IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg film-coated tablets

Section 4 has been updated to add cutaneous vasculitis as an uncommon side effect.

Section 4.8 has been updated to add the adverse reaction Cutaneous Vasculitis, with a frequency uncommon.

4.2    Posology and method of administration

 Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

 Posology

MCL

The recommended dose for the treatment of MCL is 560 mg once daily.

 CLL and WM

The recommended dose for the treatment of CLL and WM, either as a single agent or in combination, is 420 mg once daily (for details of the combination regimens, see section 5.1).

 Treatment with IMBRUVICA should continue until disease progression or no longer tolerated by the patient. In combination with venetoclax for the treatment of CLL, IMBRUVICA should be administered as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of IMBRUVICA plus venetoclax. See the venetoclax Summary of Product Characteristics (SmPC) for full venetoclax dosing information.

 When administering IMBRUVICA in combination with anti-CD20 therapy, it is recommended to administer IMBRUVICA prior to anti-CD20 therapy when given on the same day.

 Dose adjustments

Moderate and strong CYP3A4 inhibitors increase the exposure of ibrutinib (see sections 4.4 and 4.5).

 The dose of ibrutinib should be reduced to 280 mg once daily when used concomitantly with moderate CYP3A4 inhibitors.

 The dose of ibrutinib should be reduced to 140 mg once daily or withheld for up to 7 days when it is used concomitantly with strong CYP3A4 inhibitors.

 IMBRUVICA therapy should be withheld for any new onset or worsening grade 2 cardiac failure, grade 3 cardiac arrhythmias, grade ≥3 non‑haematological toxicity, grade 3 or greater neutropenia with infection or fever, or grade 4 haematological toxicities. Once the symptoms of the toxicity have resolved to grade 1 or baseline (recovery), resume IMBRUVICA therapy at the recommended dose as per the tables below.

A FOOTNOTE WAS ADDED HERE FOR THE TABLE

^†    Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for hematologic toxicities in CLL/SLL.

^*    When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the toxicity reoccurs, reduce daily dose by 140 mg.

 Recommended dose modifications for events of cardiac failure or cardiac arrhythmias events are described below:

[....]

__________________________________________________________________________________________________

5.      PHARMACOLOGICAL PROPERTIES

 5.1    Pharmacodynamic properties

[....]

Overall follow-up of 58 months (median of 52 months)

With an overall follow-up of 58 months (median follow-up time on study of 52 months) in Study CLL3011, a 77% reduction in the risk of death or progression by investigator assessment was observed for patients in the IMBRUVICA arm. The overall survival hazard ratio was 0.458 [95% CI (0.257, 0.818), nominal p=0.0068]. There were 17 (16.0%) deaths in the IMBRUVICA plus venetoclax arm and 36 (34.3%) in the chlorambucil plus obinutuzumab arm. Median time to next treatment was not reached for either arm (HR=0.164; 95% CI: 0.081, 0.330) with 9.4% of subjects in the IMBRUVICA plus venetoclax arm and 41.0% of subjects in the chlorambucil plus obinutuzumab arm having initiated subsequent anticancer therapy.

[....]

Kaplan-Meier curve for OS is shown in Figure 9.

Figure 9:   Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with CLL/SLL in Study CLL3011 with 58 Months Follow-up

[....]

A GRAPH WAS ADDED HERE

4.8    Undesirable effects

Pyogenic granuloma <1, 0

Renal and urinary disorders Common Acute kidney injury# <2 <1

10.    DATE OF REVISION OF THE TEXT

 15 September 2023

4.8    Undesirable effects

Pyogenic granuloma <1, 0

Renal and urinary disorders Common Acute kidney injury# <2 <1

10.    DATE OF REVISION OF THE TEXT

 15 September 2023

4.      Possible side effects

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:

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

·               bruising or increased tendency of bruising

·               mouth sores

·               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

·               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

·               blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury

·               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

·               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

·               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)

·               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).

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).

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:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This leaflet was last revised in 09/2023

4.      Possible side effects

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:

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

·               bruising or increased tendency of bruising

·               mouth sores

·               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

·               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

·               blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury

·               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

·               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

·               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)

·               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).

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).

