Consumer medicine information

Imbruvica Capsules and Tablets

Ibrutinib

BRAND INFORMATION

Brand name

Imbruvica

Active ingredient

Ibrutinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Imbruvica Capsules and Tablets.

SUMMARY CMI

IMBRUVICA® Capsules and Tablets

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.

1. Why am I using IMBRUVICA?

IMBRUVICA contains the active ingredient ibrutinib. IMBRUVICA is used to treat the following blood cancers in adults: Mantle Cell Lymphoma (MCL); Chronic Lymphocytic Leukaemia (CLL), including Small Lymphocytic Lymphoma (SLL); Waldenström's macroglobulinemia (WM)

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

2. What should I know before I use IMBRUVICA?

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

3. What if I am taking other medicines?

Some medicines may interfere with IMBRUVICA 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 IMBRUVICA?

  • The recommended dose of IMBRUVICA for: MCL is 560 mg once a day and for WM and CLL/SLL is 420 mg once a day. Follow your doctor's instructions on the dose appropriate for you.

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

5. What should I know while using IMBRUVICA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using IMBRUVICA
  • Your heart function will be checked before and during treatment with IMBRUVICA. Your doctor will check your blood counts before or during the treatment.
Things you should not do
  • Do not change your dose or stop taking IMBRUVICA until your doctor tells you to.
  • Do not use preparations containing St John's Wort while you are taking IMBRUVICA.
  • Do not fall pregnant while you are taking IMBRUVICA.
  • Do not breast feed while you are taking IMBRUVICA.
Driving or using machines
  • You may feel tired or dizzy after taking IMBRUVICA, which may affect your ability to drive or use any tools or machinery.
Drinking alcohol
  • No information on the effects of drinking alcohol with IMBRUVICA
Looking after your medicine
  • Store below 30°C. Keep capsules or tablets in the original container.
  • Do not store it or any medicines in the bathroom or near a sink.

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

6. Are there any side effects?

The most common side effects include diarrhoea; feeling very tired; nausea; headache; swollen hands, ankles or feet; being short of breath; dizziness; fainting; constipation; infected nose, sinuses or throat (cold); fever; vomiting; decreased appetite; bleeding; bruises; skin rash; muscle and joint pain; muscle spasms; indigestion (dyspepsia).

Call your doctor or healthcare professional if you have signs or symptoms of serious bleeding, if you have any heart problems like chest discomfort, shortness of breath or palpitations or signs of jaundice.

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.



FULL CMI

IMBRUVICA® Capsules and Tablets

Active ingredient(s): ibrutinib

Consumer Medicine Information (CMI)

This leaflet provides important information about using IMBRUVICA. 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 IMBRUVICA.

Where to find information in this leaflet:

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

1. Why am I using IMBRUVICA?

IMBRUVICA contains the active ingredient ibrutinib. IMBRUVICA is Bruton's tyrosine kinase inhibitor. By blocking this protein, IMBRUVICA may help kill and reduce the number of cancer cells and may also slow the spread of the cancer.

IMBRUVICA is used to treat the following blood cancers in adults: Mantle Cell Lymphoma (MCL); Chronic Lymphocytic Leukaemia (CLL), including Small Lymphocytic Lymphoma (SLL); Waldenström's macroglobulinemia (WM).

2. What should I know before I use IMBRUVICA?

Warnings

Do not take IMBRUVICA if:

  • you are allergic to ibrutinib, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you use preparations containing St John's Wort
  • you are pregnant, think you may be pregnant or are planning to have a baby
  • you are breast feeding

Check with your doctor if you:

  • had unusual bruising or bleeding or are on any medicines or supplements that increase your risk of bleeding
  • have had a history of high blood pressure, irregular heartbeat (atrial fibrillation, ventricular tachyarrhythmia) or severe heart failure, or if you feel any of the following: lightheadedness, dizziness, shortness of breath, chest discomfort, swollen legs, or you faint
  • if you have liver or kidney problems
  • if you have or have had Hepatitis B infection
  • if you have recently had any surgery, especially if this might affect how you absorb food or medicines from your stomach or gut
  • if you are planning to have any surgery - your doctor may ask you to stop taking IMBRUVICA for a short time.

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

Pregnancy and breastfeeding

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

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

Do not father a child while taking IMBRUVICA and for 3 months after stopping treatment.

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.

IMBRUVICA may make you bleed more easily. Tell your doctor if you take other medicines that increases your risk of bleeding. These include the following medicines:

  • warfarin, heparin or other medicines to prevent blood clots.
  • aspirin and non-steroidal anti-inflammatories (NSAIDS) such as ibuprofen or naproxen
  • fish oil and supplements containing vitamin E

Some medicines may interfere with IMBRUVICA and affect how it works.

  • medicines called antibiotics to treat bacterial infections - clarithromycin, telithromycin, ciprofloxacin, erythromycin, rifampin or azithromycin
  • medicines for fungal infections - ketoconazole, posaconazole, itraconazole, fluconazole or voriconazole
  • medicines for HIV infection - ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, darunavir/ritonavir or fosamprenavir
  • aprepitant - medicine to prevent nausea and vomiting associated with chemotherapy
  • nefazodone - medicine for depression
  • medicines called kinase inhibitors for treatment of other cancers - crizotinib, imatinib
  • medicines called calcium channel blockers for high blood pressure or chest pain - diltiazem, verapamil
  • medicines used to treat or prevent irregular heartbeat - amiodarone, dronedarone
  • fluvoxamine - medicine used to treat obsessive compulsive disorder
  • medicines to prevent seizures or to treat epilepsy or medicines to treat a painful condition of the face called trigeminal neuralgia - carbamazepine, phenytoin
  • medicines called statins to treat high cholesterol - rosuvastatin
  • St. John's Wort - herbal medicine used for depression

If you are taking digoxin, a medicine used for heart problems, or methotrexate, a medicine used to treat other cancers and to reduce the activity of the immune system (e.g., for rheumatoid arthritis or psoriasis), it should be taken at least 6 hours before or after IMBRUVICA.

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

4. How do I use IMBRUVICA?

How much to take / use

  • The recommended dose of IMBRUVICA for:
  • MCL is 560 mg once a day.
  • WM and CLL/SLL is 420 mg once a day.
  • Follow your doctor's instructions on the dose appropriate for you.

When to take / use IMBRUVICA

  • Do not take IMBRUVICA with grapefruit or Seville oranges - this includes eating them, drinking the juice, or taking supplements that might contain them. This is because they can increase the amount of IMBRUVICA in your blood.
  • Swallow IMBRUVICA capsules whole with a glass of water. Do not open, break, or chew them.
  • Swallow IMBRUVICA tablets whole with a glass of water. Do not break or chew them.
  • Try to take IMBRUVICA at the same time each day.
  • Follow the instructions provided and use IMBRUVICA until your doctor tells you to stop. Do not change your dose or stop taking IMBRUVICA until your doctor tells you to.

If you forget to use IMBRUVICA

IMBRUVICA should be used regularly at the same time each day. If you miss your dose at the usual time, if it is more than 12 hours until your next dose, take the missed dose as soon as possible. Then continue taking IMBRUVICA at the usual scheduled time..

If it is almost time for 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.

If you use too much IMBRUVICA

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

You should immediately:

  • phone the Poisons Information Centre
    (by calling in Australia 13 11 26
    or in New Zealand 0800 POISON or 0800 764 766), 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 IMBRUVICA?

Things you should do

Be sure to keep all your doctor's appointments so your progress can be checked.

Call your doctor straight away if you:

  • have diarrhoea that lasts for more than a week, your doctor may need to give you a fluid and salt replacement or another medicine.

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

Things you should not do

Do not take IMBRUVICA:

  • if the packaging is torn or shows signs of tampering.
  • if the expiry date (month and year) printed on the pack has passed. If you take IMBRUVICA after the expiry date it may not work.

Effects on the heart

  • Treatment with IMBRUVICA may affect the heart, especially if you already have heart diseases such as rhythm problems, heart failure, high blood pressure or have diabetes. The effects may be severe and could cause death, including sometimes sudden death. Your heart function will be checked before and during treatment with IMBRUVICA. Tell your doctor immediately if you feel breathless, have difficulty breathing when lying down, swelling of the feet, ankles or legs and weakness/tiredness during treatment with IMBRUVICA – these may be signs of heart failure.

