ibrutinib: prescribing information – dosing, contraindications, interactions, side effects

b
Patients randomised to ofatumumab were censored when starting IMBRUVICA if applicable.
c
Sensitivity analysis in which crossover patients from the ofatumumab arm were not censored at the date of first dose of IMBRUVICA.
d
Per IRC. Repeat CT scans required to confirm response.
e
All PRs achieved; p<0.0001 for ORR.
Median follow-up time on study=9 months
The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Table 17).

Table 17:
Subgroup analysis of PFS (Study PCYC-1112-CA)
N
Hazard Ratio
95% CI
All subjects
0.210
(0.143; 0.308)
Del17P
Yes
0.247
(0.136; 0.450)
No
0.194
(0.117; 0.323)
Refractory disease to purine analogue
Yes
0.178
(0.100; 0.320)
No
0.242
(0.145; 0.404)
Age
<65
0.166
(0.088; 0.315)
≥65
0.243
(0.149; 0.395)
Number of prior lines
<3
0.189
(0.100; 0.358)
≥3
0.212
(0.130; 0.344)
Bulky disease
<5 cm
0.237
(0.127; 0.442)
≥5 cm
0.191
(0.117; 0.311)
Hazard ratio based on non-stratified analysis
The Kaplan-Meier curve for PFS is shown in Figure 12.
Figure 12: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1112-CA
Final Analysis at 65-month follow-up
With a median follow-up time on study of 65 months in Study PCYC-1112-CA, an 85% 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 (38.47, 56.18)] in the IMBRUVICA arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR=0.15 [95% CI (0.11, 0.20)]. The updated Kaplan-Meier curve for PFS is shown in Figure 13. The investigator-assessed ORR in the IMBRUVICA arm was 87.7% versus 22.4% in the ofatumumab arm. At the time of final analysis, 133 (67.9%) of the 196 subjects originally randomised to the ofatumumab treatment arm had crossed over to ibrutinib treatment. 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 13: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1112-CA at Final Analysis with 65 Months Follow-up Combination therapy The safety and efficacy of IMBRUVICA in patients previously treated for CLL were further evaluated in a randomised, multi-centre, double-blinded phase 3 study of IMBRUVICA in combination with BR versus placebo+BR (Study CLL3001). Patients (n=578) were randomised 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles 2 through 6, Day 1. Ninety patients randomised to placebo+BR crossed over to receive IMBRUVICA following IRC confirmed progression. The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumour ≥5 cm, 26% had del11q.
Progression-free survival (PFS) was assessed by IRC according to IWCLL criteria. Efficacy results for Study CLL3001 are shown in Table 18.

Table 18:
Efficacy results in patients with CLL (Study CLL3001)
Endpoint
IMBRUVICA+BR
N=289
Placebo+BR
N=289
PFSa
Median (95% CI), months
Not reached

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology
MCL
Treatment of adult patients with previously untreated MCL
The recommended dose for the treatment of previously untreated MCL is ibrutinib 560 mg (four capsules) once daily (see Table 1).

Table 1:
IMBRUVICA dosing schedule for previously untreated MCL
Treatment Cycle number
Treatment
IMBRUVICA
Part I*
1, 3, 5
IMBRUVICA in combination with R-CHOP§
On days 1-19
2, 4, 6
R-DHAP#§
Without
IMBRUVICA
Part II±
IMBRUVICA
Daily for 24
Months
R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-DHAP= rituximab, dexamethasone, cytarabine, cisplatin *6 cycles; each cycle is 21 days.
§See the Summary of Product Characteristics (SmPC) for dosing information for each medicinal product.
#Interchangeable with R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin)§.
± Treatment should start after recovery of peripheral blood counts. Rituximab may be added as per national treatment guidelines.
Treatment of adult patients with relapsed or refractory MCL
The recommended dose for the treatment of previously treated MCL is ibrutinib 560 mg (four capsules) once daily as a single agent. Treatment with IMBRUVICA as a single agent should continue until disease progression or no longer tolerated by the patient.
CLL and WM
The recommended dose for the treatment of CLL and WM, either as a single agent or in combination, is 420 mg (three capsules) once daily (for details of the combination regimens, see section 5.1).
Treatment with IMBRUVICA as a single agent or in combination with anti-CD20 therapy 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 (two capsules) when used concomitantly with moderate CYP3A4 inhibitors.
The dose of ibrutinib should be reduced to 140 mg once daily (one capsule) 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.

Recommended dose modifications for non-cardiac events are described below:
Events†
Toxicity occurrence
MCL dose modification after recovery
CLL/WM dose modification after recovery
Grade 3 or 4 non-haematological toxicities
Grade 3 or 4 neutropenia with infection or fever
Grade 4 haematological toxicities
First* restart at 560 mg daily restart at 420 mg daily
Second restart at 420 mg daily restart at 280 mg daily
Third restart at 280 mg daily restart at 140 mg daily
Fourth discontinue IMBRUVICA discontinue IMBRUVICA
†
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 are described below:
Events
Toxicity occurrence
MCL dose modification after recovery
CLL/WM dose modification after recovery
Grade 2 cardiac failure
First restart at 420 mg daily restart at 280 mg daily
Second restart at 280 mg daily restart at 140 mg daily
Third discontinue IMBRUVICA
Grade 3 cardiac arrhythmias
First restart at 420 mg daily† restart at 280 mg daily†
Second discontinue IMBRUVICA
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First discontinue IMBRUVICA
†
Evaluate the benefit-risk before resuming treatment.
Missed dose
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The patient should not take extra capsules to make up the missed dose.
Special populations
Elderly
No specific dose adjustment is required for elderly patients (aged ≥65 years).
Renal impairment
No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in IMBRUVICA clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically.
Administer IMBRUVICA to patients with severe renal impairment (<30 mL/min creatinine clearance) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).

Hepatic impairment
Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see section 5.2). For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily (two capsules). For patients with moderate liver impairment (Child-Pugh class B), the recommended dose is 140 mg daily (one capsule). Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with severe hepatic impairment (Child-Pugh class C).
Severe cardiac disease
Patients with severe cardiovascular disease were excluded from IMBRUVICA clinical studies.
Paediatric population
IMBRUVICA is not recommended for use in children and adolescents aged 0 to 18 years as efficacy has not been established. Currently available data in patients with mature B-cell non-Hodgkin lymphoma are described in sections 4.8, 5.1 and 5.2.
Method of administration
IMBRUVICA should be administered orally once daily with a glass of water approximately at the same time each day. The capsules should be swallowed whole with water and should not be opened, broken, or chewed. IMBRUVICA must not be taken with grapefruit juice or Seville oranges (see section 4.5).

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology
MCL
Treatment of adult patients with previously untreated MCL
The recommended dose for the treatment of previously untreated MCL is ibrutinib 560 mg once daily (see Table 1).
Table 1:
IMBRUVICA dosing schedule for previously untreated MCL
Treatment Cycle number
Treatment
IMBRUVICA
Part I*
1, 3, 5
IMBRUVICA in combination with R-CHOP§
On days 1-19
2, 4, 6
R-DHAP#§
Without
IMBRUVICA
Part II±
IMBRUVICA
Daily for 24
Months
R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-DHAP= rituximab, dexamethasone, cytarabine, cisplatin.
*6 cycles; each cycle is 21 days.
§See the Summary of Product Characteristics (SmPC) for dosing information for each medicinal product.
#Interchangeable with R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin)§.
± Treatment should start after recovery of peripheral blood counts. Rituximab may be added as per national treatment guidelines.
Treatment of adult patients with relapsed or refractory MCL
The recommended dose for the treatment of previously treated MCL is ibrutinib 560 mg once daily as a single agent.Treatment with IMBRUVICA as a single agent should continue until disease progression or no longer tolerated by the patient.

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 as a single agent or in combination with anti-CD20 therapy 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.
Recommended dose modifications for non-cardiac events are described below:
Events†
Toxicity occurrence
MCL dose modification after recovery
CLL/WM dose modification after recovery
Grade 3 or 4 non-haematological toxicities
Grade 3 or 4 neutropenia with infection or fever
Grade 4 haematological toxicities
First* restart at 560 mg daily restart at 420 mg daily
Second restart at 420 mg daily restart at 280 mg daily
Third restart at 280 mg daily restart at 140 mg daily
Fourth discontinue IMBRUVICA discontinue IMBRUVICA
†
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 are described below:
Events
Toxicity occurrence
MCL dose modification after recovery
CLL/WM dose modification after recovery
Grade 2 cardiac failure
First restart at 420 mg daily restart at 280 mg daily
Second restart at 280 mg daily restart at 140 mg daily
Third discontinue IMBRUVICA
Grade 3 cardiac arrhythmias
First restart at 420 mg daily† restart at 280 mg daily†
Second discontinue IMBRUVICA
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First discontinue IMBRUVICA
†
Evaluate the benefit-risk before resuming treatment.
Missed dose
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The patient should not take extra tablets to make up the missed dose.
Special populations
Elderly
No specific dose adjustment is required for elderly patients (aged ≥65 years).
Renal impairment
No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in IMBRUVICA clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically.
Administer IMBRUVICA to patients with severe renal impairment (<30 mL/min creatinine clearance) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).
Hepatic impairment
Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see section 5.2). For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily. For patients with moderate liver impairment (Child-Pugh class B), the recommended dose is 140 mg daily. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with severe hepatic impairment (Child-Pugh class C).
Severe cardiac disease
Patients with severe cardiovascular disease were excluded from IMBRUVICA clinical studies.
Paediatric population
IMBRUVICA is not recommended for use in children and adolescents aged 0 to 18 years as efficacy has not been established. Currently available data in patients with mature B-cell non-Hodgkin lymphoma are described in sections 4.8, 5.1 and 5.2.
Method of administration
IMBRUVICA should be administered orally once daily with a glass of water approximately at the same time each day. The tablets should be swallowed whole with water and should not be broken or chewed. IMBRUVICA must not be taken with grapefruit juice or Seville oranges (see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use of preparations containing St. John’s Wort is contraindicated in patients treated with IMBRUVICA.

Summary of the safety profile
The most commonly occurring adverse reactions (≥20%) were diarrhoea, neutropenia, musculoskeletal pain, haemorrhage (e.g., bruising), rash, nausea, thrombocytopenia, arthralgia, and upper respiratory tract infection. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, lymphocytosis, thrombocytopenia, hypertension, and pneumonia.
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.
Summary for B-cell malignancies
The safety profile is based on pooled data from 1 981 patients treated with IMBRUVICA in four phase 2 clinical studies and eight randomised phase 3 studies and from post-marketing experience.
The TRIANGLE study data is not included in the pooled data and presented separately in Table 3.
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, except for studies with IMBRUVICA in combination with venetoclax where patients received fixed duration treatment (Studies CLL3011 and PCYC-1142-CA). The median duration of IMBRUVICA treatment across the pooled dataset was 14.7 months. The median duration of treatment for CLL/SLL was 14.7 months (up to 52 months); MCL was 11.7 months (up to 28 months); WM was 21.6 months (up to 37 months).
Table 2:
Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies† System organ class Frequency (All grades) Adverse reactions All Grades (%) Grade ≥3 (%) Infections and infestations Very common Pneumonia*# Upper respiratory tract infection Skin infection* Common Sepsis*# Urinary tract infection Sinusitis* Uncommon Cryptococcal infections* <1 Pneumocystis infections* # <1 <1 Aspergillus infections* <1 <1 Hepatitis B reactivation@ # <1 <1 Rare Progressive multifocal leukoencephalopathy# <1 <1

Neoplasms benign, malignant and unspecified
(incl cysts and polyps)
Common
Non-melanoma skin cancer*
Basal cell carcinoma
Squamous cell carcinoma
<1
<1
Blood and lymphatic system disorders
Very common
Neutropenia*
Thrombocytopenia*
Lymphocytosis*
Common
Febrile neutropenia
Leukocytosis
Rare
Leukostasis syndrome
<1
<1
Immune system disorders
Common
Interstitial lung disease*,#
<1
Metabolism and nutrition disorders
Common
Hyperuricaemia
Uncommon
Tumour lysis syndrome
Nervous system disorders
Very common
Dizziness
Headache
<1
Common
Peripheral neuropathy*
<1
Uncommon
Cerebrovascular accident#
Transient ischaemic attack
Ischaemic stroke#
<1
<1
<1
<1
<1
<1
Eye disorders
Common
Vision blurred
Uncommon
Eye haemorrhage‡
Uveitis*
<1
<1
Cardiac disorders
Common
Cardiac failure*, #
Atrial fibrillation
Uncommon
Ventricular tachyarrhythmia*,#
<1
Cardiac arrest#
<1
<1
Vascular disorders
Very common
Haemorrhage*#
Bruising*
Hypertension*
<1
Common
Epistaxis
Petechiae
<1
Uncommon
Subdural haematoma#
<1

Respiratory, thoracic and mediastinal disorders
Very common
Cough*
<1
Gastrointestinal disorders
Very common
Diarrhoea
Vomiting
Stomatitis*
Nausea
Constipation
Dyspepsia
<1
<1
Hepatobiliary disorders
Uncommon
Hepatic failure*,#
<1
<1
Skin and subcutaneous tissue disorders
Very common
Rash*
Common
Urticaria
Erythema
Onychoclasis
<1
<1
Uncommon
Angioedema
Panniculitis*
Neutrophilic dermatoses*
Pyogenic granuloma
Cutaneous vasculitis
<1
<1
<1
<1
<1
<1
<1
<1
Rare
Stevens-Johnson syndrome
<1
<1
Musculoskeletal and connective tissue disorders
Very common
Arthralgia
Muscle spasms
Musculoskeletal pain*
<1
Renal and urinary disorders
Common
Acute kidney injury#
<2
<1
General disorders and administration site conditions
Very common
Pyrexia
Oedema peripheral
Investigations
Very common
Blood creatinine increased
<1
†
Frequencies are rounded to the nearest integer.
*
Includes multiple adverse reaction terms.
‡
In some cases associated with loss of vision.
#
Includes events with fatal outcome.
@
Lower level term (LLT) used for selection.
Summary for patients with previously untreated MCL who were eligible for ASCT
The safety profile is based on data from 265 patients (in the IMBRUVICA arm) treated with IMBRUVICA in the phase 3 TRIANGLE study. Patients received IMBRUVICA at 560 mg once daily according to the TRIANGLE treatment schedule (see section 5.1). The median treatment duration was 28.5 months in the IMBRUVICA arm.
Table 3:
Adverse reactions reported in the IMBRUVICA arm of the TRIANGLE Study†
N=265
System Organ
Class
Frequency
(All Grades)
Adverse Reactions
All
Grades
(%)
Grade ≥3
(%)
Infections and infestations
Very common
Pneumonia* #
Skin infection*
Common
Upper respiratory tract infection
<1
Sepsis*
Urinary tract infection
<1
Sinusitis*
Uncommon
Aspergillus infections*
<1
Common
Non-Melanoma skin cancer*
<1

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
<1
Blood and lymphatic system disorders
Very common
Thrombocytopenia*
Neutropenia*
Febrile neutropenia
Common
Leukocytosis
Immune system disorders
Common
Interstitial lung disease*
Metabolism and nutrition disorders
Common
Hyperuricaemia
Tumour lysis syndrome*
Nervous system disorders
Very common
Peripheral neuropathy*
Headache
Common
Dizziness
<1
Uncommon
Transient ischaemic attack
Eye disorders
Uncommon
Vision blurred
Eye haemorrhage
<1
Cardiac disorders
Common
Atrial fibrillation
Cardiac failure*
Vascular disorders
Very common
Haemorrhage*
Hypertension*
Common
Bruising*
Epistaxis
Petechiae
Gastrointestinal disorders
Very common
Nausea
Diarrhoea
Vomiting
Stomatitis*
Constipation
<1
Common
Dyspepsia
Skin and subcutaneous tissue disorders
Very common
Rash*
Common
Erythema
Onychoclasis
Uncommon
Urticaria
<1
Angioedema
Cutaneous vasculitis
<1
Panniculitis*
Musculoskeletal and connective tissue disorders
Very common
Musculoskeletal pain*
Common
Muscle spasms
Arthralgia
Renal and urinary disorders
Very common
Acute kidney injury
General disorders and administration site conditions
Very common
Pyrexia
Common
Oedema peripheral
Investigations
Very common
Blood creatinine increased
†
Frequencies are rounded to the nearest integer.
*
Terms required grouping.
#
Includes events with fatal outcome.
Description of selected adverse reactions
Discontinuation and dose reduction due to adverse reactions
Of the 1 981 patients treated with IMBRUVICA for B-cell malignancies, 6% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, neutropenia, rash, thrombocytopenia, and haemorrhage. Adverse reactions leading to dose reduction occurred in approximately 8% of patients. In the phase 3 TRIANGLE study involving 265 patients with previously untreated MCL who were eligible for ASCT treatment discontinuation due to adverse reactions was observed in 13% in the IMBRUVICA arm. These included neutropenia, pneumonia,

atrial fibrillation, acute kidney injury, diarrhoea, rash, and interstitial lung disease. Adverse reactions leading to dose reduction occurred in approximately 12% in the IMBRUVICA arm.
Elderly
Of the 1 981 patients treated with IMBRUVICA, 50% were 65 years of age or older. Grade 3 or higher pneumonia (11% of patients age ≥65 versus 4% of patients <65 years) and thrombocytopenia (11% of patients age ≥65 years versus 5% of patients <65 years) occurred more frequently among elderly patients treated with IMBRUVICA.
Long-term safety
The safety data from long-term treatment with IMBRUVICA over 5 years from 1 284 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) 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), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%.
Paediatric population
The safety assessment is based on data from a phase 3 study of IMBRUVICA in combination with either a rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone (RICE) regimen, or a rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) regimen, as background therapy or background therapy alone in paediatric and young adult patients (aged 3 to 19 years) with relapsed or refractory mature B-cell non-Hodgkin lymphoma (see section 5.1). No new adverse reactions were observed in this study.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

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.
Summary for B-cell malignancies
The safety profile is based on pooled data from 1 981 patients treated with IMBRUVICA in four phase 2 clinical studies and eight randomised phase 3 studies and from post-marketing experience.
The TRIANGLE study data is not included in the pooled data and presented separately in Table 3.
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, except for studies with IMBRUVICA in combination with venetoclax where patients received fixed duration treatment (Studies CLL3011 and PCYC-1142-CA). The median duration of IMBRUVICA treatment across the pooled dataset was 14.7 months. The median duration of treatment for CLL/SLL was 14.7 months (up to 52 months); MCL was 11.7 months (up to 28 months); WM was 21.6 months (up to 37 months).
Table 2:
Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies† System organ class Frequency (All grades) Adverse reactions All Grades (%) Grade ≥3 (%) Infections and infestations Very common Pneumonia*# Upper respiratory tract infection Skin infection* Common Sepsis*# Urinary tract infection Sinusitis* Uncommon Cryptococcal infections* <1 Pneumocystis infections* # <1 <1 Aspergillus infections* <1 <1 Hepatitis B reactivation@ # <1 <1 Rare Progressive multifocal leukoencephalopathy# <1 <1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Non-melanoma skin cancer* Basal cell carcinoma Squamous cell carcinoma <1 <1 Blood and lymphatic system disorders Very common Neutropenia* Thrombocytopenia* Lymphocytosis* Common Febrile neutropenia Leukocytosis Rare Leukostasis syndrome <1 <1 Immune system disorders Common Interstitial lung disease*,# <1 Metabolism and nutrition disorders Common Hyperuricaemia Uncommon Tumour lysis syndrome Nervous system disorders Very common Dizziness Headache <1 Common Peripheral neuropathy* <1 Uncommon Cerebrovascular accident# Transient ischaemic attack Ischaemic stroke# <1 <1 <1 <1 <1 <1 Eye disorders Common Vision blurred

Uncommon
Eye haemorrhage‡
Uveitis*
<1
<1
Cardiac disorders
Common
Cardiac failure*, #
Atrial fibrillation
Uncommon
Ventricular tachyarrhythmia*,#
<1
Cardiac arrest#
<1
<1
Vascular disorders
Very common
Haemorrhage*#
Bruising*
Hypertension*
<1
Common
Epistaxis
Petechiae
<1
Uncommon
Subdural haematoma#
<1
Respiratory, thoracic and mediastinal disorders
Very common
Cough*
<1
Gastrointestinal disorders
Very common
Diarrhoea
Vomiting
Stomatitis*
Nausea
Constipation
Dyspepsia
<1
<1
Hepatobiliary disorders
Uncommon
Hepatic failure*,#
<1
<1
Skin and subcutaneous tissue disorders
Very common
Rash*
Common
Urticaria
Erythema
Onychoclasis
<1
<1
Uncommon
Angioedema
Panniculitis*
Neutrophilic dermatoses*
Pyogenic granuloma
Cutaneous vasculitis
<1
<1
<1
<1
<1
<1
<1
<1
Rare
Stevens-Johnson syndrome
<1
<1
Musculoskeletal and connective tissue disorders
Very common
Arthralgia
Muscle spasms
Musculoskeletal pain*
<1
Renal and urinary disorders
Common
Acute kidney injury#
<2
<1
General disorders and administration site conditions
Very common
Pyrexia
Oedema peripheral
Investigations
Very common
Blood creatinine increased
<1
†
Frequencies are rounded to the nearest integer.
*
Includes multiple adverse reaction terms.
‡
In some cases associated with loss of vision.
#
Includes events with fatal outcome.
@
Lower level term (LLT) used for selection.
Summary for patients with previously untreated MCL who were eligible for ASCT
The safety profile is based on data from 265 patients (in the IMBRUVICA arm) treated with IMBRUVICA in the phase 3 TRIANGLE study. Patients received IMBRUVICA at 560 mg once daily according to the TRIANGLE treatment schedule (see section 5.1). The median treatment duration was 28.5 months in the IMBRUVICA arm.

Table 3:
Adverse reactions reported in the IMBRUVICA arm of the TRIANGLE Study†
N=265
System Organ
Class
Frequency
(All Grades)
Adverse Reactions
All
Grades
(%)
Grade ≥3
(%)
Infections and infestations
Very common
Pneumonia* #
Skin infection*
Common
Upper respiratory tract infection
<1
Sepsis*
Urinary tract infection
<1
Sinusitis*
Uncommon
Aspergillus infections*
<1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Common
Non-Melanoma skin cancer*
<1
Basal cell carcinoma
<1
Blood and lymphatic system disorders
Very common
Thrombocytopenia*
Neutropenia*
Febrile neutropenia
Common
Leukocytosis
Immune system disorders
Common
Interstitial lung disease*
Metabolism and nutrition disorders
Common
Hyperuricaemia
Tumour lysis syndrome*
Nervous system disorders
Very common
Peripheral neuropathy*
Headache
Common
Dizziness
<1
Uncommon
Transient ischaemic attack
Eye disorders
Uncommon
Vision blurred
Eye haemorrhage
<1
Cardiac disorders
Common
Atrial fibrillation
Cardiac failure*
Vascular disorders
Very common
Haemorrhage*
Hypertension*
Common
Bruising*
Epistaxis
Petechiae
Gastrointestinal disorders
Very common
Nausea
Diarrhoea
Vomiting
Stomatitis*
Constipation
<1
Common
Dyspepsia
Skin and subcutaneous tissue disorders
Very common
Rash*
Common
Erythema
Onychoclasis
Uncommon
Urticaria
<1
Angioedema
Cutaneous vasculitis
<1
Panniculitis*
Musculoskeletal and connective tissue disorders
Very common
Musculoskeletal pain*
Common
Muscle spasms
Arthralgia
Renal and urinary disorders
Very common
Acute kidney injury
General disorders and administration site conditions
Very common
Pyrexia
Common
Oedema peripheral
Investigations
Very common
Blood creatinine increased

†
Frequencies are rounded to the nearest integer.
*
Terms required grouping.
#
Includes events with fatal outcome.
Description of selected adverse reactions
Discontinuation and dose reduction due to adverse reactions
Of the 1 981 patients treated with IMBRUVICA for B-cell malignancies, 6% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, neutropenia, rash, thrombocytopenia, and haemorrhage. Adverse reactions leading to dose reduction occurred in approximately 8% of patients. In the phase 3 TRIANGLE study involving 265 patients with previously untreated MCL who were eligible for ASCT treatment discontinuation due to adverse reactions was observed in 13% in the IMBRUVICA arm. These included neutropenia, pneumonia, atrial fibrillation, acute kidney injury, diarrhoea, rash, and interstitial lung disease. Adverse reactions leading to dose reduction occurred in approximately 12% in the IMBRUVICA arm.
Elderly
Of the 1 981 patients treated with IMBRUVICA, 50% were 65 years of age or older. Grade 3 or higher pneumonia (11% of patients age ≥65 versus 4% of patients <65 years) and thrombocytopenia (11% of patients age ≥65 years versus 5% of patients <65 years) occurred more frequently among elderly patients treated with IMBRUVICA.
Long-term safety
The safety data from long-term treatment with IMBRUVICA over 5 years from 1 284 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) 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), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%.
Paediatric population
The safety assessment is based on data from a phase 3 study of IMBRUVICA in combination with either a rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone (RICE) regimen, or a rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) regimen, as background therapy or background therapy alone in paediatric and young adult patients (aged 3 to 19 years) with relapsed or refractory mature B-cell non-Hodgkin lymphoma (see section 5.1). No new adverse reactions were observed in this study.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Bleeding-related events
There have been reports of bleeding events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.
Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA.
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.
IMBRUVICA should be held at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
The mechanism for the bleeding-related events is not fully understood. Patients with congenital bleeding diathesis have not been studied.
Leukostasis
Cases of leukostasis have been reported in patients treated with IMBRUVICA. A high number of circulating lymphocytes (>400 000/mcL) may confer increased risk. Consider temporarily withholding

IMBRUVICA. Patients should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated.
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.
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 (see section 4.8). Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural 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.
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.
Cytopenias
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) were reported in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
Interstitial Lung Disease (ILD)
Cases of ILD have been reported in patients treated with IMBRUVICA. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt IMBRUVICA and manage ILD appropriately. If symptoms persist, consider the risks and benefits of IMBRUVICA treatment and follow the dose modification guidelines.
Cardiac arrhythmias and cardiac failure
Fatal and serious cardiac arrhythmias and cardiac failure have occurred in patients treated with IMBRUVICA. Patients with advanced age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, or cardiac co-morbidities may be at greater risk of events including sudden fatal cardiac events. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia and cardiac failure have been reported, particularly in patients with acute infections or cardiac risk factors including hypertension, diabetes mellitus, and a previous history of cardiac arrhythmia.

Appropriate clinical evaluation of cardiac history and function should be performed prior to initiating IMBRUVICA. Patients should be carefully monitored during treatment for signs of clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g., ECG, echocardiogram), as indicated for patients in whom there are cardiovascular concerns.
For patients with relevant risk factors for cardiac events, carefully assess benefit/risk before initiating treatment with IMBRUVICA; alternative treatment may be considered.
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.
Cerebrovascular accidents
Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported in patients treated with IMBRUVICA, with and without concomitant atrial fibrillation and/or hypertension. Among cases with reported latency, the initiation of treatment with 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).
Tumour lysis syndrome
Tumour lysis syndrome (TLS) has been reported with IMBRUVICA therapy. Patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.
Non-melanoma skin cancer
Non-melanoma skin cancers were reported more frequently in patients treated with IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non-melanoma skin cancer.
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.
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.
Drug-drug interactions
Co-administration of strong or moderate CYP3A4 inhibitors with IMBRUVICA may lead to increased ibrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of

CYP3A4 inducers may lead to decreased IMBRUVICA exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of IMBRUVICA with strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers should be avoided whenever possible and co-administration should only be considered when the potential benefits clearly outweigh the potential risks. Patients should be closely monitored for signs of IMBRUVICA toxicity if a CYP3A4 inhibitor must be used (see sections 4.2 and 4.5). If a CYP3A4 inducer must be used, closely monitor patients for signs of IMBRUVICA lack of efficacy.
Women of childbearing potential
Women of childbearing potential must use a highly effective method of contraception while taking IMBRUVICA (see section 4.6).
Excipients with known effect
Each capsule contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

Bleeding-related events
There have been reports of bleeding events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.
Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA.
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.
IMBRUVICA should be held at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
The mechanism for the bleeding-related events is not fully understood. Patients with congenital bleeding diathesis have not been studied.
Leukostasis
Cases of leukostasis have been reported in patients treated with IMBRUVICA. A high number of circulating lymphocytes (>400 000/mcL) may confer increased risk. Consider temporarily withholding IMBRUVICA. Patients should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated.
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.
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 (see section 4.8). Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural 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.
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.
Cytopenias
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) were reported in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
Interstitial Lung Disease (ILD)
Cases of ILD have been reported in patients treated with IMBRUVICA. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt IMBRUVICA and manage ILD appropriately. If symptoms persist, consider the risks and benefits of IMBRUVICA treatment and follow the dose modification guidelines.
Cardiac arrhythmias and cardiac failure
Fatal and serious cardiac arrhythmias and cardiac failure have occurred in patients treated with IMBRUVICA. Patients with advanced age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, or cardiac co-morbidities may be at greater risk of events including sudden fatal cardiac events. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia and cardiac failure have been reported, particularly in patients with acute infections or cardiac risk factors including hypertension, diabetes mellitus, and a previous history of cardiac arrhythmia.
Appropriate clinical evaluation of cardiac history and function should be performed prior to initiating IMBRUVICA. Patients should be carefully monitored during treatment for signs of clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g., ECG, echocardiogram), as indicated for patients in whom there are cardiovascular concerns.
For patients with relevant risk factors for cardiac events, carefully assess benefit/risk before initiating treatment with IMBRUVICA; alternative treatment may be considered.
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.

Cerebrovascular accidents
Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported in patients treated with IMBRUVICA, with and without concomitant atrial fibrillation and/or hypertension. Among cases with reported latency, the initiation of treatment with 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).
Tumour lysis syndrome
Tumour lysis syndrome (TLS) has been reported with IMBRUVICA therapy. Patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.
Non-melanoma skin cancer
Non-melanoma skin cancers were reported more frequently in patients treated with IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non-melanoma skin cancer.
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.
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.
Drug-drug interactions
Co-administration of strong or moderate CYP3A4 inhibitors with IMBRUVICA may lead to increased ibrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3A4 inducers may lead to decreased IMBRUVICA exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of IMBRUVICA with strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers should be avoided whenever possible and co-administration should only be considered when the potential benefits clearly outweigh the potential risks. Patients should be closely monitored for signs of IMBRUVICA toxicity if a CYP3A4 inhibitor must be used (see sections 4.2 and 4.5). If a CYP3A4 inducer must be used, closely monitor patients for signs of IMBRUVICA lack of efficacy.
Women of childbearing potential
Women of childbearing potential must use a highly effective method of contraception while taking IMBRUVICA (see section 4.6).
Excipients with known effect
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.

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4).
Agents that may increase ibrutinib plasma concentrations
Concomitant use of IMBRUVICA and medicinal products that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and strong CYP3A4 inhibitors should be avoided.
Strong CYP3A4 inhibitors
Co-administration of ketoconazole, a very strong CYP3A4 inhibitor, in 18 fasted healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by 29- and 24-fold, respectively. Simulations using fasted conditions suggested that the strong CYP3A4 inhibitor clarithromycin may increase the AUC of ibrutinib by a factor of 14. In patients with B-cell malignancies taking IMBRUVICA with food, co-administration of the strong CYP3A4 inhibitor voriconazole increased Cmax by 6.7-fold and AUC by 5.7-fold. Strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, voriconazole and posaconazole) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the IMBRUVICA dose to 140 mg (one capsule) for the duration of the inhibitor use or withhold IMBRUVICA temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Moderate CYP3A4 inhibitors
In patients with B-cell malignancies taking IMBRUVICA with food, co-administration of the CYP3A4 inhibitor erythromycin increased Cmax by 3.4-fold and AUC by 3.0-fold. If a moderate CYP3A4 inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone and dronedarone) is indicated, reduce IMBRUVICA dose to 280 mg (two capsules) for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Mild CYP3A4 inhibitors
Simulations using fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by <2-fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.
Co-administration of grapefruit juice, containing CYP3A4 inhibitors, in eight healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by approximately 4- and 2-fold, respectively.
Grapefruit and Seville oranges should be avoided during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).

Agents that may decrease ibrutinib plasma concentrations
Administration of IMBRUVICA with inducers of CYP3A4 can decrease ibrutinib plasma concentrations.
Co-administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (Cmax and AUC) of ibrutinib by 92 and 90%, respectively. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin). Preparations containing St. John's Wort are contraindicated during treatment with IMBRUVICA, as efficacy may be reduced.
Consider alternative agents with less CYP3A4 induction. If the benefit outweighs the risk and a strong or moderate CYP3A4 inducer must be used, monitor patient closely for lack of efficacy (see sections 4.3 and 4.4). Mild inducers may be used concomitantly with IMBRUVICA, however, patients should be monitored for potential lack of efficacy.
Ibrutinib has a pH dependent solubility, with lower solubility at higher pH. A lower Cmax was observed in fasted healthy subjects administered a single 560 mg dose of ibrutinib after taking omeprazole at 40 mg once daily for 5 days (see section 5.2). There is no evidence that the lower Cmax would have clinical significance, and medicinal products that increase stomach pH (e.g., proton pump inhibitors) have been used without restrictions in the pivotal clinical studies.
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.
In studies of ibrutinib (420 mg) in combination with venetoclax (400 mg) in CLL patients, an increase in venetoclax exposure (approximately 1.8-fold based on AUC) was observed compared with monotherapy data for venetoclax.
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.

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4).

Agents that may increase ibrutinib plasma concentrations
Concomitant use of IMBRUVICA and medicinal products that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and strong CYP3A4 inhibitors should be avoided.
Strong CYP3A4 inhibitors
Co-administration of ketoconazole, a very strong CYP3A4 inhibitor, in 18 fasted healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by 29- and 24-fold, respectively. Simulations using fasted conditions suggested that the strong CYP3A4 inhibitor clarithromycin may increase the AUC of ibrutinib by a factor of 14. In patients with B-cell malignancies taking IMBRUVICA with food, co-administration of the strong CYP3A4 inhibitor voriconazole increased Cmax by 6.7-fold and AUC by 5.7-fold. Strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, voriconazole and posaconazole) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the IMBRUVICA dose to 140 mg for the duration of the inhibitor use or withhold IMBRUVICA temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Moderate CYP3A4 inhibitors
In patients with B-cell malignancies taking IMBRUVICA with food, co-administration of the CYP3A4 inhibitor erythromycin increased Cmax by 3.4-fold and AUC by 3.0-fold. If a moderate CYP3A4 inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone and dronedarone) is indicated, reduce IMBRUVICA dose to 280 mg for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Mild CYP3A4 inhibitors
Simulations using fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by <2-fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.
Co-administration of grapefruit juice, containing CYP3A4 inhibitors, in eight healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by approximately 4- and 2-fold, respectively.
Grapefruit and Seville oranges should be avoided during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).
Agents that may decrease ibrutinib plasma concentrations
Administration of IMBRUVICA with inducers of CYP3A4 can decrease ibrutinib plasma concentrations.
Co-administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (Cmax and AUC) of ibrutinib by 92 and 90%, respectively. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin). Preparations containing St. John's Wort are contraindicated during treatment with IMBRUVICA, as efficacy may be reduced.
Consider alternative agents with less CYP3A4 induction. If the benefit outweighs the risk and a strong or moderate CYP3A4 inducer must be used, monitor patient closely for lack of efficacy (see sections 4.3 and 4.4). Mild inducers may be used concomitantly with IMBRUVICA, however, patients should be monitored for potential lack of efficacy.
Ibrutinib has a pH dependent solubility, with lower solubility at higher pH. A lower Cmax was observed in fasted healthy subjects administered a single 560 mg dose of ibrutinib after taking omeprazole at 40 mg once daily for 5 days (see section 5.2). There is no evidence that the lower Cmax would have clinical significance, and medicinal products that increase stomach pH (e.g., proton pump inhibitors) have been used without restrictions in the pivotal clinical studies.

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.
In studies of ibrutinib (420 mg) in combination with venetoclax (400 mg) in CLL patients, an increase in venetoclax exposure (approximately 1.8-fold based on AUC) was observed compared with monotherapy data for venetoclax.
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.

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.
Pregnancy
IMBRUVICA should not be used during pregnancy. There are no data from the use of IMBRUVICA in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Breast-feeding
It is not known whether ibrutinib or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with IMBRUVICA.

Fertility
No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg/day) (see section 5.3). No human data on the effects of ibrutinib on fertility are available.

IMBRUVICA has minor influence on the ability to drive and use machines.
Fatigue, dizziness and asthenia have been reported in some patients taking IMBRUVICA and should be considered when assessing a patient’s ability to drive or operate machines.

There are limited data on the effects of IMBRUVICA overdose. No maximum tolerated dose was reached in the phase 1 study in which patients received up to 12.5 mg/kg/day (1 400 mg/day). In a separate study, one healthy subject who received a dose of 1 680 mg experienced reversible grade 4 hepatic enzyme increases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)].
There is no specific antidote for IMBRUVICA. Patients who ingested more than the recommended dose should be closely monitored and given appropriate supportive treatment.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EL01.
Mechanism of action
Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling

molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL. BTK’s pivotal role in signalling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
In preclinical tumour models, the combination of ibrutinib and venetoclax resulted in increased cellular apoptosis and anti-tumour activity compared to either agent alone. BTK inhibition by ibrutinib increases CLL cell dependence on BCL-2, a cell survival pathway, while venetoclax inhibits BCL-2 leading to apoptosis.
Lymphocytosis
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline and an absolute count >5 000/mcL), often associated with reduction of lymphadenopathy, has been observed in about three fourths of patients with CLL treated with IMBRUVICA. This effect has also been observed in about one third of patients with relapsed or refractory MCL treated with IMBRUVICA. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first month of IMBRUVICA therapy and typically resolves within a median of 8.0 weeks in patients with MCL and 14 weeks in patients with CLL. A large increase in the number of circulating lymphocytes (e.g., >400 000/mcL) has been observed in some patients.
Lymphocytosis was not observed in patients with WM treated with IMBRUVICA.
In vitro platelet aggregation
In an in vitro study, ibrutinib demonstrated inhibition of collagen-induced platelet aggregation.
Ibrutinib did not show meaningful inhibition of platelet aggregation using other agonists of platelet aggregation.
Effect on QT/QTc interval and cardiac electrophysiology

Absorption
Ibrutinib is rapidly absorbed after oral administration with a median Tmax of 1 to 2 hours. Absolute bioavailability in fasted condition (n=8) was 2.9% (90% CI=2.1 – 3.9) and doubled when combined

with a meal. Pharmacokinetics of ibrutinib does not significantly differ in patients with different B-cell malignancies. Ibrutinib exposure increases with doses up to 840 mg. The steady state AUC observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 ng h/mL. Administration of ibrutinib in fasted condition resulted in approximately 60% of exposure (AUClast) as compared to either 30 minutes before, 30 minutes after (fed condition) or 2 hours after a high fat breakfast.
Ibrutinib has a pH dependent solubility, with lower solubility at higher pH. In fasted healthy subjects administered a single 560 mg dose of ibrutinib after taking omeprazole at 40 mg once daily for 5 days, compared to ibrutinib alone, geometric mean ratios (90% CI) were 83% (68-102%), 92% (78-110%), and 38% (26-53%) for AUC0-24, AUClast, and Cmax, respectively.
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1 000 ng/mL. The apparent volume of distribution at steady state (Vd, ss/F) was approximately 10 000 L.
Metabolism
Ibrutinib is metabolised primarily by CYP3A4 to produce a dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Involvement of CYP2D6 in the metabolism of ibrutinib appears to be minimal.
Therefore, no precautions are necessary in patients with different CYP2D6 genotypes.
Elimination
Apparent clearance (CL/F) is approximately 1 000 L/h. The half-life of ibrutinib is 4 to 13 hours.