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:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This leaflet was last revised in 09/2023

4.      Possible side effects

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:

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

·               bruising or increased tendency of bruising

·               mouth sores

·               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

·               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

·               blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury

·               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

·               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

·               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)

·               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).

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).

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:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This leaflet was last revised in 09/2023

Type II Variation Application to update the SmPC with dose modification guidance for cardiac failure and cardiac arrhythmias

The Summary of Product Characteristics (SmPC) has been revised to incorporate information specific for dose modifications.

EMEA/H/C/003791/II/74

Type II Variation Application for IMBRUVICA® (140mg capsule, 140-, 280-, 420- and 560 mg film-coated tablet) concerning an update of the product information based on data from a paediatric study LYM3003

EMEA/H/C/003791/II/74

Type II Variation Application for IMBRUVICA® (140mg capsule, 140-, 280-, 420- and 560 mg film-coated tablet) concerning an update of the product information based on data from a paediatric study LYM3003

Changes:

Extension of the existing CLL indication to include combination treatment with venetoclax for previously untreated patients based on efficacy and safety data from phase 3 study GLOW and phase 2 study CAPTIVATE; as a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8 and 5.1 of the SmPC are updated.

Changes:

Extension of the existing CLL indication to include combination treatment with venetoclax for previously untreated patients based on efficacy and safety data from phase 3 study GLOW and phase 2 study CAPTIVATE; as a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8 and 5.1 of the SmPC are updated.

Warnings and precautions

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”).

Cardiac arrhythmia and cardiac failure

Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia and cardiac failure have been reported in patients treated with IMBRUVICA. Cases of atrial fibrillation and atrial flutter have been reported particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. At baseline and then Pperiodically monitor all patients clinically for cardiac manifestations, including cardiac arrhythmia and cardiac failure. Patients who develop arrhythmic symptoms or new onset of dyspnoea, dizziness or fainting should be evaluated clinically and if indicated have an electrocardiogram (ECG) performed.

4.4     Special warnings and precautions for use

Cases of hepatitis E, which may be chronic, have occurred in patients treated with IMBRUVICA.

Hepatic events

Cases of hepatotoxicity, hepatitis B reactivation, and cases of hepatitis E, which may be chronic, have occurred in patients treated with IMBRUVICA. Hepatic failure, including fatal events, has occurred in patients treated with IMBRUVICA. Liver function and viral hepatitis status should be assessed before initiating treatment with IMBRUVICA. Patients should be periodically monitored for changes in liver function parameters during treatment. As clinically indicated, viral load and serological testing for infectious hepatitis should be performed per local medical guidelines. For patients diagnosed with hepatic events, consider consulting a liver disease expert for management.

Viral reactivation

Cases of hepatitis B reactivation, including fatal events, have been reported in patients receiving IMBRUVICA. Hepatitis B virus (HBV) status should be established before initiating treatment with IMBRUVICA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. If patients have positive hepatitis B serology, 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.

4.8     Undesirable effects

^‡     In some cases associated with loss of vision.

Northern Ireland representative added

Section 4.4

Excipients with known effectIntolerance to excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Each film‑coated tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium‑free.

Section 4.8

Summary of the safety profile

The safety profile is based on pooled data from 1552 patients treated with IMBRUVICA in three phase 2 clinical studies and seven randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated.

The most commonly occurring adverse reactions (≥20%) were diarrhoea, neutropenia, musculoskeletal pain, rash, haemorrhage (e.g., bruising), thrombocytopenia, nausea, pyrexia, arthralgia, and upper respiratory tract infection. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, lymphocytosis, thrombocytopenia, pneumonia, and hypertension.

Tabulated list of adverse reactions

The safety profile is based on pooled data from 1552 patients treated with IMBRUVICA in three phase 2 clinical studies and seven randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated. The median duration of IMBRUVICA treatment across the pooled dataset was 17.4 months. The median duration of treatment for CLL/SLL was 18.2 months (up to 52 months); MCL was 11.7 months (up to 28 months); WM was 21.6 months (up to 37 months).

……………..

Long-term safety

The long-term safety data from long-term treatment with IMBRUVICA over 5 years from 11781284 patients (treatment-naïve CLL/SLL n = 162, relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370, and WM n = 106) treated with IMBRUVICA were analysed. 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 median duration of treatment for WM was 47 months (range, 0.3 to 61 months) with 78% and 46% 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), 67% (year 1-2), 89% (year 2-3), 9% (year 3-4), and 9% (year 4-5);. Tthe overall incidence for the 5-year period was 11%.

5.1          Pharmacodynamic properties

Progression free survival (PFS) as assessed by IRC indicated an 80% statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. Efficacy results for Study PCYC-1127-CA are shown in Table 13 and the Kaplan-Meier curve for PFS is shown in Figure 10. At the primary analysis, with a median follow‑up of 26.5 months, the IRC‑assessed PFS hazard ratio was 0.20 [95% CI (0.11, 0.38)]. 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.

Figure 10:            Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1127-CA

Grade 3 or 4 infusion-related reactions were observed in 1% of patients treated with IMBRUVICA+rituximab and 16% of patients treated with placebo+rituximab.

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.

Final Analysis at 63‑month follow‑up

With an overall follow‑up of 63 months, efficacy results as assessed by an IRC at the time of the final analysis for PCYC‑1127‑CA are shown in Table 13 and the Kaplan‑Meier curve for PFS is shown in Figure 10. PFS hazard ratios for treatment‑naïve patients (0.31 [95% CI (0.14, 0.69)]) and previously treated patients (0.22 [95% CI (0.11, 0.43)]) were consistent with the PFS hazard ratio for the ITT population.

Figure 10:      Kaplan‑Meier Curve of PFS (ITT Population) in Study PCYC‑1127‑CA (Final Analysis)

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.With an overall follow‑up of 61 months, the response rate observed in Study PCYC‑1127‑CA monotherapy arm per IRC assessment was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months (range, 2.4 to 60.2+ months). The overall response rate per IRC observed in the monotherapy arm was 87% (0% CR, 29% VGPR, 48% PR, 10% MR). The median duration of overall response was 39 months (range, 2.07 to 60.2+ months).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with IMBRUVICA in all subsets of the paediatric population in MCL, CLL and lymphoplasmacytic lymphoma (LPL) (for information on paediatric use, see section 4.2).

4.4          Special warnings and precautions for use

……………..

Infections

Infections (including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections) were observed in patients treated with IMBRUVICA. Some of these infections have been associated with hospitalisation and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for fever, abnormal liver function tests, neutropenia 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.

Cases of invasive fungal infections, including cases of Aspergillosis, Cryptococcosis and Pneumocystis jiroveci infections have been reported following the use of ibrutinib. Reported cases of invasive fungal infections have been associated with fatal outcomes.

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of ibrutinib within the context of a prior or concomitant immunosuppressive therapy. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be considered.

Cases of hepatitis E, which may be chronic, have occurred in patients treated with IMBRUVICA.

5.1          Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE27L01EL01.

4.       Possible side effects

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.
• bruising or increased tendency of bruising.
• mouth sores
• feeling dizzy
• headache
• constipation
• feeling or being sick (nausea or vomiting)
• 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
• 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
• high level of “uric acid” in the blood (shown in blood tests), which may cause gout
• 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
• blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury
• heart failure
• fast heart rate, missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)
• an increase in the number or proportion of white blood cells shown in blood tests
• low white blood cell counts with fever (febrile neutropenia)
• 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)
• non‑melanoma skin cancer, most frequently squamous cell and basal cell skin cancer
• feeling dizzy
• blurred vision
• redness of the skin
• high level of “uric acid” in the blood (shown in blood tests), which may cause gout
• inflammation within the lungs that may lead to permanent damage
• breaking of the nails
• 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
• 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 neurologic dysfunctiondecreased brain or nerve function caused by loss of blood flow, stroke
• 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).
   

4.1     Therapeutic indications 

IMBRUVICA as a single agent or in combination with rituximab or obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).

4.2     Posology and method of administration

….

 CLL and WM

The recommended dose for the treatment of CLL and WM, either as a single agent or in combination, is 420 mg once daily (for details of the combination regimens, see section 5.1).

The recommended dose for the treatment of WM is 420 mg once daily.

Treatment should continue until disease progression or no longer tolerated by the patient.

When administering IMBRUVICA in combination with anti-CD20 therapiestherapy, it is recommended to administer IMBRUVICA prior to rituximab or obinutuzumab anti-CD20 therapy when given on the same day.

4.4     Special warnings and precautions for use

…………..

Cerebrovascular accidents

Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported with the use of ibrutinibin patients treated with IMBRUVICA, with and without concomitant atrial fibrillation and/or hypertension. Latency fromAmong cases with reported latency, the initiation of treatment with ibrutinib IMBRUVICA to the onset of ischaemic central nervous vascular conditions was in the most cases after several months (more than 1 month in 78% and more than 6 months in 44% of cases) emphasising the need for regular monitoring of patients (please see section 4.4 Cardiac arrhythmia and Hypertension and section 4.8).

4.8     Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 12001552 patients treated with IMBRUVICA in three phase 2 clinical studies and sixseven randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated.

The most commonly occurring adverse reactions (≥20%) were diarrhoea, neutropenia, musculoskeletal pain, rash, haemorrhage (e.g., bruising), thrombocytopenia, neutropenia, musculoskeletal pain, nausea, pyrexia, arthralgia, and thrombocytopeniaupper respiratory tract infection. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, lymphocytosis, thrombocytopenia, pneumonia,  and hypertensionand thrombocytopenia

………

Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 12001552 patients treated with IMBRUVICA for B‑cell malignancies, 56% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, thrombocytopenia, haemorrhage, neutropenia, rash, and arthralgiaand thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 78% of patients.

Elderly

Of the 12001552 patients treated with IMBRUVICA, 6452% were 65 years of age or older. Grade 3 or higher pneumonia (12% of patients age ≥65 versus 5% of patients <65 years) and thrombocytopenia (12% of patients age ≥65 years versus 6% of patients <65 years) occurred more frequently among elderly patients treated with IMBRUVICA (12% of patients age ≥65 versus 7% of patients <65 years of age).

5.1     Pharmacodynamic properties

………………

Combination therapy

The safety and efficacy of IMBRUVICA in patients with treatment naïvepreviously untreated CLL/SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (PCYC-1130-CA) of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab

The safety and efficacy of IMBRUVICA in patients with previously untreated CLL or SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (E1912) of IMBRUVICA in combination with rituximab (IR) versus standard fludarabine, cyclophosphamide, and rituximab (FCR) chemo-immunotherapy. The study enrolled previously untreated patients with CLL or SLL who were 70 years or younger. Patients with del17p were excluded from the study. Patients (n=529) were randomised 2:1 to receive either IR or FCR.  IMBRUVICA was administered at a dose of 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 IR arm and in Cycle 1 for the FCR arm and was administered at a dose of 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, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1 (98%) or 2 (2%). At baseline, 43% of patients presented with Rai Stage III or IV, and 59% of patients presented with CLL/SLL 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 7. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria, and OS are shown in Figures 6 and 7, respectively.

Figure 6:     Kaplan-Meier Curve of PFS (ITT Population) in Study E1912

Graph added to SmPC

The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.23 [95% CI (0.13, 0.40)], p <0.0001, as shown in Table 8. The 3-year PFS rate estimates for the high-risk CLL/SLL population were 90.4% [95% CI (85.4, 93.7)] and 60.3% [95% CI (46.2, 71.8)] in the IR and FCR arms, respectively

Figure 7:     Kaplan-Meier Curve of OS (ITT Population) in Study E1912

Graph added to the SmPC.

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.Tell your doctor immediately if you notice breathlessness, difficulty breathing when lying down, swelling of the feet, ankles or legs and weakness/tiredness (these may be signs of heart failure) during treatment with IMBRUVICA. 

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.

Common (may affect up to 1 in 10 people)

addition

• heart failure

Uncommon (may affect up to 1 in 100 people)

addition

• 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).

4.4     Special warnings and precautions for use

 ……………

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 IMBRUVICA 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.

………..

Cardiac arrhythmia and cardiac failure

Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia and cardiac failure have been reported in patients treated with IMBRUVICA. Cases of atrial fibrillation and atrial flutter have been reported particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor all patients clinically for cardiac manifestations, including cardiac arrhythmia and cardiac failure. Patients who develop arrhythmic symptoms or new onset of dyspnoea, dizziness or fainting should be evaluated clinically and if indicated have an electrocardiogram (ECG) performed.

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 preexisting 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, tightly controlled treatment with anticoagulants should be considered.

Patients should be monitored for signs and symptoms of cardiac failure during IMBRUVICA treatment. In some of these cases cardiac failure resolved or improved after IMBRUVICA withdrawal or dose reduction.

……………….

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 characterised by clinical signs and symptoms of extreme systemic inflammation. HLH is characterised 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.

4.8     Undesirable effects

4.4     Special warnings and precautions for use

Viral reactivation

Cases of hepatitis B reactivation, including fatal events, have been reported in patients receiving IMBRUVICA. Hepatitis B virus (HBV) status should be established before initiating treatment with IMBRUVICA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. If patients have positive hepatitis B serology, 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.

4.5     Interaction with other medicinal products and other forms of interaction

Agents that may have their plasma concentrations altered by ibrutinib

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, oral 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 in the liver and increase the exposure of medicinal products that undergo BCRP‑mediated hepatic efflux, such as rosuvastatin.

Based on in vitro data, ibrutinib is a weak reversible inhibitor towards CYP3A4 at the intestinal level and may therefore increase the exposure to CYP3A4 substrates sensitive to gut CYP3A metabolism. No clinical data are available on this interaction. Caution should be exercised if co‑administering ibrutinib with CYP3A4 substrates administered orally with narrow therapeutic range (such as dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus and tacrolimus).

Based on in vitro data, ibrutinib is a weak CYP2B6 inducer and may have the potential to affect the expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR), e.g. CYP2C9, CYP2C19, UGT1A1 and MRP2. The clinical relevance is not known, but the exposure to substrates of CYP2B6 (such as efavirenz and bupropion) and of co‑regulated enzymes may be reduced upon co‑administration with ibrutinib.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 (ethinylestradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the CYP2B6 substrate bupropion.

4.6     Fertility, pregnancy and lactation

Women of child‑bearing potential/Contraception in females

Based on findings in animals, IMBRUVICA may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking IMBRUVICA and for up to 3 months after ending treatment. Therefore, women of child‑bearing potential must use highly effective contraceptive measures while taking IMBRUVICA and for three months after stopping treatment. It is currently unknown whether ibrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.

4.8     Undesirable effects

5.1     Pharmacodynamic properties

Administrative updates~ spelling correction

5.2     Pharmacokinetic properties

Hepatic impairment

Ibrutinib is metabolised in the liver. A hepatic impairment trial was performed in non‑cancer subjects administered a single dose of 140 mg of medicinal product under fasting conditions. The effect of impaired liver function varied substantially between individuals, but on average a 2.7‑, 8.2‑, and 9.8‑fold increase in ibrutinib exposure (AUC_last) was observed in subjects with mild (n=6, Child‑Pugh class A), moderate (n=10, Child‑Pugh class B) and severe (n=8, Child‑Pugh class C) 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. The corresponding increase in unbound ibrutinib exposure (AUC_{unbound, last}) is estimated to be 4.1‑, 9.8‑, and 13‑fold in subjects with mild, moderate, and severe hepatic impairment, respectively (see section 4.2).

Co‑administration with CYP substrates

In vitro studies indicated that ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and intestinal (but not hepatic) CYP3A4 and does not display clinically relevant time‑dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. The dihydrodiol metabolite is at most a weak inducer of CYP450 isoenzymes in vitro. Although ibrutinib is a sensitive CYP3A4 substrate, it does not have a clinically relevant effect on its own exposure.

Co‑administration with transport 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 P‑gp and BCRP (see section 4.5).

4.8     Undesirable effects

Long-term safety

The long-term safety data over 4 years from 1177 patients (CLL/SLL n=807 and MCL n=370) treated with IMBRUVICA were analyzed. The median duration of treatment for CLL/SLL was 45 months with 70% and 40% of patients receiving treatment for more than 2 years and 4 years. The median duration of treatment for MCL was 11 months with 31% and 14% of patients receiving treatment for more than 2 years and 4 years. 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), and 8% (year 3-4). The incidence for the 4-year period was 10%.

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 analysed. 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%.

5.1     Pharmacodynamic properties

Final Analysis at 5665-month follow-up

With a median follow-up time on study of 5665 months in Study PCYC-1112-CA, an 8685% 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 (38.5447, 56.8718)] in the IMBRUVICA arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR=0.1514 [95% CI (0.11, 0.2019)]. The updated Kaplan-Meier curve for PFS is shown in Figure 7. The investigator-assessed ORR in the IMBRUVICA arm was 87.72% versus 22.4% in the ofatumumab arm. At the time of long-term follow-upfinal analysis, 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 median investigator-assessed PFS2 (time from randomisation until PFS event after first subsequent anti-neoplastic therapy) according to IWCLL criteria was 65.4 months [95% CI (51.61, not estimable)] in the IMBRUVICA arm and 38.5 months [95% CI (19.98, 47.24)] in the ofatumumab arm, respectively; HR=0.54 [95% CI (0.41, 0.71)]. The median OS was 67.7 months [95% CI (61.0, not estimable)] in the IMBRUVICA arm.

The treatment effect of ibrutinib in Study PCYC-1112-CA was consistent across high-risk patients with deletion 17p/TP53 mutation, deletion 11q, and/or unmutated IGHV.

Figure 7:    Kaplan‑Meier Curve of PFS (ITT Population) in Study PCYC‑1112‑CA with 56 Months Follow-upat Final Analysis with 65 Months Follow-up

.

Combination therapy

The safety and efficacy of IMBRUVICA in WM were further evaluated in patients with treatment-‑naïve or previously treated WM in a randomized, multicenter, double-blinded phase 3 study of IMBRUVICA in combination with rituximab versus placebo in combination with rituximab (PCYC‑1127‑CA). Patients (n=150) were randomized 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 or 6.8 mmol/L) 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 in the IMBRUVICA arm. Efficacy results for Study PCYC-1127-CA are shown in Table 11 and the Kaplan-Meier curve for PFS is shown in Figure 8. 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.

4.4     Special warnings and precautions for use

Cerebrovascular accidents

Cases of cerebrovascular accident, transient ischaemic attack and ischaemic 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 (more than 1 month in 78% and more than 6 months in 44% of cases) emphasizing the need for regular monitoring of patients (please see section 4.4 Cardiac arrhythmia and Hypertension and section 4.8).

4.8     Undesirable effects

4.4       Special warnings and precautions for use

Bleeding‑related events

There have been reports of haemorrhagicbleeding events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor haemorrhagicbleeding events such as contusion, epistaxis, and petechiae; and major haemorrhagicbleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.

Patients were excluded from participation in IMBRUVICA phase 2 and 3 studies if they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA.

Supplements such as fish oil and vitamin E preparations should be avoided. Use of IMBRUVICA in patients requiring other anticoagulants or medicinal products that inhibit platelet function may increase the risk of bleeding, and particular care should be taken if anticoagulant therapy is used.Use of either anticoagulants or medicinal products that inhibit platelet function (antiplatelet agents) concomitantly with IMBRUVICA increases the risk of major bleeding. 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.

Infections

Cases of invasive fungal infections, including cases of Aspergillosis, Cryptococcosis and Pneumocystis jiroveci infections have been reported following the use of ibrutinib. Reported cases of invasive fungal infections have been associated with fatal outcomes.

4.8       Undesirable effects

4.1     Therapeutic indications

IMBRUVICA as a single agent is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

IMBRUVICA as a single agent or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).

IMBRUVICA as a single agent or in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

IMBRUVICA as a single agent is indicated for the treatment of adult patients with Waldenström’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 WM.

4.2     Posology and method of administration

When administering IMBRUVICA in combination with anti-CD20 therapies, it is recommended to administer IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.

4.4     Special warnings and precautions for use

Hypertension

Hypertension has occurred in patients treated with IMBRUVICA (see section 4.8). Regularly monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust antihypertensive medication throughout treatment with IMBRUVICA as appropriate.

4.8     Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 9811200 patients treated with IMBRUVICA in three phase 2 clinical studies and foursix randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated.

The most commonly occurring adverse reactions (≥20%) were diarrhoea, rash, neutropenia, haemorrhage (e.g., bruising), neutropenia, musculoskeletal pain, nausea, rash, and pyrexiathrombocytopenia. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, pneumonia, and thrombocytopenia, and febrile neutropenia.

Tabulated list of adverse reactions

Adverse reactions in patients treated with ibrutinib for B‑cell malignancies and post‑marketing adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.