Tests and check-ups before and during treatment

  • Laboratory tests may show that your blood count contains more white blood cells (called "lymphocytes"), in the first few weeks of treatment. This is expected and may last for a few months. This does not necessarily mean that your blood cancer is getting worse. Your doctor will check your blood counts before or during the treatment and in rare cases they may need to give you another medicine. Talk to your doctor about what your test results mean.

Driving or using machines

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

IMBRUVICA may cause dizziness in some people which may affect your ability to drive or use any tools or machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

We have no information on how alcohol affects IMBRUVICA.

Looking after your medicine

  • Store below 30°C. Keep capsules or tablets in the original container.

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal:
  • diarrhoea; nausea, constipation; vomiting; sore stomach; indigestion (dyspepsia); sore or inflamed mouth; decreased appetite
Infections:
  • infected nose; sinuses or throat; fever; feeling tired; urinary tract infection; chills; body aches; cold or flu symptoms; feel short of breath; yellowing of the skin or eyes (jaundice); confusion
Musculoskeletal:
  • muscle and joint pain; muscle spasms
Skin:
  • rash, bruising; swollen hands or feet; bleeding
Nervous system:
  • dizziness, fainting; headache; blurred vision
Metabolism:
  • low blood sodium; high levels of uric acid or creatine in your blood
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
Bleeding:

Bleeding in the eye or serious internal bleeding, such as bleeding in your stomach, intestine, or brain may occur. Signs or symptoms of serious bleeding include blood in your stools or urine or bleeding that lasts for a long time or that you cannot control.

Interstitial lung disease (ILD):

Inflammation within the lungs that may lead to permanent damage has happened with IMBRUVICA treatment. Contact your doctor if you have difficulty breathing or have a persistent cough.

Haemophagocytic lymphohistiocytosis:

There have been rare reports of excessive activation of white blood cells associated with inflammation, which can be fatal if not diagnosed and treated early. If you experience multiple symptoms such as fever, swollen glands, bruising, or skin rash, contact your doctor immediately.

Stroke:

Temporary or permanent decrease of brain or nerve function due to reduced blood flow to the brain (mini-stroke or stroke).

Heart problems:

Irregular heartbeat (atrial fibrillation, ventricular tachyarrhythmia) and high blood pressure have occurred with IMBRUVICA treatment. Tell your doctor or healthcare professional if you have any heart problems like chest discomfort, shortness of breath or palpitations. Heart failure has also been reported. Tell your doctor immediately if you notice breathlessness, difficulty breathing when lying down, swelling of the feet, ankles or legs and weakness/tiredness during treatment with IMBRUVICA.

Rupture of spleen:

Cases of splenic rupture have been reported after stopping IMBRUVICA treatment. Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the rib cage or at the tip of your left shoulder.

Changes in blood cell counts:

IMBRUVICA may cause you to have a low number of red blood cells (anaemia), a low number of neutrophils a type of white blood cell (neutropenia) or a low number of platelets a type cell that help blood to clot (thrombocytopenia). You may experience an increase in the number of white blood cells, specifically lymphocytes in your blood. In rare cases, this increase may be severe, causing cells to clump together. Your doctor or healthcare professional should check your blood counts regularly.

Liver problems:

Very rarely patients may experience changes in their liver function. Your doctor will monitor your liver function by periodic blood tests. If you notice signs of jaundice such as yellowing of the whites of the eyes please call your doctor immediately.

Tumour lysis syndrome (TLS):

Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer andsometimes even without treatment. This may lead to changes in kidney function, abnormal heartbeat, or seizures. Your doctor or another healthcare provider may do blood tests to check for TLS.

Other cancers:

New cancers have occurred in people taking IMBRUVICA, including skin cancer and other cancers.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What IMBRUVICA capsules contain

Active ingredient
(main ingredient)		Ibrutinib
Each hard capsule contains 140 mg of ibrutinib.
Other ingredients
(inactive ingredients)		croscarmellose sodium
microcrystalline cellulose
sodium lauryl sulphate
magnesium stearate
gelatin
titanium dioxide (E171)
black ink
Potential allergensNone

What IMBRUVICA tablets contain

Active ingredient
(main ingredient)		Ibrutinib
Each tablet contains 140 mg, 280 mg, 420 mg or 560 mg of ibrutinib
Other ingredients
(inactive ingredients)

colloidal anhydrous silica
croscarmellose sodium
lactose monohydrate
magnesium stearate
microcrystalline cellulose
povidone
sodium lauryl sulfate

The film-coating contains:
iron oxide black (140 mg, 280 mg and 420 mg tablets)
polyvinyl alcohol
macrogol
iron oxide red (280 mg and 560 mg tablets)
talc
titanium dioxide
iron oxide yellow (140 mg, 420 mg and 560 mg tablets)

Potential allergensContains lactose

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

What IMBRUVICA looks like

140 mg capsule: AUST R 228499

140 mg tablet: AUST R 319356

280 mg tablet: AUST R 319357

420 mg tablet: AUST R 319360

560 mg tablet: AUST R 319380

Capsules

The hard capsules are white opaque, with "ibr 140 mg" printed in black ink.

IMBRUVICA capsules are supplied in bottles containing 90 or 120 capsules. Not all pack sizes may be marketed.

Tablets

140 mg tablets are yellow-green to green, round, debossed with “ibr” on one side and “140” on the other.

280 mg tablets are purple, oblong-shaped, debossed with “ibr” on one side and “280” on the other.

420 mg tablets are yellow-green to green, oblong-shaped debossed with “ibr” on one side and “420” on the other.

560 mg tablets are yellow to orange, oblong-shaped, debossed with “ibr” on one side and “560” on the other.

IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg tablets are supplied in cartons containing 30 tablets (3 cardboard wallets containing 10 film-coated tablets each).

Not all pack sizes may be marketed

Who distributes IMBRUVICA

Janssen-Cilag Pty Ltd
1-5 Khartoum Rd
Macquarie Park
NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland, New Zealand
Telephone: 0800 800 806

This leaflet was prepared in March 2023

®IMBRUVICA is a registered trademark of Janssen-Cilag.

Co-developed with Pharmacyclics.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Imbruvica

Active ingredient

Ibrutinib

Schedule

S4

 

1 Name of Medicine

Ibrutinib.

2 Qualitative and Quantitative Composition

Capsules.

140 mg capsules.

Imbruvica capsules contain 140 mg ibrutinib as the active ingredient.

Film-coated tablets.

Imbruvica tablets contain 140 mg, 280 mg, 420 mg or 560 mg of ibrutinib.

Excipients with known effect.

Sugars as lactose.
The characterization data demonstrate that ibrutinib at pH 1.2 is considered slightly soluble and at pH 3 to 8 ibrutinib is considered practically insoluble as defined by USP and European Pharmacopoeia nomenclature. Ibrutinib is non-hygroscopic and the melting onset temperature is 149-158°C. The drug substance has one ionizable group, the protonated pyrimidine moiety, with a pKa of 3.74 in an aqueous solution with methanol as a co-solvent.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsules.

140 mg capsules.

White opaque, size 0, hard gelatin capsule is marked with "ibr 140 mg" in black ink.

Film-coated tablets.

140 mg tablets.

Yellow-green to green round film-coated tablet debossed with "ibr" on one side and "140" on the other.

280 mg tablets.

Purple oblong film-coated tablet debossed with "ibr" on one side and "280" on the other.

420 mg tablets.

Yellow-green to green oblong film-coated tablet debossed with "ibr" on one side and "420" on the other.

560 mg tablets.

Yellow to orange oblong film-coated tablet debossed with "ibr" on one side and "560" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Imbruvica is indicated for the treatment of patients with MCL who have received at least one prior therapy.
Imbruvica as a single agent is indicated for the treatment of adult patients with Waldenstrom's macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.
Imbruvica in combination with rituximab is indicated for the treatment of adult patients with Waldenstrom's macroglobulinaemia (WM).
Imbruvica as a single agent or in combination with rituximab or obinutuzumab or venetoclax is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).
Imbruvica as a single agent or in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) who have received at least one prior therapy.

4.2 Dose and Method of Administration

Dosage.

Imbruvica should be administered orally once daily with a glass of water at approximately the same time each day. Imbruvica can be taken with or without food. The capsules or tablets should be swallowed whole with water. Do not open, break, or chew the capsules. Do not break or chew the tablets. Imbruvica must not be taken with grapefruit juice or Seville oranges.

Mantle cell lymphoma.

The recommended dose of Imbruvica for MCL is 560 mg once daily until disease progression or no longer tolerated by the patient.

Waldenstrom's macroglobulinemia (WM).

The recommended dose of Imbruvica is 420 mg once daily.
Imbruvica can be administered as a single agent, or in combination with rituximab, until disease progression or it is no longer tolerated by the patient.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).

The recommended dose of Imbruvica for CLL/SLL is 420 mg once daily.
Imbruvica can be administered as a single agent or in combination with anti-CD20 therapy (rituximab or obinutuzumab), or in combination with bendamustine and rituximab (BR) until disease progression or is no longer tolerated by the patient.
In combination with venetoclax, Imbruvica should be administered as a single agent for an initial 3 cycles (1 cycle is 28 days), followed by 12 cycles of Imbruvica plus venetoclax.
For additional information concerning rituximab, BR, obinutuzumab or venetoclax, see the corresponding local rituximab, bendamustine, obinutuzumab or venetoclax prescribing information. When administering Imbruvica in combination with anti-CD20 therapies, it is recommended to administer Imbruvica prior to anti-CD20 therapy when given on the same day.

Dose modification guidelines.

Dose modifications are required for the concomitant use of moderate and strong CYP3A inhibitors as these can increase the exposure of ibrutinib (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Imbruvica therapy should be withheld for any new onset or worsening Grade 2 cardiac failure, Grade 3 cardiac arrhythmias, Grade ≥ 3 non-haematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 haematological toxicities. If ≥ Grade 3 elevations in liver function tests occur, with or without a rise in bilirubin, therapy should be withheld.
Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), resume Imbruvica therapy at the recommended dose as per Tables 1 and 2.

Missed dose.

If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The patient should not take extra doses to make up the missed dose.

Special populations.

Elderly.

No specific dose adjustment is required for elderly patients (aged ≥ 65 years).

Severe cardiac disease.

Patients with severe cardiovascular disease were excluded from Imbruvica clinical studies.

Paediatrics (18 years of age and younger).

The safety and efficacy of Imbruvica in children have not yet been evaluated.

Renal impairment.

Ibrutinib has minimal renal clearance. No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in ibrutinib clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There are no data in patients with severe renal impairment or patients on dialysis (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

Ibrutinib is metabolized in the liver. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3 x upper limit of normal (ULN) were excluded from Imbruvica clinical studies. In a dedicated hepatic impairment study in non-cancer patients, preliminary data showed an increase in ibrutinib exposure (see Section 5.2 Pharmacokinetic Properties). For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily. For patients with moderate liver impairment, the recommended dose is 140 mg daily. Monitor patients for signs of ibrutinib toxicity and follow dose modification guidance as needed. It is not recommended to administer Imbruvica to patients with severe hepatic impairment (Child-Pugh class C).

Immunisations.

There is no clinical data on the safety and efficacy of immunisations concomitantly administered with ibrutinib. Immunisations may be less effective in patients on ibrutinib therapy.

4.3 Contraindications

Imbruvica is contraindicated in patients who have known hypersensitivity (e.g. anaphylactic and anaphylactoid reactions) to ibrutinib or to the excipients in its formulation.
Use of preparations containing St. John's wort is contraindicated in patients treated with Imbruvica.

4.4 Special Warnings and Precautions for Use

Bleeding-related events.

There have been reports of bleeding events in patients treated with ibrutinib, both with and without thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were observed (see Section 5.1 Pharmacodynamic Properties). Use of either anticoagulant or antiplatelet agents concomitantly with Imbruvica increases the risk of major bleeding. Across clinical trials, 3.1% of 2,838 patients who received Imbruvica without antiplatelet or anticoagulant therapy experienced major haemorrhage. A higher risk for major bleeding was observed with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with Imbruvica. Monitor for signs and symptoms of bleeding.
Supplements such as fish oil and vitamin E preparations should be avoided.
Ibrutinib should be withheld at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Patients with congenital bleeding diathesis have not been studied.

Cardiac events.

Fatal and serious cardiac arrhythmias or cardiac failure have occurred in patients treated with Imbruvica. Patients with significant cardiac co-morbidities may be at greater risk of events, including sudden fatal cardiac events. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia, and cardiac failure, have been reported, particularly in patients with acute infections or cardiac risk factors including hypertension, diabetes mellitus and a previous history of cardiac arrhythmia. In some of these cases cardiac failure resolved or improved after Imbruvica withdrawal or dose reduction. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.3% of patients and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1981 patients who received Imbruvica in clinical trials. Appropriate clinical evaluation of cardiac history and function should be performed prior to initiating Imbruvica. Patients should be carefully monitored during treatment for signs of clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g. ECG, echocardiogram), as indicated for patients in whom there are cardiovascular concerns. Consider the risks and benefits of Imbruvica treatment and follow the dose modification guidelines.
In patients who develop signs and/or symptoms of ventricular tachyarrhythmia, Imbruvica should be temporarily discontinued and a thorough clinical benefit/risk assessment should be performed before possibly restarting therapy.
In patients with pre‐existing atrial fibrillation requiring anticoagulant therapy, alternative treatment options to Imbruvica should be considered. In patients who develop atrial fibrillation on therapy with Imbruvica a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to Imbruvica are non‐suitable, and benefit-risk evaluation dictates the treatment with anticoagulants, patients should be closely monitored.

Leukostasis.

There were isolated cases of leukostasis reported in patients treated with ibrutinib. Leukostasis is characterized by abnormal intravascular leukocyte aggregation and clumping, and may cause local hypoxemia and haemorrhage manifesting as headache, blurred vision, transient ischemic attacks, cerebrovascular accidents and dyspnoea. A high number of circulating lymphocytes (> 400 x 109/L) may confer increased risk. Consider temporarily withholding ibrutinib. Patients should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated.

Infections.

Infections (including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections) were observed in patients treated with ibrutinib. Some of these infections have been associated with hospitalisation and death. Most patients with fatal infections also had neutropenia. Cases of hepatitis E, which may be chronic, have occurred in patients treated with ibrutinib. Patients should be monitored for signs and symptoms (such as fever, chills, weakness, confusion, neutropenia, vomiting, jaundice, abnormal liver function tests and infections) and appropriate anti-infective therapy should be instituted as indicated. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Progressive multifocal leukoencephalopathy (PML).

Although causality has not been established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with ibrutinib. Patients should be monitored for new or worsening neurological, cognitive, or behavioural signs or symptoms, which may be suggestive of PML. If these occur, ibrutinib should be held pending appropriate investigations.

Cytopenias.

Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anemia) were reported in patients treated with ibrutinib. Monitor complete blood counts monthly.

Interstitial lung disease (ILD).

Cases of ILD have been reported in patients treated with ibrutinib. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt Imbruvica and manage ILD appropriately. If symptoms persist, consider the risks and benefits of Imbruvica treatment and follow the dose modification guidelines.

Hypertension.

Hypertension has occurred in patients treated with Imbruvica. Hypertension occurred in 18% of 1981 patients who received Imbruvica in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months). Regularly monitor blood pressure in patients treated with Imbruvica and initiate or adjust antihypertensive medication throughout treatment with Imbruvica as appropriate.

Cerebrovascular accidents.

Cases of cerebrovascular accident, transient ischemic attack and ischemic stroke including fatalities have been reported with the use of ibrutinib, with and without concomitant atrial fibrillation and/or hypertension. Latency from the initiation of treatment with ibrutinib to the onset of ischemic central nervous vascular conditions was in the most cases after several months emphasising the need for regular monitoring of patients (please see Section 4.4, Cardiac events, Hypertension; Section 4.8).

Non-melanoma skin cancer.

Non-melanoma skin cancers were reported more frequently in patients treated with Imbruvica than in patients treated with comparators in pooled comparative randomised phase 3 studies. Other malignancies (8%), including non-skin carcinomas (3%), occurred among the 1981 patients who received Imbruvica in clinical trials. Monitor patients for the appearance of non melanoma skin cancer.

Splenic rupture.

Cases of splenic rupture have been reported following discontinuation of Imbruvica treatment. Disease status and spleen size should be carefully monitored (e.g. clinical examination, ultrasound) when ibrutinib treatment is interrupted or ceased. Patients who develop left upper abdominal or shoulder tip pain should be evaluated, and a diagnosis of splenic rupture should be considered.

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) has been reported with Imbruvica therapy. Patients at risk of tumor lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.

Haemophagocytic lymphohistiocytosis (HLH).

Cases of HLH (including fatal cases) have been reported in patients treated with Imbruvica. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. HLH is characterized by fever, hepatosplenomegaly, hypertriglyceridaemia, high serum ferritin and cytopenias. Patients should be informed about symptoms of HLH. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.

Hepatotoxicity.

Severe liver toxicity, such as hepatic failure (Grade 3 and 4 elevations in ALT and AST) have occurred in the post-marketing setting in patients taking ibrutinib. The time to onset was variable (5 days - 3 months after commencing ibrutinib) and monitoring of liver function tests is recommended. These events were very rare and in most cases, resolved upon dose modification. Ibrutinib treatment should be interrupted if ≥ Grade 3 liver function abnormalities develop (see Section 4.2 Dose and Method of Administration).

Hepatitis B reactivation.

Cases of hepatitis B reactivation, including fatal events, have been reported in patients receiving ibrutinib. Hepatitis B virus (HBV) status should be established before initiating treatment with ibrutinib. For patients with hepatitis B serology indicative of prior infection, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Use in the elderly.

Please see Section 4.8 Adverse Effects (Undesirable Effects), Elderly.

Paediatric use.

The safety and efficacy of Imbruvica in children have not yet been evaluated.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4.

Agents that may increase ibrutinib plasma concentrations.

Concomitant use of Imbruvica and drugs that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and strong CYP3A inhibitors should be avoided.

Strong CYP3A inhibitors.

Co-administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects, increased exposure (Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, respectively. In a dedicated drug-drug interaction study in patients with B-cell malignancies, co-administration of voriconazole increased Cmax and AUC by 6.7-fold and 5.7-fold, respectively. In clinical studies, the maximal observed ibrutinib exposure (AUC) was ≤ 2-fold in 37 patients treated with mild and/or moderate CYP3A inhibitors when compared with the ibrutinib exposure in 76 patients not treated concomitantly with CYP3A4 inhibitors. Clinical safety data in 66 patients treated with moderate (n = 47) or strong CYP3A4 inhibitors (n = 19) did not reveal meaningful increases in toxicities. Voriconazole and posaconazole can be used concomitantly with Imbruvica as per dose recommendations in Table 3. All other strong inhibitors of CYP3A (e.g. ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat and posaconazole) should be avoided and an alternative with less CYP3A inhibitory potential should be considered. If the benefit clearly outweighs the risk and a strong CYP3A4 inhibitor must be used, see recommended dose modifications in Table 3.

Moderate and mild CYP3A4 inhibitors.

In patients with B cell malignancies, coadministration of CYP3A inhibitors erythromycin and voriconazole increased Cmax by 3.4-fold and 6.7-fold and increased AUC by 3.0-fold and 5.7-fold, respectively. If a moderate CYP3A4 inhibitor (e.g. fluconazole, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) is indicated, reduce Imbruvica dose as per recommended dose modifications in Table 3. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during Imbruvica treatment as these contain moderate inhibitors of CYP3A4 (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Simulations using fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by a factor of less than 2-fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.
After discontinuation of a CYP3A inhibitor, resume previous dose of Imbruvica (see Section 4.2 Dose and Method of Administration).

Agents that may decrease ibrutinib plasma concentrations.

Administration of Imbruvica with strong inducers of CYP3A4 decreases ibrutinib plasma concentrations by approximately 90%. Avoid concomitant use of strong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin and St. John's wort). Consider alternative agents with less CYP3A4 induction. If a CYP3A4 inducer must be used, closely monitor patients for lack of efficacy with Imbruvica.
As ibrutinib solubility is pH dependent, there is a theoretical risk that medicinal products increasing stomach pH (e.g. proton pump inhibitors) may decrease ibrutinib exposure. This interaction has not been studied in vivo.

Agents that may have their plasma concentrations altered by ibrutinib.

Based on in vitro data, ibrutinib is predicted to be a weak OCT2 inhibitor in vivo. Ibrutinib is a P-gp and breast cancer resistance protein (BCRP) inhibitor in vitro. As no clinical data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic dose. To minimise the potential for an interaction in the GI tract, narrow therapeutic range P-gp or BCRP substrates such as digoxin or methotrexate should be taken at least 6 hours before or after Imbruvica. Ibrutinib may also inhibit BCRP systemically and increase the exposure of drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin.
In a drug interaction study in patients with B-cell malignancies, a single 560 mg dose of ibrutinib did not have a clinically meaningful effect on the exposure of the CYP3A4 substrate midazolam. In the same study, 2 weeks of treatment with ibrutinib at 560 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the CYP2B6 substrate bupropion.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day with estimated systemic exposures in female rats approximately 14 times the AUC of ibrutinib and 8 times the AUC of the dihydrodiol metabolite in patients dosed 560 mg ibrutinib daily (exposures in male rats were less than half the exposures in female rats).
Fertility studies with ibrutinib have not been conducted in animals.
(Category D)
There are no adequate and well controlled studies of ibrutinib in pregnant women. Based on findings in animals, ibrutinib may cause fetal harm when administered to pregnant women.
Imbruvica should not be used during pregnancy. Women of childbearing potential must use highly effective contraceptive measures while taking Imbruvica. Women should avoid becoming pregnant while taking Imbruvica and for up to 3 months after ending treatment. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a foetus. The time period following treatment with Imbruvica where it is safe to become pregnant is unknown.
Men should be advised not to father a child or donate sperm while receiving Imbruvica, and for 3 months following completion of treatment.
Ibrutinib was studied for effects on embryofetal development in pregnant rats given oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at 80 mg/kg/day (approximately 14 times the AUC of ibrutinib and 10 times the AUC of the dihydrodiol metabolite compared to patients at the dose of 560 mg daily) was associated with increased post implantation loss and increased visceral malformations (heart and major vessels). Ibrutinib at ≥ 40 mg/kg/day (approximately 6 times the AUC of ibrutinib and 4 times the AUC of the dihydrodiol metabolite compared to patients at a dose of 560 mg daily) was associated with decreased maternal and fetal weights and increased skeletal variations (unossified sternebrae).
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at oral doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal malformations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased post implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15 mg/kg/day (approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560 mg daily).
 It is not known whether ibrutinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Imbruvica, breast-feeding should be discontinued during Imbruvica treatment.

4.7 Effects on Ability to Drive and Use Machines

Fatigue, dizziness and asthenia have been reported in some patients taking ibrutinib and should be considered when assessing a patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety profile is based on pooled data from 1981 patients with B-cell malignancies treated with Imbruvica in four phase 2 clinical studies (PCYC-1102-CA, PCYC-1104-CA, PCYC-1118E and PCYC-1142-CA) and eight phase 3 studies (PCYC-1112-CA, PCYC-1115-CA, CLL3001, PCYC-1130-CA, MCL3001, PCYC-1127-CA, E1912 and CLL3011). Patients treated for MCL received Imbruvica at 560 mg once daily and patients treated for CLL/SLL and WM received Imbruvica at 420 mg once daily. All patients received Imbruvica until disease progression or no longer tolerated.
The most commonly occurring adverse reactions (≥ 20%) were diarrhoea, musculoskeletal pain, haemorrhage, bruising, rash, nausea, neutropenia, arthralgia, upper respiratory tract infection and thrombocytopenia. The most common grade 3/4 adverse reactions (≥ 5%) were neutropenia, lymphocytosis, pneumonia, hypertension and thrombocytopenia.

Tabulated list of adverse reactions.

Treatment emergent adverse reactions for MCL, CLL/SLL or WM are listed in Table 4 by system organ class and frequency grouping. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Discontinuation and dose reduction due to ADRs.

Of the 1981 patients treated with Imbruvica for B-cell malignancies, 6% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, haemorrhage, neutropenia, rash, arthralgia and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 8% of patients.

Elderly.

Of the 1981 patients treated with Imbruvica, 50% were above 65 years of age. Grade 3 or higher pneumonia occurred more frequently (≥ 5%) among elderly patients treated with Imbruvica (11% of patients ≥ 65 years of age versus 4% of patients < 65 years of age) and thrombocytopenia (11% of patients ≥ 65 years of age versus 5% of patients < 65 years of age).

Long-term safety.

The long-term safety data over 5 years from 1178 patients (treatment-naïve CLL/SLL n = 162, relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370) treated with Imbruvica were analyzed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 70% and 52% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of patients receiving treatment for more than 2 years and 4 years, respectively. The overall known safety profile of Imbruvica-exposed patients remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4) and 9% (year 4-5). The incidence for the 5-year period was 11%.

Post-marketing data.

Adverse reactions identified during post-marketing experience with frequency category estimated from spontaneous reporting rates:

System organ class: eye disorders.

Uncommon: eye hemorrhage.

System organ class: immune system disorders.

Uncommon: interstitial lung disease*#.

System organ class: metabolism and nutrition disorders.

Very rare: tumour lysis syndrome.

System organ class: cardiac disorders.

Common: cardiac failure*#; ventricular tachyarrhythmia*#.

System organ class: hepatobiliary disorders.

Uncommon: Hepatic failure*#.
Very rare: hepatotoxicity.

System organ class: infections and infestations.

Uncommon: hepatitis B reactivation#.

System organ class: skin and subcutaneous tissue disorders.

Uncommon: onychoclasis.
Rare: Neutrophilic dermatoses*.
Rare: Stevens-Johnson syndrome, panniculitis*.
Very rare: angioedema, erythema, urticaria.

System organ class: nervous system disorders.

Uncommon: Peripheral neuropathy*; cerebrovascular accident#.
Rare: Transient ischemic attack; ischemic stroke#.
* Includes multiple adverse reaction terms.
# Includes events with fatal outcome.

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

4.9 Overdose

Symptoms and signs.

There are limited data on the effects of Imbruvica overdose.
No Maximum Tolerated Dose was reached in the Phase 1 study in which patients received up to 12.5 mg/kg/day (1400 mg/day). In a separate study, one healthy subject who received a dose of 1680 mg experienced reversible Grade 4 hepatic enzyme increases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)]. There is no specific antidote for Imbruvica. Patients who ingested more than the recommended dosage should be closely monitored and given appropriate supportive treatment.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE27.
Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys 481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B cell malignancies, including MCL, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and CLL/SLL. BTK's pivotal role in signalling through the B cell surface receptors results in activation of pathways necessary for B cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib inhibits B cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
In primary tumour cells, cultured tumour cell lines and preclinical tumour models, the combination of ibrutinib and venetoclax resulted in increased cytotoxicity, cellular apoptosis and/or anti-tumour activity compared to either agent alone.

Lymphocytosis.

Upon initiation of single agent treatment with Imbruvica, a reversible increase in lymphocyte counts (i.e. ≥ 50% increase from baseline and above absolute count 5000/mcL), often associated with reduction of lymphadenopathy, has been observed in most patients (66%) with CLL/SLL. This effect has also been observed in some patients (35%) with MCL treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy and typically resolves within a median of 8 weeks in patients with MCL and 14 weeks in patients with CLL/SLL (range 0.1 to 104 weeks).
A large increase in the number of circulating lymphocytes (e.g. > 400 x 109/L) has been observed in some patients.
Lymphocytosis was not observed in patients with WM treated with Imbruvica.
When Imbruvica was administered in combination, lymphocytosis was infrequent (7% with Imbruvica + BR versus 6% with placebo + BR and 7% with Imbruvica + obinutuzumab versus 1% with chlorambucil + obinutuzumab).

In vitro platelet aggregation.

In an in vitro study (n = 32), ibrutinib at therapeutically relevant concentrations demonstrated inhibition of collagen induced platelet aggregation in samples from 4 cohorts of subjects (n = 8 in each) with either renal dysfunction, those on warfarin, healthy subjects or healthy subjects on aspirin. The magnitude of inhibition of collagen induced platelet aggregation in the cohort of subjects on aspirin was less pronounced since collagen induced platelet aggregation was already reduced without ibrutinib. Ibrutinib did not show meaningful inhibition of platelet aggregation for the 4 agonists adenosine diphosphate (ADP), arachidonic acid, ristocetin, and thrombin receptor activating peptide 6 (TRAP-6) across any of these cohorts of subjects or healthy subjects.

Effects on the QT/QTc interval and cardiac electrophysiology.

A randomized, double-blind, placebo- and positive-controlled, single-dose crossover study was performed to evaluate the effects of ibrutinib at supratherapeutic doses of 840 mg and 1680 mg on ECG interval parameters in healthy subjects. The study was early terminated after 20 subjects (out of 52 planned) received 3 out of 4 treatments. Results were based on the 20 treated subjects, 9 of whom received ibrutinib (either 840 or 1680 mg), the negative control (placebo), and the positive control (moxifloxacin). In this study, ibrutinib did not prolong the QTc interval to any clinically relevant extent. A concentration dependent shortening in the QTc interval was observed (-5.3 ms [90% CI: -9.4, -1.1] at a Cmax of 719 nanogram/mL following the supratherapeutic dose of 1680 mg dose) that was considered not clinically relevant.

Clinical trials. Mantle cell lymphoma.

The safety and efficacy of ibrutinib in MCL patients who received at least one prior therapy were evaluated in a single open label, multi-centre Phase 2 study (PCYC-1104-CA) of 111 patients. The median age was 68 years (range, 40 to 84 years), 77% were male and 92% were Caucasian. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 35% with prior high dose chemotherapy, 43% with prior bortezomib, 24% with prior lenalidomide, and 11% with prior stem cell transplant. At baseline, 39% of patients had bulky disease (≥ 5 cm), 49% had high risk score by Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal and/or bone marrow involvement) at screening.
Ibrutinib was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumour response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to Imbruvica are shown in Table 5.
The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an ORR of 69%, with a 21% CR rate and a 48% PR rate. The IRC estimated median DOR was 19.6 months.
The overall response to Imbruvica was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognosis, bulky disease, gender or age (Figure 1).

MCL3001 (Ray).

The safety and efficacy of Imbruvica were demonstrated in a randomized phase 3, open-label, multicentre study including 280 patients with MCL who received at least one prior therapy. Patients were randomized 1:1 to receive either Imbruvica orally at 560 mg once daily on a 21-day cycle or temsirolimus intravenously at 175 mg on days 1, 8, 15 of the first cycle followed by 75 mg on days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until disease progression or unacceptable toxicity. The median age was 68 years (range, 34; 88), 74% were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high dose chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell transplant. At baseline, 53% of patients had bulky disease (≥ 5 cm), 21% had high risk score by Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening.
Progression-free survival (PFS) as assessed by IRC according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria showed a 57% statistically significant reduction in the risk of death or progression for patients in the Imbruvica arm. Efficacy results for Study MCL3001 are shown in Table 6 and the Kaplan-Meier curve for PFS Figure 2.
A smaller proportion of patients treated with ibrutinib experienced a clinically meaningful worsening of lymphoma symptoms versus temsirolimus (27% versus 52%) and time to worsening of symptoms occurred more slowly with ibrutinib versus temsirolimus (HR 0.27, p < 0.0001).

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

The safety and efficacy of ibrutinib in patients with CLL/SLL were demonstrated in two uncontrolled studies and six randomised, controlled studies.
Patients with treatment naïve CLL/SLL. Single agent.

PCYC-1115-CA (RESONATE-2).

A randomised, multicentre, open-label Phase 3 study of Imbruvica versus chlorambucil was conducted in patients with treatment-naïve CLL/SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either Imbruvica 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on days 1 and 15 of each 28 day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability. After confirmed disease progression, patients on chlorambucil were able to crossover to ibrutinib.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Patients between 65 and 70 years of age were required to have at least 1 of the following additional comorbidities that could preclude the use of frontline chemoimmunotherapy combination with fludarabine, cyclophosphamide, and rituximab (FCR): Creatinine clearance < 70 mL/min; Platelet count < 100,000 microL or hemoglobin < 10 g/dL; Clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune thrombocytopenia); Eastern Cooperative Oncology Group (ECOG) PS score of 1 or 2. Forty-two percent of patients had a baseline ECOG performance status of 0, 49% had an ECOG performance status of 1, and 9% had an ECOG performance status of 2. The study enrolled 269 patients with CLL or SLL. At baseline, 45% had advanced clinical stage (Rai Stage III or IV), 35% of patients had at least one tumour ≥ 5 cm, 39% with baseline anaemia, 23% with baseline thrombocytopenia, 65% had elevated β2 microglobulin > 3500 microgram/L, 47% had a CrCl < 60 mL/min, 20% of patients presented with del11q, 6% of patients presented with del17p/tumor protein 53 (TP53) mutation, and 44% of patients presented with unmutated immunoglobulin heavy chain variable region (IGHV).
Progression free survival (PFS) as assessed by IRC according to IWCLL criteria indicated an 84% statistically significant reduction in the risk of death or progression in the Imbruvica arm. With a median follow up of 18 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm. Significant improvement in ORR was observed in the ibrutinib arm (82%) versus the chlorambucil arm (35%). The results from investigator and IRC assessments for PFS and ORR were consistent. Analysis of overall survival (OS) also demonstrated an 84% statistically significant reduction in the risk of death for patients in the Imbruvica arm. Efficacy results for Study PCYC-1115-CA are shown in Table 7 and the Kaplan-Meier curves for PFS and OS are shown in Figures 3 and 4, respectively.
There was a statistically significant sustained platelet or haemoglobin improvement in the ITT population in favour of ibrutinib vs. chlorambucil. In patients with baseline cytopenias, sustained haematologic improvement was: platelets 77% versus 43%; haemoglobin 84% versus 45% for ibrutinib and chlorambucil respectively.

Overall follow-up of 55 months (median of 48 months).

With an overall follow-up of 55 months (median of 48 months) in Study PCYC-1115-CA and its extension study, an 86% reduction in the risk of death or progression by investigator assessment was observed for patients in the Imbruvica arm. The median investigator-assessed PFS was not reached in the Imbruvica arm and was 15 months [95% CI (10.22, 19.35)] in the chlorambucil arm; (HR = 0.14 [95% CI (0.09, 0.21)]). The 4-year PFS estimate was 73.9% in the Imbruvica arm and 15.5% in the chlorambucil arm, respectively. The updated Kaplan-Meier curve for PFS is shown in Figure 5. The investigator-assessed ORR was 91.2% in the Imbruvica arm versus 36.8% in the chlorambucil arm. The CR rate according to IWCLL criteria was 16.2% in the Imbruvica arm versus 3.0% in the chlorambucil arm. At the time of long-term follow-up, a total of 73 subjects (54.9%) originally randomized to the chlorambucil arm subsequently received ibrutinib as cross-over treatment. The Kaplan-Meier landmark estimate for OS at 48-months was 85.5% in the Imbruvica arm.
The treatment effect of ibrutinib in Study PCYC-1115-CA was consistent across high-risk patients with del17p/TP53 mutation, del11q, and/or unmutated IGHV.
Combination therapy.

PCYC-1130-CA (iLLUMINATE).

A randomised, multi-centre, open-label, Phase 3 study of Imbruvica in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab was conducted in patients with treatment naïve CLL/SLL. The study enrolled patients who were 65 years of age or older or < 65 years of age with coexisting medical conditions, reduced renal function as measured by creatinine clearance < 70 mL/min, or presence of del17p/TP53 mutation. Patients (n = 229) were randomised 1:1 to receive either Imbruvica 420 mg daily until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 100, 900, 1000, and 1000 mg of obinutuzumab on days 1, 2, 8 and 15 of the first cycle, respectively, followed by treatment of 1000 mg of obinutuzumab on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each).
The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). At baseline, 52% had advanced clinical stage (Rai Stage III or IV), 32% of patients had bulky disease (≥ 5 cm), 44% with baseline anaemia, 22% with baseline thrombocytopenia, 28% had a CrCl < 60 mL/min, and the median Cumulative Illness Rating Score for Geriatrics (CIRS-G) was 4 (range, 0 to 12). At baseline, 65% of patients presented with CLL/SLL with high risk factors (del17p/TP53 mutation [18%], del11q [15%], or unmutated IGHV [54%]).
Progression free survival (PFS) as assessed by IRC according to IWCLL criteria indicated a 77% statistically significant reduction in the risk of death or progression in the Imbruvica arm. With a median follow up time on study of 31 months, the median PFS was not reached in the Imbruvica + obinutuzumab arm and was 19 months in the chlorambucil + obinutuzumab arm. The results from investigator and IRC assessments for PFS and ORR were consistent.
Efficacy results for Study PCYC 1130 CA are shown in Table 8 and the Kaplan-Meier curve for PFS is shown in Figure 6.
The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (del17p/TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.15 [95% CI (0.09, 0.27)], as shown in Table 9. The 2-year PFS rate estimates for the high-risk CLL/SLL population were 78.8% [95% CI (67.3, 86.7)] and 15.5% [95% CI (8.1, 25.2)] in the Imbruvica + obinutuzumab and chlorambucil + obinutuzumab arms, respectively.
Any grade infusion-related reactions were observed in 25% of patients treated with Imbruvica + obinutuzumab and 58% of patients treated with chlorambucil + obinutuzumab. Grade 3 or higher or serious infusion-related reactions were observed in 3% of patients treated with Imbruvica + obinutuzumab and 9% of patients treated with chlorambucil + obinutuzumab.

Study E1912/PCYC-1126e-CA.

The E1912 study (A Randomized Phase III Study of Ibrutinib based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab [FCR] Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia [CLL]) (NCT02048813) was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL requiring systemic therapy. All patients had a CLcr > 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n = 529) were randomized 2:1 to receive either Imbruvica plus rituximab (R) or FCR. Imbruvica was administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of 250 mg/m2, both on days 1, 2, and 3 of cycles 1-6. Rituximab was initiated in cycle 2 for the Imbruvica + R arm and in cycle 1 for the FCR arm and was administered at 50 mg/m2 on day 1 of the first cycle, 325 mg/m2 on day 2 of the first cycle, and 500 mg/m2 on day 1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.
The median age was 58 years (range, 28 to 70 years), 67% were male, 90% were White and 98% had a ECOG performance status of 0-1. At baseline, 43% of patients were Rai stage 3 or 4 and 59% of patients presented with high risk factors (TP53 mutation [6%], del11q [22%], or unmutated IGHV [53%]).
With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 10. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in Figure 7.
With a median follow-up time on study of 49 months, median overall survival was not reached with a total of 23 deaths: 11 (3%) in the Imbruvica plus rituximab and 12 (7%) in the FCR treatment arms.
Fixed duration combination therapy.

Study CLL3011 (GLOW).

A randomised, open-label, Phase 3 study of Imbruvica in combination with venetoclax versus chlorambucil in combination with obinutuzumab, was conducted in patients with previously untreated CLL or SLL who were 65 years or older, and adult patients < 65 years of age with a CIRS score > 6 or CrCL ≥ 30 to < 70 mL/min. Patients with del17p or known TP53 mutations were excluded.
Patients (n = 211) were randomised 1:1 to receive either Imbruvica in combination with venetoclax or chlorambucil in combination with obinutuzumab. Patients in the Imbruvica plus venetoclax arm received single agent Imbruvica for 3 cycles followed by Imbruvica in combination with venetoclax for 12 cycles (including 5-week dose ramp up). Each cycle was 28 days. Imbruvica was administered at a dose of 420 mg daily. Venetoclax was administered daily, starting with 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg. Patients randomized to the chlorambucil plus obinutuzumab arm received treatment for 6 cycles. Obinutuzumab was administered at a dose of 1000 mg on days 1, 8 and 15 in cycle 1. In cycles 2 to 6, 1000 mg obinutuzumab was given on day 1. Chlorambucil was administered at a dose of 0.5 mg/kg body weight on days 1 and 15 of cycles = 1 to 6. Patients with confirmed progression by IWCLL criteria after completion of either fixed duration regimen could be treated with single-agent Imbruvica.
The median age was 71 years (range, 47 to 93 years), 58% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (35%), 1 (53%), or 2 (12%). The trial enrolled 197 patients with CLL and 14 patients with SLL. At baseline, 18% of patients presented with CLL/SLL with del11q and 52% with unmutated IGHV. The most common reasons for initiating CLL therapy included: constitutional symptoms (59%), progressive marrow failure (48%), lymphadenopathy (36%), splenomegaly (28%) and progressive lymphocytosis (19%). At baseline assessment for risk of tumour lysis syndrome, 25% of patients had high tumour burden. After 3 cycles of single-agent Imbruvica lead-in therapy, 2% of patients had high tumour burden. High tumour burden was defined as any lymph node ≥ 10 cm; or any lymph node ≥ 5 cm and absolute lymphocyte count ≥ 25 x 109/L.
With a median follow-up time on study of 28 months, efficacy results for study CLL3011 assessed by an IRC according to IWCLL criteria are shown in Table 11, the Kaplan-Meier curve for PFS is shown in Figure 8, and rates of minimal residual disease (MRD) negativity are shown in Table 12.
Across the high-risk CLL/SLL population (n=123), including TP53 mutation (n=9), del11q (n=38), or unmutated IGHV (n=109), the treatment effect of Imbruvica plus venetoclax was consistent, with a PFS HR of 0.23 [95% CI (0.13, 0.41)].
With a median follow-up of 46.1 months, 15 (out of 106, 14.2%) death events were observed in the Ibr+Ven arm versus 30 (out of 105, 28.6%) death events in the Clb+Ob arm. This corresponds to a HR of 0.487 (95% CI: 0.262, 0.907) and a nominal p=0.0205.
Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 49.1% (52/106) by NGS assay and 54.7% (58/106) by flow cytometry in patients treated with Imbruvica plus venetoclax and, at the corresponding time point, was 12.4% (13/105) by NGS assay and 16.2% (17/105) by flow cytometry in patients treated with chlorambucil plus obinutuzumab.
TLS was reported in 6 patients treated with chlorambucil plus obinutuzumab and no TLS was reported in Imbruvica in combination with venetoclax as the study protocol included a specific tumour lysis syndrome management strategy.

Study PCYC-1142-CA (CAPTIVATE).

A Phase 2, multi-centre, 2-cohort study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with Imbruvica in combination with venetoclax, was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL. The study enrolled 323 patients, of these, 159 patients were enrolled to fixed duration therapy consisting of 3 cycles of single agent Imbruvica followed by Imbruvica in combination with venetoclax for 12 cycles (including 5-week dose ramp-up). Each cycle was 28 days. Imbruvica was administered at a dose of 420 mg daily. Venetoclax was administered daily, starting with 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg. Patients with confirmed progression by IWCLL criteria after completion of the fixed duration regimen could be retreated with single-agent Imbruvica, and 9 patients received this treatment.
The median age was 60 years (range, 33 to 71 years), 67% were male, and 92% were White. All patients had a baseline ECOG performance status of 0 (69%) or 1 (31%). The trial enrolled 146 patients with CLL and 13 patients with SLL. At baseline, 13% of patients had CLL/SLL with del17p, 18% with del11q, 17% with del17p/TP53 mutation, 56% with unmutated IGHV and 19% with complex karyotype. The most common reasons for initiating CLL therapy included: lymphadenopathy (65%), progressive lymphocytosis (51%), splenomegaly (30%), fatigue (24%), progressive marrow failure demonstrated by anemia and/or thrombocytopenia (23%), and night sweats (21%). At baseline assessment for risk of tumour lysis syndrome, 21% of patients had high tumour burden. After 3 cycles of single-agent Imbruvica lead-in therapy, 1% of patients had high tumour burden. High tumour burden was defined as any lymph node ≥ 10 cm, or any lymph node ≥ 5 cm and absolute lymphocyte count ≥ 25 x 109/L.
With a median follow-up time on study of 28 months, efficacy results for PCYC-1142-CA assessed by an IRC according to IWCLL criteria and rates of minimal residual disease (MRD) negativity are described below for patients with or without del17p/TP53 mutation.

CLL/SLL without del17p/TP53 in PCYC-1142-CA.

In patients without del17p/TP53 mutation (n=136) the overall response rate based on IRC assessment was 95.6%; complete response rate was 61.0% and the median duration of complete response was not reached (range, 0.03 to 24.9 months). The MRD negativity rate in patients without del17p/TP53 mutation 3 months after completion of treatment in bone marrow and peripheral blood was 54.4% and 57.4%, respectively.

CLL/SLL with del17p/TP53 in PCYC-1142-CA.

In patients with del17p/TP53 mutation (n = 27) the overall response rate based on IRC assessment was 96.3%; complete response rate was 55.6% and the median duration of complete response was not reached (range, 4.3 to 22.6 months). The MRD negativity rate in patients with del17p/TP53 mutation 3 months after completion of treatment in bone marrow and peripheral blood was 40.7% and 59.3%, respectively.
At this assessment, 84 patients who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 76 patients (90%) were MRD negative in both peripheral blood and bone marrow.
In the fixed duration cohort, no TLS was reported in patients treated with Imbruvica in combination with venetoclax.
Patients with CLL/SLL who received at least one prior therapy. Single agent.

PCYC-1102-CA.

An open label, multi-centre study included 51 CLL/SLL patients with CLL/SLL who had relapsed or refractory disease and received 420 mg of ibrutinib once daily. Ibrutinib was administered until disease progression or unacceptable toxicity. The median age was 68 (range, 37 to 82 years), median time since diagnosis was 80 months, and median number of prior treatments was 4 (range, 1 to 12 treatments), including 92.2% with a prior nucleoside analog, 98.0% with prior rituximab, 86.3% with a prior alkylating agent, 39.2% with prior bendamustine and 19.6% with prior ofatumumab. At study entry, 54.9% of patients had Rai Stage III or IV, 45.1% had bulky disease (≥ 5 cm), 35.3% had del17p, 31.4% had del11q.
ORR was investigator-assessed according to the 2008 International Workshop on CLL (IWCLL) criteria. At a median duration of follow up of 16.4 months, responses to Imbruvica for the 51 patients are shown in Table 13.
The efficacy data were further evaluated using IWCLL criteria by an independent review committee (IRC), demonstrating an ORR of 64.7% (95% CI: 50.1%, 77.6%), all partial responses. The DOR ranged from 3.9 to 24.2+ months. The median DOR was not reached.

PCYC 1112-CA (RESONATE).

A randomized, multi-centre, open-label Phase 3 study of ibrutinib versus ofatumumab was conducted in patients with CLL/SLL. Patients (n = 391) were randomized 1:1 to receive either ibrutinib 420 mg daily until disease progression or unacceptable toxicity, or ofatumumab for up to 12 doses (300/2000 mg). Fifty-seven (n = 57) patients randomized to ofatumumab crossed over following progression to receive ibrutinib. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumour ≥ 5 cm. Thirty-two percent (32%) of patients had deletion 17p (with 50% of patients having deletion 17p/TP53 mutation), 24% had 11q deletion, and 47% of patients had unmutated IGHV.
Progression free survival (PFS) as assessed by independent review committee (IRC) according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression for patients in the ibrutinib arm. The results from investigator and IRC assessments for PFS were consistent. Analysis of OS demonstrated a 57% statistically significant reduction in the risk of death for patients in the ibrutinib arm. Efficacy results for Study PCYC 1112 CA are shown in Table 14.
The Kaplan-Meier curves for PFS and OS are shown in Figures 9 and 10, respectively.
The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Figure 11).

Overall follow-up of 63 months (median of 56 months).

With an overall follow-up of 63 months (median of 56 months) in Study PCYC-1112-CA, an 86% reduction in the risk of death or progression by investigator assessment was observed for patients in the Imbruvica arm. The median investigator-assessed PFS according to IWCLL criteria was 44.1 months [95% CI (38.54, 56.87)] in the Imbruvica arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR = 0.14 [95% CI (0.11, 0.19)]. The updated Kaplan-Meier curve for PFS is shown in Figure 12. The investigator-assessed ORR in the Imbruvica arm was 87.2% versus 22.4% in the ofatumumab arm. At the time of long-term follow-up, 133 (67.9%) of the 196 subjects originally randomized to the ofatumumab treatment arm had crossed over to ibrutinib treatment. The Kaplan-Meier landmark estimate for OS at 60-months was 62.2% in the Imbruvica arm.
The treatment effect of ibrutinib in Study PCYC-1112-CA was consistent across high-risk patients with del17p/TP53 mutation, del11q, and/or unmutated IGHV.
Combination therapy.

CLL3001 (HELIOS).

The safety and efficacy of Imbruvica in patients previously treated for CLL/SLL were further evaluated in a randomized, multicentre, double-blinded Phase 3 study of Imbruvica in combination with BR versus placebo + BR. Patients (n = 578) were randomized 1:1 to receive either Imbruvica 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on cycle 1, days 2 and 3, and on cycles 2 6, days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, day 1, and 500 mg/m2 cycles 2 through 6, day 1.
Ninety patients randomized to placebo + BR crossed over to receive Imbruvica following IRC confirmed progression. The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumour > 5 cm, 26% presented with del11q, and 72% had unmutated IGHV.
Progression free survival (PFS) as assessed by IRC according to IWCLL criteria indicated an 80% statistically significant reduction in the risk of death or progression. Efficacy results for Study CLL3001 are shown in Table 15 and the Kaplan-Meier curves for PFS are shown in Figure 13.

Waldenstrom's macroglobulinemia (WM).

The safety and efficacy of Imbruvica in WM (IgM excreting lymphoplasmacytic lymphoma) were evaluated in one single-arm and one randomized, controlled study.

PCYC-1118E.

An open-label, multicentre, single arm trial (PCYC-1118E) was conducted in 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL), and 60% of patients were anaemic (haemoglobin ≤ 11 g/dL).
Imbruvica was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR were assessed using criteria adopted from the Third International Workshop of Waldenstrom's Macroglobulinemia. Responses to Imbruvica are shown in Table 16.
The median time to response was 1.0 month (range: 0.7-13.4 months).
Efficacy results were also assessed by an IRC demonstrating an ORR of 82.5%, with a 11% VGPR rate and a 51% PR rate.

PCYC-1127-CA (iNNOVATE).

A randomised, multicentre, double-blinded phase 3 study of Imbruvica in combination with rituximab versus placebo in combination with rituximab (PCYC-1127-CA) was conducted in patients with treatment-naïve or previously treated WM. Patients (n = 150) were randomised 1:1 to receive either Imbruvica 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).
The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 55% of patients were previously treated. The median time since diagnosis was 52.6 months (treatment-naïve patients = 6.5 months and previously treated patients = 94.3 months). Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were anaemic (haemoglobin ≤ 11 g/dL) and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.
Progression free survival (PFS) as assessed by IRC indicated an 80% statistically significant reduction in the risk of death or progression. Efficacy results for Study PCYC-1127-CA are shown in Table 17 and the Kaplan-Meier curve for PFS is shown in Figure 14. PFS hazard ratios for treatment-naïve patients, previously treated patients, and patients with or without MYD88 L265P mutations were consistent with the PFS hazard ratio for the ITT population.
Tumor flare in the form of IgM increase occurred in 8.0% of subjects in the Imbruvica + rituximab arm and 46.7% of subjects in the placebo + rituximab arm.
Study PCYC-1127-CA had a separate monotherapy arm of 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single agent Imbruvica. The median age was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The median number of prior treatments was 4 (range, 1 to 7 treatments). The response rate per IRC observed in the monotherapy arm was 71% (0% CR, 29% VGPR, 42% PR). The overall response rate per IRC observed in the monotherapy arm was 87% (0% CR, 29% VGPR, 42% PR, 16% MR). With a median follow-up time on study of 34 months (range, 8.6+ to 37.7 months), the median duration of response has not been reached. Median PFS per IRC assessment was not reached (95% CI: 27.4, NE); the 30-month landmark estimate was 57.5% (95% CI: 38.2, 72.7).

5.2 Pharmacokinetic Properties

Absorption.

Ibrutinib is rapidly absorbed after oral administration with a median Tmax of 1 to 2 hours. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 - 3.9) and doubled when combined with a meal. Pharmacokinetics of ibrutinib does not significantly differ in patients with different B cell malignancies. Ibrutinib exposure increases with doses up to 840 mg. The steady state AUC observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 nanogram.h/mL. Administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

Distribution.

Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 nanogram/mL. The apparent volume of distribution at steady state (Vd,ss/F) is approximately 10,000 L.

Metabolism.

Ibrutinib is metabolised primarily by cytochrome P450, CYP3A4, to produce a prominent dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Systemic steady state exposure to the dihydrodiol metabolite is comparable to that of the parent drug.
In vitro studies indicated that CYP2D6 involvement in ibrutinib oxidative metabolism is < 2%. Moreover, as part of the human mass balance study, two subjects genotyped as poor metabolisers for CYP2D6, showed a similar pharmacokinetic profile as extensive metabolisers. Therefore, no precautions are necessary in patients with different CYP2D6 genotypes.

Elimination.

Apparent clearance (CL/F) is approximately 1000 L/h. The half-life of ibrutinib is 4 to 6 hours.
After a single oral administration of radiolabeled [14C] ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the faeces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in faeces and none in urine, with the remainder of the dose being metabolites.

Additional information on special populations.

Paediatrics (18 years of age and younger).

No pharmacokinetic studies were performed with Imbruvica in patients under 18 years of age.

Elderly (65 years of age and older).

Population pharmacokinetics indicated that in older patients (67 to 81 years), a 14% higher ibrutinib exposure is predicted. Dose adjustment by age is not warranted.

Renal impairment.

Ibrutinib has minimal renal clearance; urinary excretion of metabolites is < 10% of the dose. No specific clinical studies have been conducted to date in subjects with impaired renal function. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically. There are no data in patients with severe renal impairment or patients on dialysis.

Hepatic impairment.

Ibrutinib is metabolized in the liver. In a dedicated hepatic impairment study in non cancer patients administered a single dose of 140 mg of Imbruvica, preliminary data showed an approximate 4, 8, and 9-fold increase in ibrutinib exposure in subjects with mild (n = 6), moderate (n = 10) and severe (n = 8) hepatic impairment, respectively. The free fraction of ibrutinib also increased with degree of impairment, with 3.0, 3.8 and 4.8% in subjects with mild, moderate and severe liver impairment, respectively, compared to 3.3% in plasma from matched healthy controls within this study. An increase in unbound ibrutinib exposure is estimated to be 4, 9, and 13-fold in subjects with mild, moderate, and severe hepatic impairment, respectively.

Gender.

Population pharmacokinetics data indicated that gender does not significantly influence ibrutinib clearance from the circulation.

Race.

There are insufficient data to evaluate the potential effect of race on ibrutinib pharmacokinetics.

Body weight.

Population pharmacokinetics data indicated that bodyweight (range: 41-146 kg; mean [SD]: 83 (19) kg) had a negligible effect on ibrutinib clearance.

Co-administration with transporter substrates/inhibitors.

In vitro studies indicated that ibrutinib is not a substrate of P-gp, nor other major transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P-gp substrates. Ibrutinib is an in vitro inhibitor of OCT2, P-gp and BCRP (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

Ibrutinib has no genotoxic properties when tested for mutagenicity in bacteria or clastogenicity in in vitro assays (chromosomal aberration in Chinese hamster ovary cells) or in vivo (mouse micronucleus test).

Carcinogenicity.

Ibrutinib was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse at oral doses up to 2000 mg/kg/day resulting in exposures approximately 23 (males) to 37 (females) times higher than the exposure in humans at a dose of 560 mg daily based on plasma AUC.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsules.

Each ibrutinib capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate.
The capsule shell contains: gelatin, Opacode monogramming ink S-1-17822 black (ARTG PI No: 12390), Opacode monogramming ink S-1-17823 black (ARTG PI No: 12108).

Film-coated tablets.

Each ibrutinib tablet also contains the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate.
The film-coating contains: Opadry II Complete Film Coating System 85F210036 green (140 mg tablets, 420 mg tablets) (ARTG PI No. 112970), Opadry II Complete Film Coating System 85F200011 purple (280 mg tablets) (ARTG PI No. 119906), Opadry II Complete Film Coating System 85F32547 yellow (560 mg tablets) (ARTG PI No. 119892).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Capsules.

Imbruvica 140 mg ibrutinib capsules are supplied in a white high-density polyethylene (HDPE) bottle with a child resistant closure.
Each HDPE bottle with a polypropylene closure contains 90 or 120 hard capsules.

Film-coated tablets.

Imbruvica film-coated tablets are supplied in two polyvinyl chloride (PVC) laminated with polychlorotrifluoroethylene (PCTFE)/ aluminum push-through blisters of 5 film-coated tablets in a cardboard wallet.
The pack sizes are cartons of 30 film-coated tablets (3 cardboard wallets containing 10 film-coated tablets each).
Not all presentations 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.


The chemical name of the ibrutinib is 1 [(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]- 1-piperidinyl]-2-propen-1-one.
Molecular formula: C25H24N6O2. Molecular weight: 440.50.

CAS number.

936563-96-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes