ibrutinib: package leaflet

What IMBRUVICA is
IMBRUVICA is an anticancer medicine that contains the active substance ibrutinib. It belongs to a class of medicines called protein kinase inhibitors.
What IMBRUVICA is used for
It is used to treat the following blood cancers in adults:

Mantle cell lymphoma (MCL), a type of cancer affecting the lymph nodes. IMBRUVICA is used in patients who have not previously been treated for MCL, and for whom blood stem cell transplant would be suitable, or when the disease has come back or has not responded to treatment.

Chronic lymphocytic leukaemia (CLL) a type of cancer affecting white blood cells called lymphocytes that also involves the lymph nodes. IMBRUVICA is used in patients who have not previously been treated for CLL or when the disease has come back or has not responded to treatment.

Waldenström’s macroglobulinaemia (WM), a type of cancer affecting white blood cells called lymphocytes. It is used in patients who have not previously been treated for WM or when the disease has come back or has not responded to treatment or in patients for whom chemotherapy given together with an antibody is not a suitable therapy.
How IMBRUVICA works
In MCL, CLL and WM, IMBRUVICA works by blocking Bruton's tyrosine kinase, a protein in the body that helps these cancer cells grow and survive. By blocking this protein, IMBRUVICA helps kill and reduce the number of cancer cells. It also slows down the worsening of the cancer.

Do not take IMBRUVICA
 if you are allergic to ibrutinib or any of the other ingredients of this medicine (listed in section 6)  if you are taking a herbal medicine called St. John’s Wort, used for depression. If you are not sure about this, talk to your doctor, pharmacist or nurse before taking this medicine.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking IMBRUVICA:
 if you have ever had unusual bruising or bleeding or are on any medicines or supplements that increase your risk of bleeding (see section “Other medicines and IMBRUVICA”)  if you have irregular heart beat or have a history of irregular heart beat or severe heart failure, or if you feel any of the following: shortness of breath, weakness, dizziness, light-headedness, fainting or near fainting, chest pain or swollen legs  if you have liver problems, including if you ever had or now have a hepatitis B infection (a liver infection)  if you have high blood pressure  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 (3 to 7 days) before and after your surgery  if you have kidney problems.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before or while taking this medicine (see section “Possible side effects”).
When taking IMBRUVICA, tell your doctor immediately if you notice or someone notices in you:
memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a rare but serious brain infection which can be fatal (Progressive Multifocal Leukoencephalopathy or PML) (see section “Possible side effects”).
Tell your doctor immediately if you notice or someone notices in you: sudden numbness or weakness in the limbs (especially on one side of the body), sudden confusion, trouble speaking or understanding speech, sight loss, difficulty walking, loss of balance or lack of coordination, sudden severe headache with no known cause. These may be signs and symptoms of stroke.
Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder (these may be symptoms of rupture of the spleen) after you stop taking IMBRUVICA.
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, have diabetes or are of advanced age. 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.
Infections
You may experience viral, bacterial, or fungal infections during treatment with IMBRUVICA. Contact your doctor if you have fever, chills, weakness, confusion, body aches, cold or flu symptoms, feel tired or feel short of breath, yellowing of the skin or eyes (jaundice). These could be signs of an infection.
Haemophagocytic lymphohistiocytosis
There have been rare reports of excessive activation of white blood cells associated with inflammation (haemophagocytic lymphohistiocytosis), 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.
Tests and check-ups before and during treatment
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 and sometimes 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.
Lymphocytosis: Laboratory tests may show an increase in white blood cells (called “lymphocytes”) in your blood 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.
Events related to the liver: Your doctor will do some blood tests to check whether your liver is working properly or that you do not have a liver infection, known as viral hepatitis, or whether hepatitis B has become active again, which could be fatal.
Children and adolescents
IMBRUVICA should not be used in children and adolescents.
Other medicines and IMBRUVICA
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription, herbal medicines and supplements. This is because IMBRUVICA may affect the way some other medicines work. Also some other medicines can affect the way IMBRUVICA works.
IMBRUVICA may make you bleed more easily. This means you should tell your doctor if you take other medicines that increase your risk of bleeding. This includes:
 acetyl salicylic acid and non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen or naproxen  blood thinners such as warfarin, heparin or other medicines for blood clots  supplements that may increase your risk of bleeding such as fish oil, vitamin E or flaxseed.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking IMBRUVICA.
Also tell your doctor if you take any of the following medicines – The effects of IMBRUVICA or other medicines may be influenced if you take IMBRUVICA together with any of the following medicines:
 medicines called antibiotics to treat bacterial infections – clarithromycin, telithromycin, ciprofloxacin, erythromycin or rifampicin  medicines for fungal infections – posaconazole, ketoconazole, itraconazole, fluconazole or voriconazole  medicines for HIV infection – ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, or fosamprenavir  medicines to prevent nausea and vomiting associated with chemotherapy - aprepitant  medicines for depression - nefazodone  medicines called kinase inhibitors for treatment of other cancers – crizotinib or imatinib  medicines called calcium channel blockers for high blood pressure or chest pain – diltiazem or verapamil  medicines called statins to treat high cholesterol - rosuvastatin  heart medicines/anti-arrhythmics – amiodarone or dronedarone  medicines to prevent seizures or to treat epilepsy, or medicines to treat a painful condition of the face called trigeminal neuralgia – carbamazepine or phenytoin.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking IMBRUVICA.

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.
IMBRUVICA with food
Do not take IMBRUVICA with grapefruit or Seville oranges (bitter oranges) – this includes eating them, drinking the juice or taking a supplement that might contain them. This is because it can increase the amount of IMBRUVICA in your blood.
Pregnancy and breast-feeding
Do not get pregnant while you are taking this medicine. IMBRUVICA should not be used during pregnancy. There is no information about the safety of IMBRUVICA in pregnant women.
Women of childbearing age must use a highly effective method of birth control during and up to three months after receiving IMBRUVICA, to avoid becoming pregnant while being treated with IMBRUVICA.

Tell your doctor immediately if you become pregnant.

Do not breast-feed while you are taking this medicine.
Driving and using machines
You may feel tired or dizzy after taking IMBRUVICA, which may affect your ability to drive or use any tools or machines.
IMBRUVICA contains sodium
IMBRUVICA contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.
How much to take
Mantle cell lymphoma (MCL)
The recommended dose of IMBRUVICA is four capsules (560 mg) once a day.
Chronic lymphocytic leukaemia (CLL)/Waldenström’s macroglobulinaemia (WM)
The recommended dose of IMBRUVICA is three capsules (420 mg) once a day.
Your doctor may adjust your dose.
Taking this medicine

Take the capsules orally (by mouth) with a glass of water.

Take the capsules about the same time each day.

Swallow the capsules whole. Do not open, break or chew them.
If you take more IMBRUVICA than you should
If you take more IMBRUVICA than you should, talk to a doctor or go to a hospital straight away.
Take the capsules and this leaflet with you.
If you forget to take IMBRUVICA

If you miss a dose, it can be taken as soon as possible on the same day with a return to the normal schedule the following day.

Do not take a double dose to make up for a forgotten dose.

If you are not sure, talk to your doctor, pharmacist or nurse about when to take your next dose.

If you stop taking IMBRUVICA
Do not stop taking this medicine unless your doctor tells you.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects may happen with this medicine:
Stop taking IMBRUVICA and tell a doctor straight away if you notice any of the following side effects:
itchy bumpy rash, difficulty breathing, swelling of your face, lips, tongue or throat – you may be having an allergic reaction to the medicine.
Tell a doctor straight away if you notice any of the following side effects:
Patients treated with IMBRUVICA for B-cell malignancies:
Very common (may affect more than 1 in 10 people)
 fever, chills, body aches, feeling tired, cold or flu symptoms, being short of breath – these could be signs of an infection (viral, bacterial or fungal). These could include infections of the nose, sinus or throat (upper respiratory tract infection), or lung, or skin  blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury  bruising or increased tendency of bruising  mouth sores  cough  feeling dizzy  headache  constipation  feeling or being sick (nausea or vomiting)  indigestion  diarrhoea, your doctor may need to give you a fluid and salt replacement or another medicine  skin rash  painful arms or legs  back pain or joint pain  muscle cramps, aches or spasms  fever  low number of cells that help blood clot (platelets), very low number of white blood cells – shown in blood tests  an increase in the number or proportion of white blood cells shown in blood tests  swollen hands, ankles or feet  high blood pressure  increased level of “creatinine” in the blood.
Common (may affect up to 1 in 10 people)
 severe infections throughout the body (sepsis)
 infections of the urinary tract
 nose bleeds, small red or purple spots caused by bleeding under the skin
 heart failure
 missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)  low white blood cell counts with fever (febrile neutropenia)

 non-melanoma skin cancer, most frequently squamous cell and basal cell skin cancer  blurred vision  redness of the skin  inflammation within the lungs that may lead to permanent damage  high level of “uric acid” in the blood (shown in blood tests), which may cause gout  breaking of the nails  hives  sudden kidney damage  weakness, numbness, tingling or pain in your hands or feet or other parts of the body (peripheral neuropathy).
Uncommon (may affect up to 1 in 100 people)
 liver failure, including events with fatal outcome
 severe fungal infections

‘reactivation’ of hepatitis B (if you had previously had hepatitis B, it may come back)  bleeding on the surface of the brain  confusion, headache with slurred speech or feeling faint – these could be signs of serious internal bleeding in your brain  unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)  allergic reaction, sometimes severe, that may include a swollen face, lip, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives)  inflammation of the fatty tissue underneath the skin  temporary episode of decreased brain or nerve function caused by loss of blood flow, stroke  bleeding in the eye (in some cases associated with loss of vision)  inflammation inside the eye that may affect vision (uveitis)  cardiac arrest (heart stops beating)  abnormally fast heart beat  painful skin ulceration (pyoderma gangrenosum) or red, raised painful patches on the skin, fever and an increase in white blood cells (these may be signs of acute febrile neutrophilic dermatosis or Sweet’s syndrome)  small, red bump on the skin that may bleed easily (pyogenic granuloma)  inflamed blood vessels in the skin, which may lead to a rash (cutaneous vasculitis).
Rare (may affect up to 1 in 1 000 people)
 severely increased white blood cell count that may cause cells to clump together  severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome)  memory loss, trouble thinking, difficulty walking or sight loss - these may be signs of a serious brain infection (Progressive Multifocal Leukoencephalopathy or PML).
Patients treated with IMBRUVICA for previously untreated MCL
Very common (may affect more than 1 in 10 people)
 low number of cells that help blood clot (platelets), very low number of white blood cells – shown in blood tests  low white blood cell counts with fever (febrile neutropenia)  feeling or being sick (nausea or vomiting)  diarrhoea, your doctor may need to give you a fluid and salt replacement or another medicine  mouth sores  constipation  fever

 fever, chills, body aches, feeling tired, cold or flu symptoms, being short of breath – these could be signs of an infection (viral, bacterial or fungal). These could include infections of the lung, or skin  increased level of “creatinine” in the blood  painful arms or legs  weakness, numbness, tingling or pain in your hands or feet or other parts of the body (peripheral neuropathy).
 headache
 sudden kidney damage
 skin rash
 blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury  high blood pressure.
Common (may affect up to 1 in 10 people)
 increased white blood cell count
 infections of the nose, sinus or throat (upper respiratory tract infection)
 missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)  heart failure  indigestion  swollen hands, ankles or feet  inflammation within the lungs that may lead to permanent damage  severe infections throughout the body (sepsis)  infections of the urinary tract  high level of “uric acid” in the blood (shown in blood tests), which may cause gout  unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)  muscle cramps, aches or spasms  back pain or joint pain  non‑melanoma skin cancer, including basal cell skin cancer  feeling dizzy  redness of the skin  breaking of the nails  hives  bruising or increased tendency of bruising  nose bleeds, small red or purple spots caused by bleeding under the skin.
Uncommon (may affect up to 1 in 100 people)
 blurred vision
 severe fungal infections
 bleeding in the eye
 temporary episode of decreased brain or nerve function caused by loss of blood flow, stroke  allergic reaction, sometimes severe, that may include a swollen face, lip, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives)  inflamed blood vessels in the skin, which may lead to a rash (cutaneous vasculitis)  inflammation of the fatty tissue underneath the skin.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and bottle label after EXP.
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What IMBRUVICA contains

The active substance is ibrutinib. Each hard capsule contains 140 mg of ibrutinib.

The other ingredients are:
- capsule content: croscarmellose sodium, magnesium stearate, microcrystalline cellulose and sodium lauril sulfate (E487)
- capsule shell: gelatin and titanium dioxide (E171)
- printing ink: shellac, black iron oxide (E172), and propylene glycol (E1520).
What IMBRUVICA looks like and contents of the pack
IMBRUVICA are white opaque, hard capsules marked with “ibr 140 mg” in black ink on one side.
The capsules are provided in a plastic bottle with a child resistant polypropylene closure. Each bottle contains either 90 or 120 capsules. Each pack contains one bottle.
Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
Janssen-Cilag SpA
Via C. Janssen
Loc. Borgo S. Michele
04100 Latina
Italy
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: 0800 93 377 info_belux@its.jnj.com
Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88 lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00 jjsafety@its.jnj.com
Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: 800 29 504 info_belux@its.jnj.com
Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227
Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858 janssenhu@its.jnj.com
Danmark
Janssen-Cilag A/S
Tlf.: +45 4594 8282 jacdk@its.jnj.com
Malta
AM MANGION LTD
Tel: +356 2397 6000
Deutschland
Janssen-Cilag GmbH
Tel: 0800 086 9247 / +49 2137 955 6955 medinfo-de@its.jnj.com
Nederland
Janssen-Cilag B.V.
Tel: 0800 242 42 42 info_nl@its.jnj.com
Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410 ee@its.jnj.com
Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00 jacno@its.jnj.com
Ελλάδα
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη
Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000
Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300
España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00 contacto@its.jnj.com
Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00
France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 medisource@its.jnj.com
Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600
Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700 jjsafety@JNJCR.JNJ.com
România
Johnson & Johnson România SRL
Tel: +40 21 207 1800
Ireland
Janssen Sciences Ireland UC
Tel: 1 800 709 122 medinfo@its.jnj.com
Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
JNJ-SI-safety@its.jnj.com
Ísland
Janssen-Cilag AB c/o Vistor ehf.
Sími: +354 535 7000 janssen@vistor.is
Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800 688 777 / +39 02 2510 1 janssenita@its.jnj.com
Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300 jacfi@its.jnj.com
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700
Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00 jacse@its.jnj.com
Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561 lv@its.jnj.com
This leaflet was last revised in
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

What IMBRUVICA is
IMBRUVICA is an anticancer medicine that contains the active substance ibrutinib. It belongs to a class of medicines called protein kinase inhibitors.
What IMBRUVICA is used for
It is used to treat the following blood cancers in adults:

Mantle cell lymphoma (MCL), a type of cancer affecting the lymph nodes. IMBRUVICA is used in patients who have not previously been treated for MCL, and for whom blood stem cell transplant would be suitable, or when the disease has come back or has not responded to treatment.

Chronic lymphocytic leukaemia (CLL) a type of cancer affecting white blood cells called lymphocytes that also involves the lymph nodes. IMBRUVICA is used in patients who have not previously been treated for CLL or when the disease has come back or has not responded to treatment.

Waldenström’s macroglobulinaemia (WM), a type of cancer affecting white blood cells called lymphocytes. It is used in patients who have not previously been treated for WM or when the disease has come back or has not responded to treatment or in patients for whom chemotherapy given together with an antibody is not a suitable therapy.
How IMBRUVICA works
In MCL, CLL and WM, IMBRUVICA works by blocking Bruton's tyrosine kinase, a protein in the body that helps these cancer cells grow and survive. By blocking this protein, IMBRUVICA helps kill and reduce the number of cancer cells. It also slows down the worsening of the cancer.

Do not take IMBRUVICA
 if you are allergic to ibrutinib or any of the other ingredients of this medicine (listed in section 6)  if you are taking a herbal medicine called St. John’s Wort, used for depression. If you are not sure about this, talk to your doctor, pharmacist or nurse before taking this medicine.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking IMBRUVICA:
 if you have ever had unusual bruising or bleeding or are on any medicines or supplements that increase your risk of bleeding (see section “Other medicines and IMBRUVICA”)  if you have irregular heart beat or have a history of irregular heart beat or severe heart failure, or if you feel any of the following: shortness of breath, weakness, dizziness, light-headedness, fainting or near fainting, chest pain or swollen legs  if you have liver problems, including if you ever had or now have a hepatitis B infection (a liver infection)  if you have high blood pressure  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 (3 to 7 days) before and after your surgery  if you have kidney problems.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before or while taking this medicine (see section “Possible side effects”).
When taking IMBRUVICA, tell your doctor immediately if you notice or someone notices in you:
memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a rare but serious brain infection which can be fatal (Progressive Multifocal Leukoencephalopathy or PML) (see section “Possible side effects”.
Tell your doctor immediately if you notice or someone notices in you: sudden numbness or weakness in the limbs (especially on one side of the body), sudden confusion, trouble speaking or understanding speech, sight loss, difficulty walking, loss of balance or lack of coordination, sudden severe headache with no known cause. These may be signs and symptoms of stroke.
Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder (these may be symptoms of rupture of the spleen) after you stop taking IMBRUVICA.
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, have diabetes or are of advanced age. 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.
Infections
You may experience viral, bacterial, or fungal infections during treatment with IMBRUVICA. Contact your doctor if you have fever, chills, weakness, confusion, body aches, cold or flu symptoms, feel tired or feel short of breath, yellowing of the skin or eyes (jaundice). These could be signs of an infection.
Haemophagocytic lymphohistiocytosis
There have been rare reports of excessive activation of white blood cells associated with inflammation (haemophagocytic lymphohistiocytosis), 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.
Tests and check-ups before and during treatment
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 and sometimes 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.
Lymphocytosis: Laboratory tests may show an increase in white blood cells (called “lymphocytes”) in your blood 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.
Events related to the liver: Your doctor will do some blood tests to check whether your liver is working properly or that you do not have a liver infection, known as viral hepatitis, or whether hepatitis B has become active again, which could be fatal.
Children and adolescents
IMBRUVICA should not be used in children and adolescents.
Other medicines and IMBRUVICA
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription, herbal medicines and supplements. This is because IMBRUVICA may affect the way some other medicines work. Also some other medicines can affect the way IMBRUVICA works.
IMBRUVICA may make you bleed more easily. This means you should tell your doctor if you take other medicines that increase your risk of bleeding. This includes:
 acetyl salicylic acid and non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen or naproxen  blood thinners such as warfarin, heparin or other medicines for blood clots  supplements that may increase your risk of bleeding such as fish oil, vitamin E or flaxseed.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking IMBRUVICA.
Also tell your doctor if you take any of the following medicines – The effects of IMBRUVICA or other medicines may be influenced if you take IMBRUVICA together with any of the following medicines:
 medicines called antibiotics to treat bacterial infections – clarithromycin, telithromycin, ciprofloxacin, erythromycin or rifampicin  medicines for fungal infections – posaconazole, ketoconazole, itraconazole, fluconazole or voriconazole  medicines for HIV infection – ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, or fosamprenavir  medicines to prevent nausea and vomiting associated with chemotherapy - aprepitant  medicines for depression - nefazodone  medicines called kinase inhibitors for treatment of other cancers – crizotinib or imatinib  medicines called calcium channel blockers for high blood pressure or chest pain – diltiazem or verapamil  medicines called statins to treat high cholesterol - rosuvastatin  heart medicines/anti-arrhythmics – amiodarone or dronedarone  medicines to prevent seizures or to treat epilepsy, or medicines to treat a painful condition of the face called trigeminal neuralgia – carbamazepine or phenytoin.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking IMBRUVICA.
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.
IMBRUVICA with food
Do not take IMBRUVICA with grapefruit or Seville oranges (bitter oranges) – this includes eating them, drinking the juice or taking a supplement that might contain them. This is because it can increase the amount of IMBRUVICA in your blood.
Pregnancy and breast-feeding
Do not get pregnant while you are taking this medicine. IMBRUVICA should not be used during pregnancy. There is no information about the safety of IMBRUVICA in pregnant women.
Women of childbearing age must use a highly effective method of birth control during and up to three months after receiving IMBRUVICA, to avoid becoming pregnant while being treated with IMBRUVICA.

Tell your doctor immediately if you become pregnant.

Do not breast-feed while you are taking this medicine.
Driving and using machines
You may feel tired or dizzy after taking IMBRUVICA, which may affect your ability to drive or use any tools or machines.
IMBRUVICA contains lactose
IMBRUVICA contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
IMBRUVICA contains sodium
IMBRUVICA contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.
How much to take
Mantle cell lymphoma (MCL)
The recommended dose of IMBRUVICA is 560 mg once a day.
Chronic lymphocytic leukaemia (CLL)/Waldenström’s macroglobulinaemia (WM)
The recommended dose of IMBRUVICA is 420 mg once a day.
Your doctor may adjust your dose.
Taking this medicine

Take the tablets orally (by mouth) with a glass of water.

Take the tablets about the same time each day.

Swallow the tablets whole. Do not break or chew them.

If you take more IMBRUVICA than you should
If you take more IMBRUVICA than you should, talk to a doctor or go to a hospital straight away.
Take the tablets and this leaflet with you.
If you forget to take IMBRUVICA

If you miss a dose, it can be taken as soon as possible on the same day with a return to the normal schedule the following day.

Do not take a double dose to make up for a forgotten dose.

If you are not sure, talk to your doctor, pharmacist or nurse about when to take your next dose.
If you stop taking IMBRUVICA
Do not stop taking this medicine unless your doctor tells you.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects may happen with this medicine:
Stop taking IMBRUVICA and tell a doctor straight away if you notice any of the following side effects:
itchy bumpy rash, difficulty breathing, swelling of your face, lips, tongue or throat – you may be having an allergic reaction to the medicine.
Tell a doctor straight away if you notice any of the following side effects:
Patients treated with IMBRUVICA for B-cell malignancies:
Very common (may affect more than 1 in 10 people)
 fever, chills, body aches, feeling tired, cold or flu symptoms, being short of breath – these could be signs of an infection (viral, bacterial or fungal). These could include infections of the nose, sinus or throat (upper respiratory tract infection), or lung, or skin  blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury  bruising or increased tendency of bruising  mouth sores  cough  feeling dizzy  headache  constipation  feeling or being sick (nausea or vomiting)  indigestion  diarrhoea, your doctor may need to give you a fluid and salt replacement or another medicine  skin rash  painful arms or legs  back pain or joint pain  muscle cramps, aches or spasms  fever  low number of cells that help blood clot (platelets), very low number of white blood cells – shown in blood tests  an increase in the number or proportion of white blood cells shown in blood tests  swollen hands, ankles or feet  high blood pressure  increased level of “creatinine” in the blood.

Common (may affect up to 1 in 10 people)
 severe infections throughout the body (sepsis)
 infections of the urinary tract
 nose bleeds, small red or purple spots caused by bleeding under the skin
 heart failure
 missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)  low white blood cell counts with fever (febrile neutropenia)  non-melanoma skin cancer, most frequently squamous cell and basal cell skin cancer  blurred vision  redness of the skin  hives  inflammation within the lungs that may lead to permanent damage  high level of “uric acid” in the blood (shown in blood tests), which may cause gout  breaking of the nails  sudden kidney damage  weakness, numbness, tingling or pain in your hands or feet or other parts of the body (peripheral neuropathy).
Uncommon (may affect up to 1 in 100 people)
 liver failure, including events with fatal outcome
 severe fungal infections

‘reactivation’ of hepatitis B (if you had previously had hepatitis B, it may come back)  bleeding on the surface of the brain  confusion, headache with slurred speech or feeling faint – these could be signs of serious internal bleeding in your brain  unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)  allergic reaction, sometimes severe, that may include a swollen face, lip, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives)  inflammation of the fatty tissue underneath the skin  temporary episode of decreased brain or nerve function caused by loss of blood flow, stroke  bleeding in the eye (in some cases associated with loss of vision)  inflammation inside the eye that may affect vision (uveitis)  cardiac arrest (heart stops beating)  abnormally fast heart beat  painful skin ulceration (pyoderma gangrenosum) or red, raised painful patches on the skin, fever and an increase in white blood cells (these may be signs of acute febrile neutrophilic dermatosis or Sweet’s syndrome)  small, red bump on the skin that may bleed easily (pyogenic granuloma)  inflamed blood vessels in the skin, which may lead to a rash (cutaneous vasculitis).
Rare (may affect up to 1 in 1 000 people)
 severely increased white blood cell count that may cause cells to clump together  severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome)  memory loss, trouble thinking, difficulty walking or sight loss - these may be signs of a serious brain infection (Progressive Multifocal Leukoencephalopathy or PML).
Patients treated with IMBRUVICA for previously untreated MCL
Very common (may affect more than 1 in 10 people)
 low number of cells that help blood clot (platelets), very low number of white blood cells – shown in blood tests

 low white blood cell counts with fever (febrile neutropenia)
 feeling or being sick (nausea or vomiting)
 diarrhoea, your doctor may need to give you a fluid and salt replacement or another medicine  mouth sores  constipation  fever  fever, chills, body aches, feeling tired, cold or flu symptoms, being short of breath – these could be signs of an infection (viral, bacterial or fungal). These could include infections of the lung, or skin  increased level of “creatinine” in the blood  painful arms or legs  weakness, numbness, tingling or pain in your hands or feet or other parts of the body (peripheral neuropathy).
 headache
 sudden kidney damage
 skin rash
 blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury  high blood pressure.
Common (may affect up to 1 in 10 people)
 increased white blood cell count
 infections of the nose, sinus or throat (upper respiratory tract infection)
 missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)  heart failure  indigestion  swollen hands, ankles or feet  inflammation within the lungs that may lead to permanent damage  severe infections throughout the body (sepsis)  infections of the urinary tract  high level of “uric acid” in the blood (shown in blood tests), which may cause gout  unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)  muscle cramps, aches or spasms  back pain or joint pain  non‑melanoma skin cancer, including basal cell skin cancer  feeling dizzy  redness of the skin  breaking of the nails  hives  bruising or increased tendency of bruising  nose bleeds, small red or purple spots caused by bleeding under the skin.
Uncommon (may affect up to 1 in 100 people)
 blurred vision
 severe fungal infections
 bleeding in the eye
 temporary episode of decreased brain or nerve function caused by loss of blood flow, stroke  allergic reaction, sometimes severe, that may include a swollen face, lip, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives)  inflamed blood vessels in the skin, which may lead to a rash (cutaneous vasculitis)  inflammation of the fatty tissue underneath the skin.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What IMBRUVICA contains

The active substance is ibrutinib.
- IMBRUVICA 140 mg film-coated tablets: Each tablet contains 140 mg of ibrutinib.
- IMBRUVICA 280 mg film-coated tablets: Each tablet contains 280 mg of ibrutinib.
- IMBRUVICA 420 mg film-coated tablets: Each tablet contains 420 mg of ibrutinib.
- IMBRUVICA 560 mg film-coated tablets: Each tablet contains 560 mg of ibrutinib.

The other ingredients are:

Tablet core: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate (see section 2 “IMBRUVICA contains lactose”), magnesium stearate, microcrystalline cellulose, povidone, sodium lauril sulfate (E487).

Tablet film-coat: polyvinyl alcohol, macrogol, talc, titanium dioxide (E171);
IMBRUVICA 140 mg and IMBRUVICA 420 mg film-coated tablets also contain black iron oxide (E172) and yellow iron oxide (E172);
IMBRUVICA 280 mg film-coated tablets also contain black iron oxide (E172) and red iron oxide (E172);
IMBRUVICA 560 mg film-coated tablets also contain red iron oxide (E172) and yellow iron oxide (E172).
What IMBRUVICA looks like and contents of the pack
IMBRUVICA 140 mg film-coated tablets
Yellow-green to green round (9 mm) tablets, written with “ibr” on one side and “140” on the other side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 10 film-coated tablets each.
IMBRUVICA 280 mg film-coated tablets
Purple oblong (15 mm in length and 7 mm in width), written with “ibr” on one side and “280” on the other side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 10 film-coated tablets each.
IMBRUVICA 420 mg film-coated tablets
Yellow-green to green oblong tablets (17.5 mm in length and 7.4 mm in width), written with “ibr” on one side and “420” on the other side. Each 28 day carton contains 28 film-coated tablets in 2

cardboard wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 10 film-coated tablets each.
IMBRUVICA 560 mg film-coated tablets
Yellow to orange oblong tablets (19 mm in length and 8.1 mm in width), written with “ibr” on one side and “560” on the other side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 10 film-coated tablets each.
Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
Manufacturer
Janssen-Cilag SpA
Via C. Janssen
Loc. Borgo S. Michele
04100 Latina
Italy
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: 0800 93 377 info_belux@its.jnj.com
Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88 lt@its.jnj.com
България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00 jjsafety@its.jnj.com
Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: 800 29 504 info_belux@its.jnj.com
Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227
Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858 janssenhu@its.jnj.com
Danmark
Janssen-Cilag A/S
Tlf.: +45 4594 8282 jacdk@its.jnj.com
Malta
AM MANGION LTD
Tel: +356 2397 6000
Deutschland
Janssen-Cilag GmbH
Tel: 0800 086 9247 / +49 2137 955 6955 medinfo-de@its.jnj.com
Nederland
Janssen-Cilag B.V.
Tel: 0800 242 42 42 info_nl@its.jnj.com
Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410 ee@its.jnj.com
Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00 jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη
Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000
Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300
España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00 contacto@its.jnj.com
Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00
France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 medisource@its.jnj.com
Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600
Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700 jjsafety@JNJCR.JNJ.com
România
Johnson & Johnson România SRL
Tel: +40 21 207 1800
Ireland
Janssen Sciences Ireland UC
Tel: 1 800 709 122 medinfo@its.jnj.com
Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
JNJ-SI-safety@its.jnj.com
Ísland
Janssen-Cilag AB c/o Vistor ehf.
Sími: +354 535 7000 janssen@vistor.is
Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400
Italia
Janssen-Cilag SpA
Tel: 800 688 777 / +39 02 2510 1 janssenita@its.jnj.com
Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300 jacfi@its.jnj.com
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700
Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00 jacse@its.jnj.com
Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561 lv@its.jnj.com
This leaflet was last revised in
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATION(S)

Scientific conclusions
Taking into account the PRAC Assessment Report on the PSUR(s) for ibrutinib, the scientific conclusions of PRAC are as follows:
In view of available data on progressive multifocal leukoencephalopathy (PML) from clinical trials, literature, real-world data sources, spontaneous reports including 3 cases assessed as probably related to ibrutinib therapy and 22 cases assessed as possibly related to ibrutinib and in view of a plausible mechanism of action as well as a potential class effect, the PRAC Rapporteur considers a causal relationship between ibrutinib and PML is at least a reasonable possibility. The PRAC Rapporteur concluded that the product information of products containing ibrutinib should be amended accordingly.
In view of available data on cough from clinical trials, literature, real-world data sources, spontaneous reports including 52 cases with a positive dechallenge and 6 cases with a positive rechallenge and in view of a plausible mechanism of action as well as a potential class effect, the PRAC Rapporteur considers a causal relationship between ibrutinib and cough is at least a reasonable possibility. The PRAC Rapporteur concluded that the product information of products containing ibrutinib should be amended accordingly.
Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions and grounds for recommendation.
Grounds for the variation to the terms of the marketing authorisation(s)
On the basis of the scientific conclusions for ibrutinib the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing ibrutinib is unchanged subject to the proposed changes to the product information.
The CHMP recommends that the terms of the marketing authorisation(s) should be varied.