events is greater in patients with AP-CML or BP-CML/Ph+ ALL than in patients with CP-CML. A complete blood count should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Iclusig temporarily or reducing the dose (see Section 4.2 Dose and Method of Administration, Table 2, Myelosuppression).

Fluid retention.

In PACE, fluid retention adverse events occurred in 31.6% of 449 Iclusig-treated patients with 4.2% experienced serious fluid retention. These events included peripheral oedema, pericardial effusion, pleural effusion, and ascites. One instance of brain oedema was fatal.
In OPTIC, fluid retention adverse events occurred in 5.3% of 94 Iclusig-treated CP-CML patients who received 45 mg. The most frequent fluid retention events were peripheral oedema and pleural effusion.
Patients should be monitored for fluid retention. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Neuropathy.

In PACE, 20% of 449 patients experienced a peripheral neuropathy event of any grade (1.8%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4.5%), paraesthesia (5.3%), hypoesthesia (3.6%), and hyperesthesia (1%). Cranial neuropathy developed in 3% of patients (0.7% grade 3/4). Cases of ataxia and convulsion were also reported.
In OPTIC, peripheral neuropathy occurred in 6% of patients. The most frequently reported peripheral neuropathies were hypoesthesia (2.1%), muscular weakness (2.1%), and paraesthesia (2.1%). Cranial neuropathy developed in 2 patients.
Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Hepatotoxicity.

Iclusig may result in severe drug induced liver injury. Iclusig may result in elevation in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase (see Section 4.8 Adverse Effects (Undesirable Effects)). Most patients who reported an event of hepatoxicity had their first event in the first year of treatment. Isolated cases of fatal hepatic failure have occurred in Iclusig treated patients. Monitor liver function tests (LFTs) and transaminase level measurements at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated (see Section 4.2 Dose and Method of Administration, Table 2, Hepatic toxicity).

Pancreatitis and serum lipase.

Pancreatitis and acute pancreatitis have occurred in Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Elevation of serum lipase and amylase have also been reported.
Pancreatitis developed in the majority of the patients within the first 2 months of ponatinib use. Check serum amylase/lipase every 2 weeks for the first 2 months and then regularly thereafter. Dose modification may be required (see Section 4.2 Dose and Method of Administration).
If lipase elevations are accompanied by abdominal symptoms, Iclusig should be immediately withheld and patients evaluated for evidence of pancreatitis. Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients with severe or very severe hypertriglyceridemia should be appropriately managed to reduce the risk of pancreatitis.

Tumour lysis syndrome.

In PACE, tumour lysis syndrome (TLS) occurred in 3 patients (0.7%) with advanced CML treated with Iclusig-treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Hyperuricemia also occurred in Iclusig-treated patients (7%), most of whom were CP-CML patients. Ensure adequate hydration and high uric acid levels should be corrected prior to initiating therapy with Iclusig.
Of the 94 CP-CML patients who received a starting dose of 45 mg in OPTIC, serious TLS developed in 1.1% of patients. Hyperuricemia occurred in 2.1% of patients.

Reversible posterior leukoencephalopathy syndrome (RPLS).

Post-marketing cases of reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible encephalopathy syndrome (PRES), have been reported in Iclusig-treated patients. RPLS is a neurological disorder with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.
If diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if the benefit of treatment outweighs the risk of RPLS.

Hepatitis B virus reactivation.

Reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL1 tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Patients should be tested for HBV infection before initiating treatment with Iclusig. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Iclusig should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Lactose.

Iclusig contains lactose. Inform patients who have or may have intolerance to lactose.

Use in hepatic impairment.

Hepatic elimination is a major route of excretion for Iclusig. Single doses of ponatinib 30 mg were administered to patients with mild, moderate and severe hepatic impairment (Child-Pugh Classes A, B, and C) and to control healthy subjects. Overall, no major differences in ponatinib PK were observed in patients with varying degrees of hepatic impairment as compared to healthy subjects. Iclusig has not been studied in patients with hepatic impairment (Child-Pugh Classes A, B and C) at doses above 30 mg. Therefore, it is recommended that patients with hepatic impairment begin on a starting dose of 30 mg. Caution is recommended when administering Iclusig to patients with moderate to severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Patients with hepatic impairment).

Use in renal impairment.

Iclusig has not been studied in patients with severe renal impairment. Caution is recommended when administering Iclusig to patients with severe renal impairment or endstage renal disease (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Patients aged ≥ 65 years or older are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral oedema, increased lipase, dyspnoea, asthenia, muscle spasm, and decreased appetite. In general dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant medical conditions or medications.
Of the 449 patients in the PACE study who received Iclusig, 155 (35%) were ≥ 65 years of age at entry. In patients with CP-CML, patients of age ≥ 65 years were less likely to achieve a major cytogenetic response than those younger than 65 years. Compared to patients < 65 years, patients older than 65 years may be more likely to experience adverse reactions. Thirty six (51/155) percent of patients ≥ 65 years had arterial occlusive events.
Of the 94 patients with CP-CML who received Iclusig at a starting dose of 45 mg in OPTIC, 16 (17%) were ≥ 65 years. Patients aged ≥ 65 had a lower ≤ 1% BCR-ABL1IS rate at 12 months (27%) as compared with patients less than 65 years of age (47%). Nineteen (3/16) percent of patients ≥ 65 had arterial occlusive events.

Paediatric use.

The safety and efficacy of Iclusig in patients less than 18 years of age have not been studied.

Effects on laboratory tests.

No data available.

Patient counselling information.

Advise patients of the following and provide a copy of the Consumer Medicine Information.

Arterial occlusion and venous thromboembolism.

Inform patients that serious arterial occlusive events (including fatal myocardial infarction, stroke, severe peripheral vascular disease, and arterial stenosis sometimes requiring revascularisation) and venous thromboembolic events have occurred. Advise patients to immediately contact their health care provider with any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, leg swelling, or decreased or blurred vision.

Heart failure and cardiac arrhythmias.

Inform patients of the possibility of heart failure, and abnormally slow or fast heart rates. Advise patients to contact their health care provider if they experience symptoms such as shortness of breath, chest pain, palpitations, fluid retention, dizziness, or fainting.

Fluid retention.

Inform patients of the possibility of developing fluid retention and to contact their health care provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath.

Neuropathy.

Inform patients of the possibility of developing peripheral or cranial neuropathy while being treated with Iclusig. Advise patients to report symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain, or weakness.

Hepatotoxicity.

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising.

Hypertension.

Inform patients of the possibility of new or worsening of existing hypertension. Advise patients to contact their health care provider for elevated blood pressure or if symptoms of hypertension occur including headache, dizziness, chest pain, or shortness of breath.

Pancreatitis.

Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, abdominal pain, or abdominal discomfort, and to promptly report these symptoms.

Haemorrhage.

Inform patients of the possibility of serious bleeding and to immediately contact their health care provider with any signs or symptoms suggestive of haemorrhage such as unusual bleeding or easy bruising.

Myelosuppression.

Inform patients of the possibility of developing low blood cell counts; inform patients to report immediately should fever develop, particularly in association with any suggestion of infection.

Embryo-fetal toxicity.

Inform patients that Iclusig can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to a fetus and to avoid becoming pregnant.

Aneurysms and artery dissections.

Inform patients that Iclusig is patients with or without hypertension may promote the formation of aneurysms and/or artery dissections.

Instructions for taking Iclusig.

Advise patients to take Iclusig exactly as prescribed and not to change their dose or to stop taking Iclusig unless they are told to do so by their health care provider. Iclusig may be taken with or without food. Iclusig tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Patients should not take two doses at the same time to make up for a missed dose.

Lactose.

Inform patients that Iclusig contains 121 mg of lactose monohydrate in a 45 mg daily dose.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ponatinib is metabolised by esterases and/or amidases, CYP3A4 and to a lesser extent by CYP2C8 and CYP2D6. Avoid concurrent use of Iclusig and strong CYP3A inhibitors and strong CYP3A inducers.
In vitro studies indicate that clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A or CYP2D6. An in vitro study in human hepatocytes indicated that clinical medicinal product interactions are also unlikely to occur as a result of ponatinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, or CYP3A.
At therapeutic serum concentrations, ponatinib did not inhibit OATP1B1 or OATP1B3, OCT1 or OCT2, organic anion transporters OAT1 or OAT3, or bile salt export pump (BSEP) in vitro. Therefore, clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of substrates for these transporters.
Based on in vitro data, inhibition of P-glycoprotein and breast cancer resistance protein (BCRP) are possible (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Substances that may have their serum concentrations altered by ponatinib).

Substances that may increase ponatinib serum concentrations.

CYP3A inhibitors.

Coadministration of a single 15 mg oral dose of Iclusig in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with ponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen when ponatinib was administered alone. Coadministration of ponatinib with strong CYP3A inhibitors (e.g. boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole and grapefruit juice) increases ponatinib plasma concentrations, which may increase the risk of ponatinib adverse reactions. Avoid co-administration of Iclusig with strong CYP3A inhibitors. If co-administration of a strong CYP3A inhibitor cannot be avoided, reduce the Iclusig dosage as recommended in Table 4. After the strong CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Iclusig dosage that was tolerated prior to initiating the strong CYP3A inhibitor (see Section 5.2 Pharmacokinetic Properties).

Substances that may decrease ponatinib serum concentrations.

CYP3A inducers.

Co-administration of a single 45 mg dose of ponatinib (on day 7) in the presence of rifampicin (600 mg daily for 9 days), a strong CYP3A inducer, resulted in decreases in ponatinib systemic exposure, with ponatinib AUC0-inf and Cmax values that were 62% and 42% lower, than those seen when ponatinib was administered alone. Coadministration of ponatinib with strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's wort should be avoided unless the benefit outweighs the possible risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medications with no or minimal CYP3A induction potential is recommended (see Section 5.2 Pharmacokinetic Properties).

Elevated gastric pH.

The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. In 18 healthy subjects, the effect of gastric pH on ponatinib exposure was investigated by administration of a single 45 mg dose of ponatinib following multiple doses of a potent inhibitor of gastric acid secretion (lansoprazole 60 mg daily for 2 days). On average, following lansoprazole pretreatment, ponatinib Cmax decreased by 25%, overall systemic exposure (AUC0-inf) decreased by 6%, and median Tmax was increased by 1 hour, respective to when ponatinib was administered alone.
Iclusig may be administered concurrently with drugs that raise gastric pH without the need for adjustment of Iclusig dose or separation of administration.

Substances that may have their serum concentrations altered by ponatinib.

Transporter substrates.

In vitro, ponatinib is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Therefore, ponatinib may have the potential to increase plasma concentrations of coadministered substrates of P-gp (e.g. digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g. methotrexate, rosuvastatin, sulfasalazine) and may increase their adverse reactions. Close monitoring is recommended when ponatinib is administered with these medicinal products.

Drug-food interactions.

Administration of Iclusig with a high or low fat meal, or without food, does not change the pharmacokinetics of ponatinib (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Iclusig on male and female fertility in humans is unknown. Animal data indicate potential impairment of fertility in both sexes. Ponatinib decreased fertility in female rats at an oral dose of 1.5 mg/kg/day, associated with exposure levels (plasma AUC) less than half that of patients. No effect on fertility was observed in male rats, but the highest tested dose produced exposure only two-thirds of the clinical AUC. Microscopic changes in the testes (minimal germ cell degeneration), ovaries (increased follicular atresia) and uterus (endometrial atrophy) as well as reduced ovarian weight were evident in monkeys that received daily oral doses of ponatinib (5 mg/kg) for 28 days, with exposure at the no effect level approximately equivalent to the clinical AUC. In the 6-month monkey study, there were variable increases and decreases in ovarian weights without a consistent direction of change, dose dependency, or microscopic correlates.
(Category D)
There are no adequate data from the use of Iclusig in pregnant women. Based on studies in animals, ponatinib may cause fetal harm. A rat embryofetal development study showed that ponatinib causes embryofetal toxicity. Embryofetal lethality (increased post-implantation loss), embryofetal toxicity (reduced fetal weights and whole body edema) and teratogenicity (multiple soft tissue and skeletal abnormalities) were seen in rats that received oral doses of ponatinib (≥ 1 mg/kg/day; approximately 25% of the AUC in patients) during the period of organogenesis.
Women of childbearing age being treated with Iclusig should be advised not to become pregnant and men being treated with Iclusig should be advised not to father a child during treatment. An effective method of contraception should be used during treatment. Iclusig should be used during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus. It is unknown whether Iclusig affects the effectiveness of systemic hormonal contraceptives. An alternative or additional method of contraception should be used.
 It is unknown whether ponatinib is excreted in human milk. Breastfeeding should be stopped during treatment with Iclusig.

4.7 Effects on Ability to Drive and Use Machines

Adverse reactions such as lethargy, dizziness, blurred vision, visual impairment, mental status changes, and confusion have been associated with Iclusig. Therefore, patients should be advised not to drive or operate machines if they experience any of these symptoms while taking Iclusig.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial adverse drug reactions.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Previously treated CML or Ph+ ALL (PACE study).

PACE is a single-arm, open-label, international, multi-centre study that included adult patients (N=449) with CML or Ph+ ALL in two eligible categories: those who were resistant or intolerant to prior dasatinib or nilotinib therapy, and those with T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily and were entered into I of 6 cohorts based on disease phase diagnosis (CP-CML, AP-CML, or blast phase CML [BP-CML]/Ph+ ALL). They were also divided into those who were resistant or intolerant to dasatinib or nilotinib (i.e. they did not have a detectable T315I mutation) or those who had the T315I mutation. The primary endpoint of this trial was major cytogenetic response (MCyR) by 12 months for CP-CML and major haematologic response (MaHR) for advanced phase patients by 6 months.

Tabulated list of adverse reactions.

Adverse reactions reported in Table 5 are listed by system organ class, preferred term and frequency. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Previously treated CP-CML (OPTIC study).

The safety of Iclusig was evaluated in OPTIC is patients with CP-CML whose disease was considered to be resistant to at least two prior kinase inhibitors or who have the T315I mutation. Patients received one of three starting doses of Iclusig: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94) or 15 mg orally once daily (n=94). Patients who received a starting dose of ponatinib 45 mg or 30 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤ 1% BCR ABL1IS (see Section 5.1 Pharmacodynamic Properties).
Adverse reactions reported in CP-CML patients from OPTIC were generally similar to those reported for CP-CML patients from PACE.

Description of selected adverse reactions.

The description of selected adverse reactions observed in the phase 2 studies PACE and OPTIC (45 mg cohort) is presented below:

Arterial occlusive events.

In PACE, AOEs, including fatal cases, occurred in 25% of Iclusig-treated patients (n=449). Cardiovascular, cerebrovascular, and peripheral vascular AOEs occurred in 13%, 9% and 11% of patients, respectively.
In OPTIC (45 mg cohort), AOEs occurred in 10% of Iclusig-treated patients. Cardiovascular, cerebrovascular, and peripheral vascular AOEs occurred in 4.3%, 2.1%, and 3.2% of patients, respectively.
(See Section 4.4 Special Warnings and Precautions for Use, Arterial occlusive events, Venous thromboembolism events; Section 4.2 Dose and Method of Administration.)

Venous thromboembolic events.

Venous thromboembolic events occurred in 6% of Iclusig-treated patients in PACE.
Of the 94 patients in OPTIC (45 mg cohort), 1 patient experienced a VTE (Grade 1 retinal vein occlusion).
(See Section 4.4 Special Warnings and Precautions for Use, Arterial occlusive events, Venous thromboembolism events; Section 4.2 Dose and Method of Administration.)

Heart failure.

Heart failure or left ventricular dysfunction, including fatal cases, occurred in 9% of Iclusig-treated patients in PACE.
Heart failure or left ventricular dysfunction occurred in 3.2% of Iclusig-treated in OPTIC (45 mg cohort).
(See Section 4.4 Special Warnings and Precautions for Use, Heart failure; Section 4.2 Dose and Method of Administration.)

Hepatotoxicity.

Events of hepatoxicity occurred in 30% (n=449) of Iclusig-treated patients in PACE.
Events of hepatoxicity occurred in 28% (n=94) of Iclusig-treated patients in OPTIC (45 mg cohort).
(See Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity; Section 4.2 Dose and Method of Administration.)

Hypertension.

Hypertension occurred in 32% (n=449) of Iclusig-treated patients from PACE study.
Hypertension occurred in 32% (n=94) of Iclusig-treated patients from OPTIC study (45 mg cohort).
(See Section 4.4 Special Warnings and Precautions for Use, Hypertension; Section 4.2 Dose and Method of Administration.)

Pancreatitis and serum lipase.

Pancreatitis and acute pancreatitis have occurred in 7% (n=449) of Iclusig-treated patients from PACE. Elevation of serum lipase and amylase have also been reported in 22% and 7% of patients, respectively.
Pancreatitis and acute pancreatitis have occurred in 2.1% (n=94) of Iclusig-treated patients from OPTIC (45 mg cohort). Elevations of serum lipase and amylase have also been reported in 20% and 5% of patients, respectively.
(See Section 4.4 Special Warnings and Precautions for Use, Pancreatitis and serum lipase; Section 4.2 Dose and Method of Administration.)

Haemorrhage.

Haemorrhage and bleeding events, including fatal cases, have occurred in 28% (n=449) of Iclusig-treated patients from PACE.
Haemorrhage has occurred in 12% (n=94) of Iclusig-treated patients from OPTIC (45 mg cohort).
(See Section 4.4 Special Warnings and Precautions for Use, Haemorrhage; Section 4.2 Dose and Method of Administration.)

Myelosuppression.

Myelosuppression events were reported in 60% (n=449) of Iclusig-treated patients from PACE. Most commonly reported events included neutropenia, thrombocytopenia, and anaemia occurring in 25%, 44%, and 25% of Iclusig-treated patients, respectively.
Myelosuppression events were reported in 63% (n=94) of Iclusig-treated patients from OPTIC (45 mg cohort). Most commonly reported events included neutropenia, thrombocytopenia, and anaemia occurring in 30%, 44%, and 21% of Iclusig-treated patients, respectively.
(See Section 4.4 Special Warnings and Precautions for Use, Myelosuppression; Section 4.2 Dose and Method of Administration.)

Hepatitis B virus reactivation.

Hepatitis B virus reactivation has been reported in association with BCR-ABL1 TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see Section 4.4 Special Warnings and Precautions for Use, Hepatitis B virus reactivation).

Post-marketing experience.

The following adverse drug reactions, which are not mentioned above, have been observed in the post-marketing setting:

Nervous system disorders.

Posterior reversible encephalopathy syndrome (PRES).

Skin and subcutaneous tissue disorders.

Severe cutaneous reaction (e.g. erythema multiforme, Stevens-Johnson syndrome).

Vascular disorders.

Arterial dissections and aneurysms.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and noncardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.
In the event of an overdose of Iclusig, the patient should be observed and appropriate supportive treatment given.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE24.

Mechanism of action.

Ponatinib is a BCR-ABL1 tyrosine kinase inhibitor. In vitro, ponatinib inhibited the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 values of 0.4 and 2.0 nanoM, respectively. Ponatinib inhibits the in vitro activity of other kinases, including RET, FLT3, and KIT and members of the FGFR, PDGFR, VEGFR, EPH and SRC families of kinases with IC50 values below 20 nanoM. In cellular assays, ponatinib reduced the viability of cells expressing various BCR-ABL1 mutants, including those resistant to imatinib, dasatinib, and/or nilotinib. Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing native or T315I mutant BCR-ABL1. In preclinical studies, 40 nanoM was determined as the concentration of ponatinib sufficient to inhibit viability of cells expressing all tested BCR-ABL1 mutants by > 50% (including T315I). In the phase 1 study, plasma steady-state trough concentrations of ponatinib typically exceeded 21 nanogram/mL (40 nanoM) at doses of 30 mg or greater. At doses of 15 mg or greater, 32 of 34 patients (94%) demonstrated a ≥ 50% reduction of CRKL phosphorylation, a biomarker of BCR-ABL1 inhibition, in peripheral blood mononuclear cells. The clinical utility of CRKL phosphorylation as a biomarker has not been established.

Cardiac electrophysiology.

The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients who received 30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and at steady state to evaluate the effect of ponatinib on QT intervals. No clinically significant changes in the mean QTc interval (i.e. > 20 ms) from baseline were detected in the study. In addition, the pharmacokinetic-pharmacodynamic models show no exposure-effect relationship, with an estimated QTcF mean change of -6.4 ms (upper confidence interval -0.9 ms) at Cmax for the 60 mg group (111.34 nanogram/mL). However, due to limitations in the design of this study, the possibility of QT prolongation due to ponatinib has not been excluded (see Section 4.4 Special Warnings and Precautions for Use, QT prolongation).

Clinical trials.

Previously treated CML or Ph+ ALL (PACE study).

The safety and efficacy of Iclusig in chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) patients who were resistant or intolerant to nilotinib or dasatinib, or who had the T315I mutation were evaluated in a single-arm, phase 2, open-label, international, multicentre trial. All patients were administered 45 mg of Iclusig once daily with the possibility of dose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patients were assigned to one of six cohorts based on disease phase (chronic phase (CP)-CML; accelerated phase (AP)-CML; or blast phase (BP)-CML/Ph+ ALL), resistance or intolerance (R/I) to dasatinib or nilotinib, and the presence of the T315I mutation. Although not an entry requirement, 96% of patients in the phase 2 trial had experienced failure of prior imatinib therapy.
Resistance in CP-CML was defined as failure to achieve either a complete haematological response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered resistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either a major haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of major haematological response (at any time), or development of kinase domain mutation in the absence of a major haematological response while on dasatinib or nilotinib.
Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal management in the absence of a complete cytogenetic response for CP-CML patients or major haematological response for AP-CML, BP-CML, or Ph+ ALL patients.
The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR) by 12 monthsa, which included complete and partial cytogenetic responses (CCyR and PCyR). The secondary efficacy endpoints in CP-CML were complete haematological response (CHR) and major molecular response (MMR).
The primary efficacy endpoint in AP-CML and BP-CML/Ph+ ALL was major haematological response (MaHR) by 6 months, defined as either a complete haematological response (CHR) or no evidence of leukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyR and MMR.
For all patients, additional secondary efficacy endpoints included: confirmed MCyR, time to response, duration of response, progression free survival (PFS), and overall survival (OS).
The trial enrolled 449 patients of which 444 were eligible for analysis: 267 CP-CML patients (R/I cohort: n = 203, T315I cohort: n = 64), 83 AP-CML patients (R/I cohort: n = 65, T315I cohort: n = 18), 62 BP-CML (R/I cohort: n = 38, T315I cohort: n = 24), and 32 Ph+ ALL patients (R/I cohort: n = 10, T315I cohort: n = 22). A response of MCyR or better (MCyR, MMR, or CMR), or MMR or better (MMR or CMR) to the most recent course of dasatinib or nilotinib treatment was only achieved in 26% and 3% of the patients in the CP-CML cohorts, respectively. A prior MaHR or better (MaHR, MCyR, MMR, or CMR) was only achieved in 21% and 24% of patients in the AP-CML and BP-CML/Ph+ ALL cohorts, respectively. The median duration of follow-up on all patients was 37.3 months (range: 0.07 months to 73.1 months). Baseline demographic characteristics are described in Table 6.
a In PACE, a month is defined as 30.43 days for all calculations.
Overall, 55% of patients had one or more BCR-ABL1 kinase domain mutation at entry with the most frequent being: T315I (29%), F317L (8%), E255K (4%) and F359V (4%). In 67% of CP-CML patients in the R/I cohort, no mutations were detected at study entry.
The median duration of Iclusig treatment was 32.2 months in CP-CML patients, 19.4 months in AP-CML patients, 2.9 months in BP-CML patients, and 2.7 months in Ph+ ALL patients. Efficacy results are summarised in Table 7 and Table 8.
CP-CML patients who received fewer prior TKIs attained higher cytogenetic, haematological, and molecular responses. Of the CP-CML patients previously treated with one, two, or three, or four prior TKIs, 79% (15/19), 68% (66/97), 44% (63/142) and 58% (7/12) achieved a MCyR while on Iclusig, respectively. CP-CML patients who achieved MCyR or MMR within the first year had statistically significantly improved progression free and overall survival compared to those patients who did not meet those treatment milestones.
Of the CP-CML patients with no mutation detected at entry, 49% (66/136) achieved a MCyR.
There were 27 different types of BCR-ABL1 mutation detected in the CP-CML cohort at baseline. Of these, the following 15 mutations were seen in more than one patient: T315I, F317L, E255K, F359V, G250E, Y253H, V299L, E255V, M244V, F359C, H396R, F359I, E355A, E459K and L248V. At least one patient with each of these 15 mutations achieved a MCyR following treatment with Iclusig.
In CP-CML patients who achieved MCyR, the median time to MCyR was 2.8 months (range: 1.6 to 11.3 months) and in patients who achieved MMR, the median time to MMR was 5.5 months (range: 1.8 to 55.5 months). The median durations of MCyR and MMR had not yet been reached at data cut-off. Of the CP-CML patients who achieved MCyR and MMR, 82.4% (95% CI: 74.1-88.2) and 61.0 (95% CI: [50.6% - 69.8%]), respectively, were estimated to maintain their response after 5 years.
The median time to MaHR in patients with AP-CML and BP-CML/Ph+ ALL among responders was 0.7 months (range: 0.4 to 5.8 months), 1.0 month (range: 0.4 to 3.7 months), and 0.7 months (range: 0.4 to 5.5 months), respectively.
The median duration of MaHR for patients with AP-CML (median duration of treatment: 19.4 months), BP-CML (median duration of treatment: 2.9 months), and Ph+ ALL (median duration of treatment: 2.7 months) patients was estimated as 12.9 months (range: 1.2 to 68.4 months), 6.0 months (range: 1.8 to 59.6 months), and 3.2 months (range: 1.8 to 12.8 months, respectively).

Previously treated CP-CML (OPTIC study).

The efficacy of Iclusig was evaluated in OPTIC, a dose-optimisation trial. Eligible patients had CP-CML whose disease was considered to be resistant to at least 2 prior kinase inhibitors or who have the T315I mutation. Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete haematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or development of a new BCR-ABL1 kinase domain mutation or new clonal evolution. Patients were required to have > 1% BCR-ABL1IS (by real-time polymerase chain reaction) at trial entry. Patients received one of three starting dosages: 45 mg orally once daily, 30 mg orally once daily, or 15 mg orally once daily. Patients who received a starting dose of 45 mg or 30 mg had a dose reduction to 15 mg once daily upon achieving ≤ 1% BCR-ABL1IS. The primary efficacy endpoint was a molecular response based on the achievement of ≤ 1% BCR-ABL1IS at 12 monthsa. All patients reached the 12 month time point (primary endpoint) by the data cut-off. The median duration of follow-up for the 45 mg cohort (N=94) was 31.1 months (95% CI: 24.1, 36.0). Only the efficacy results for the recommended starting dose of 45 mg are described below.
a In OPTIC, a month is defined as 28 days (cycle of treatment for ponatinib) for all calculations.
A total of 282 patients received Iclusig: 94 received a starting dose of 45 mg, 94 received a starting dose of 30 mg, and 94 received a starting dose of 15 mg. Baseline demographic characteristics are described in Table 9 for patients who received a starting dose of 45 mg.
Efficacy results are summarised in Table 10. The primary endpoint was met in patients who received a starting dose of 45 mg. Overall, 44% of patients had one or more BCR-ABL1 kinase domain mutations at study entry with the most frequent being T315I (27%). The subgroup analysis based on baseline T315I mutation status showed similar ≤ 1% BCR-ABL1IS rates at 12 months in patients with and without T3151 (see Table 10). No mutations were detected at study entry for 54% of the patients who received the starting dose of 45 mg.
The secondary efficacy endpoints included complete cytogenic response (CCyR) at 12 months, major molecular response (MMR) at 12 and 24 months, complete hematologic response at 3 months, time to response, duration of response, maintenance of response, progression free survival (PFS), and overall survival (OS). In addition, additional assessment included the rates of molecular response at each patient visit at 3-month intervals for 36 months based on the achievement of ≤ 1% BCR-ABL1IS.
At 12 months, 34% (31/91) and 17% (16/93) of patients achieved CCyR, and MMR, respectively. At 24 months, 24% (18/75) of patients achieved MMR. The median duration of MMR had not yet been reached.
Eighty seven percent (95% CI: 79% - 93%) patients achieved or maintained a complete hematologic response at 3 months.
A response of ≤ 1% BCR-ABL1IS was achieved as early as 2.9 months. The median time to response was 6 (95% CI: 3.1, 6) months.
The median duration of ponatinib treatment was 21 months.
Of the 45 patients who had a dose reduction after achieving ≤ 1% BCR-ABL1IS, 28 patients (62%) maintained their response at the reduced dose for at least 90 days. Of the 28 patients, 18 patients (64%) maintained the response for at least one year. Median duration of response (MR2) was not reached at data cut-off.
Long-term outcomes (PFS and OS) were favourable. The PFS rates were 92% at 12 months and 80% at 24 months. The OS rates were 98% at 12 months and 92% at 24 months.
The rates of efficacy response ≤ 1% BCR-ABL1IS analysed by patient visits at prespecified timepoints were 22% (3 months), 41% (6 months), 47% (9 months), 52% (12 months), 56% (18 months), 56% (24 months), 56% (30 months) and 56% (36 months).
The molecular response rates (measured by achievement of ≤ 1% BCR-ABL1IS) at 12 months was lower among patients who had received treatment with ≤ 2 prior TKIs compared with patients who had received ≥ 3 prior TKIs (40% vs 48%), respectively.

5.2 Pharmacokinetic Properties

Absorption.

Peak concentrations of ponatinib are observed approximately 4 hours after oral administration. Within the range of clinically relevant doses evaluated in patients (10 mg to 60 mg), ponatinib exhibited dose proportional increases in both Cmax and AUC. The geometric mean (CV%) Cmax and AUC(0-τ) exposures achieved for ponatinib 45 mg daily at steady state were 77 nanogram/mL (50%) and 1296 h.nanogram/mL (48%), respectively. The absolute bioavailability of ponatinib has not been determined. Following either a high fat and low fat meal, plasma ponatinib exposures (Cmax and AUC) were not different versus fasting conditions. Iclusig may be administered with or without food.

Distribution.

Ponatinib is highly bound (> 99%) to plasma proteins in vitro. The blood/plasma partition ratio of ponatinib is 0.96. In vitro studies suggested that ponatinib is either not a substrate or is a weak substrate for both P-gp and breast cancer resistance protein BCRP. Ponatinib is not a substrate for the human organic anion transporting polypeptides OATP1B1 and OATP1B3 or the organic cation transporter OCT-1.

Metabolism.

Ponatinib undergoes extensive metabolism with 74% of the circulating drug related material consisting of metabolites. Ponatinib is metabolised to an inactive carboxylic acid by esterases and/or amidases, and to oxidative metabolites by CYP3A4 and to a lesser extent by CYP2C8 and CYP2D6.

Excretion.

Following single and multiple 45 mg doses of Iclusig, the terminal elimination half-life of ponatinib was 22 hours, and steady-state conditions are typically achieved within 1 week of continuous dosing. With once daily dosing, plasma exposures of ponatinib are increased by approximately 1.5-fold between first dose and steady-state conditions. Ponatinib is mainly eliminated via faeces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the faeces and approximately 5% in the urine. Unchanged ponatinib accounted for 24% and < 1% of the administered dose in faeces and urine, respectively, with the remainder of the dose excreted as metabolites.

Renal impairment.

Iclusig has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min). Mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min) did not have a clinically meaningful effect on the pharmacokinetics of ponatinib based on a population pharmacokinetic analysis (see Section 4.2 Dose and Method of Administration, Patients with renal impairment).

Hepatic impairment.

A single dose of ponatinib 30 mg was administered to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, there was no trend of increased ponatinib exposure in subjects with hepatic impairment. Iclusig has not been studied in patients with hepatic impairment (Child-Pugh Classes A, B and C) at doses above 30 mg. There was an increased incidence of adverse reactions in subjects with hepatic impairment compared subjects with normal hepatic function (see Section 4.2 Dose and Method of Administration, Table 2, Hepatic toxicity). Therefore, it is recommended that patients with hepatic impairment begin on a starting dose of 30 mg.

Intrinsic factors affecting ponatinib pharmacokinetics.

No specific studies have been performed to evaluate the effects of age, sex, race, or body weight on ponatinib pharmacokinetics. Based on an integrated population pharmacokinetic analysis, age, sex, race, and body weight do not have clinically meaningful effect on the pharmacokinetics of ponatinib.

5.3 Preclinical Safety Data

Genotoxicity.

Ponatinib was not mutagenic in a bacterial mutagenicity assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, nor was it clastogenic in an in vivo mouse micronucleus test.

Carcinogenicity.

The carcinogenic potential of ponatinib was investigated in a study in male and female rats involving oral administration for 92-100 weeks. No carcinogenic activity was evident in males up to the highest dose tested (0.2 mg/kg/day), but systemic exposure at this dose was low (4% of the plasma AUC in patients at 45 mg/day). Female rats showed increases (compared to both concurrent and historical controls) in the incidence of ovarian mixed sex cord stromal benign tumours at doses ≥ 0.4 mg/kg/day and of squamous cell carcinoma of the clitoral gland at 0.8 mg/kg/day. Carcinogenic doses in female rats are associated with low multiples of the clinical plasma AUC (10% and 28% at 0.4 mg/kg/day and 0.8 mg/kg/day, respectively). The clinical relevance of these findings is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet also contains: lactose monohydrate, microcrystalline cellulose, sodium starch glycollate, colloidal silicon dioxide, magnesium stearate and a tablet coating. The tablet film coating consists of talc, macrogol 4000, polyvinyl alcohol, and titanium dioxide.

6.2 Incompatibilities

Not applicable. Please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

15 mg, 30 mg, and 45 mg tablets.

Store below 30°C.

10 mg tablets.

Store below 25°C.
Store in the original container in order to protect from light.

6.5 Nature and Contents of Container

Iclusig film coated tablets are supplied in high density polyethylene (HDPE) bottles with desiccant canister and foil induction sealed child resistant, screw-top closures.
Each bottle contains either:
10 mg: 30 film-coated tablets.
15 mg: 30 or 60 film-coated tablets.
30 mg: 30 film-coated tablets.
45 mg: 30 film-coated tablets.
Not all strengths 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

Chemical structure.


Chemical name: {Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl])}.
Molecular weight: 569.02 g/mol (HCl salt).
Molecular formula: C29H28ClF3N6O (HCl salt).
Ponatinib HCl is an off-white to yellow powder with pKa of 2.77 and 7.8. The solubility of ponatinib in pH 1.7, 2.7, and 7.5 buffers is 7790 microgram/mL, 3.44 microgram/mL, and 0.16 microgram/mL, respectively, indicating a decrease in solubility with increasing pH.

CAS number.

1114544-31-8 (HCl salt).

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes