Imbruvica

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 140 mg of ibrutinib.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule).

White opaque, hard capsule of 22 mm in length, marked with “ibr 140 mg” in black ink.

4. CLINICAL PARTICULARS

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

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 (four capsules) once daily.

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

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

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.



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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 ≥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), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity 
reoccurs, the once daily dose should be reduced by one capsule (140 mg). A second reduction of dose 
by 140 mg may be considered as needed. If these toxicities persist or recur following two dose 
reductions, discontinue the medicinal product.

Recommended dose modifications are described below:

Toxicity 
occurrence

MCL dose modification after 
recovery

CLL/WM dose modification after 
recovery

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

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.



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Paediatric population
The safety and efficacy of IMBRUVICA in children and adolescents aged 0 to 18 years have not been
established. No data are available.

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).

4.3 Contraindications

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.

4.4 Special warnings and precautions for use

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 



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and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for 
fever, 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.

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.



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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. 

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 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 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.

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.

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 



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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).

4.5 Interaction with other medicinal products and other forms of interaction

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, nefazodon, 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. 



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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 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. 

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.



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4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile
The safety profile is based on pooled data from 1200 patients treated with IMBRUVICA in three 
phase 2 clinical studies and six 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, haemorrhage (e.g., 
bruising), neutropenia, musculoskeletal pain, nausea, and thrombocytopenia. The most common
grade 3/4 adverse reactions (≥5%) were neutropenia, pneumonia, and thrombocytopenia.

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.

Table 1: 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*

16
18
14

10
1
3

Common Sepsis*#

Urinary tract infection
Sinusitis*

5
10
10

4
2
1

Uncommon Cryptococcal infections* <1 0

Pneumocystis infections* # 1 1

Aspergillus infections* 1 <1

Hepatitis B reactivation@ # <1 <1

Neoplasms benign and 
malignant (incl cysts and 
polyps)

Common Non-melanoma skin cancer*

Basal cell carcinoma
Squamous cell carcinoma

6
3
2

1
<1
<1

Blood and lymphatic 
system disorders

Very common Neutropenia
Thrombocytopenia

30
21

26
10

Common Febrile neutropenia
Leukocytosis
Lymphocytosis

5
2
1

5
1
1

Rare Leukostasis syndrome <1 <1
Immune system disorders Common Interstitial lung disease*,#,a 2 <1

Metabolism and nutrition 
disorders

Common Tumour lysis syndromea

Hyperuricaemia

1
8

1
2

Nervous system disorders Very common Headache 13 1
Common Peripheral neuropathy*,a

Dizziness

5
9

<1
0



10

Uncommon Cerebrovascular accident a, #

Transient ischaemic attacka

Ischaemic stroke a, #

<1
1

<1

<1
<1
<1

Eye disorders Common Vision blurred 7 0
Cardiac disorders Common Cardiac failurea,*

Atrial fibrillation

2
7

1
4

Uncommon Ventricular tachyarrhythmia*,a,b 1 <1

Vascular disorders Very common Haemorrhage*#

Bruising*

Hypertension*

31
22
12

1
1
5

Common Epistaxis
Petechiae

8
7

<1
0

Uncommon Subdural haematoma# 1 1

Gastrointestinal disorders Very common Diarrhoea
Vomiting
Stomatitis*

Nausea
Constipation

39
13
12
25
16

3
<1
1
1

<1

Hepatobiliary disorders Uncommon Hepatic failure*,a # <1 <1

Skin and subcutaneous 
tissue disorders

Very common Rash* 31 3

Common Urticariaa

Erythemaa

Onychoclasisa

1
2
3

<1
0
0

Uncommon Angioedemaa

Panniculitis*,a

Neutrophilic dermatoses*, a

<1
1

<1

<1
0

<1

Not known Stevens-Johnson syndromea Not known Not known

Musculoskeletal and 
connective tissue 
disorders

Very common Arthralgia
Muscle spasms
Musculoskeletal pain*

14
14
30

1
<1
3

General disorders and 
administration site 
conditions

Very common Pyrexia
Oedema peripheral

20
15

2
1

† Frequencies are rounded to the nearest integer.
* Includes multiple adverse reaction terms.
# Includes events with fatal outcome.
@ Lower level term (LLT) used for selection.
a Spontaneous reports from post-marketing experience.
b Frequency calculated from monotherapy clinical studies.

Description of selected adverse reactions
Discontinuation and dose reduction due to adverse reactions
Of the 1200 patients treated with IMBRUVICA for B-cell malignancies, 5% discontinued treatment 
primarily due to adverse reactions. These included pneumonia, atrial fibrillation, haemorrhage, and 
thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 7% of 
patients.

Elderly
Of the 1200 patients treated with IMBRUVICA, 64% were 65 years of age or older. Grade 3 or higher 
pneumonia occurred more frequently among elderly patients treated with IMBRUVICA (12% of 
patients age ≥65 versus 7% of patients <65 years of age).

Long-term safety
The long-term safety data over 5 years from 1178 patients (treatment-naïve CLL/SLL n = 162, 
relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370) treated with 
IMBRUVICA were 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 



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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%.

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.

4.9 Overdose

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE27.

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.

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.

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Effect on QT/QTc interval and cardiac electrophysiology
The effect of ibrutinib on the QTc interval was evaluated in 20 healthy male and female subjects in a 
randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic 
dose of 1,680 mg, ibrutinib did not prolong the QTc interval to any clinically relevant extent. The 
largest upper bound of the 2-sided 90% CI for the baseline adjusted mean differences between 
ibrutinib and placebo was below 10 ms. In this same study, a concentration dependent shortening in 
the QTc interval was observed (-5.3 ms [90% CI: -9.4, -1.1] at a Cmax of 719 ng/mL following the 
supratherapeutic dose of 1,680 mg).

Clinical efficacy and safety
MCL
The safety and efficacy of IMBRUVICA in patients with relapsed or refractory MCL were evaluated 
in a single open-label, multi-center phase 2 study (PCYC-1104-CA) of 111 patients. The median age 
was 68 years (range: 40 to 84 years), 77% were male and 92% were Caucasian. Patients with Eastern 
Cooperative Oncology Group (ECOG) performance status of 3 or greater were excluded from the 
study. The median time since diagnosis was 42 months, and median number of prior treatments was 
3 (range: 1 to 5 treatments), including 35% with prior high-dose chemotherapy, 43% with prior 
bortezomib, 24% with prior lenalidomide, and 11% with prior autologous or allogeneic stem cell 
transplant. At baseline, 39% of patients had bulky disease (≥5 cm), 49% had high-risk score by 
Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal 
and/or bone marrow involvement) at screening.

IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable 
toxicity. Tumour response was assessed according to the revised International Working Group (IWG) 
for non-Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in this study was 
investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 2.

Table 2: ORR and DOR in patients with relapsed or refractory MCL (Study
PCYC-1104-CA)

Total
N=111

ORR (%) 67.6
95% CI (%) (58.0; 76.1)
CR (%) 20.7
PR (%) 46.8
Median DOR (CR+PR) (months) 17.5 (15.8, NR)
Median time to initial response, months (range) 1.9 (1.4-13.7)
Median time to CR, months (range) 5.5 (1.7-11.5)
CI=confidence interval; CR=complete response; DOR=duration of response; ORR=overall response rate; PR=partial 
response; NR=not reached

The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an 
ORR of 69%, with a 21% complete response (CR) rate and a 48% partial response (PR) rate. The IRC 
estimated median DOR was 19.6 months.

The overall response to IMBRUVICA was independent of prior treatment including bortezomib and 
lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age.

The safety and efficacy of IMBRUVICA were demonstrated in a randomised phase 3, open-label, 
multicenter study including 280 patients with MCL who received at least one prior therapy (Study 
MCL3001). Patients were randomised 1:1 to receive either IMBRUVICA orally at 560 mg once daily 
for 21 days or temsirolimus intravenously at 175 mg on Days 1, 8, 15 of the first cycle followed by 
75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until 
disease progression or unacceptable toxicity. The median age was 68 years (range, 34; 88 years), 74% 
were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median 
number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high-dose 



13

chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell 
transplant. At baseline, 53% of patients had bulky disease (≥5 cm), 21% had high-risk score by 
Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening.

Progression-free survival (PFS) was assessed by IRC according to the revised International Working 
Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. Efficacy results for Study MCL3001 are 
shown in Table 3 and the Kaplan-Meier curve for PFS in Figure 1.

Table 3: Efficacy Results in patients with relapsed or refractory MCL (Study MCL3001)
Endpoint IMBRUVICA

N=139
Temsirolimus

N=141
PFSa

Median PFS (95% CI), (months)
14.6 (10.4, NE) 6.2 (4.2, 7.9)

HR=0.43 [95% CI: 0.32, 0.58]
ORR (%) 71.9 40.4
p-value p<0.0001
NE=not estimable; HR=hazard ratio; CI=confidence interval; ORR=overall response rate; PFS=progression-free survival
a IRC evaluated.

A smaller proportion of patients treated with ibrutinib experienced a clinically meaningful worsening 
of lymphoma symptoms versus temsirolimus (27% versus 52%) and time to worsening of symptoms 
occurred more slowly with ibrutinib versus temsirolimus (HR 0.27, p<0.0001).

Figure 1: Kaplan-Meier curve of PFS (ITT Population) in Study MCL3001



14

CLL
Patients previously untreated for CLL
Single agent
A randomised, multicenter, open-label phase 3 study (PCYC-1115-CA) of IMBRUVICA versus 
chlorambucil was conducted in patients with treatment-naïve CLL who were 65 years of age or older. 
Patients between 65 and 70 years of age were required to have at least one comorbidity that precluded
the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab.
Patients (n=269) were randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease 
progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on days 1 and 15 
of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up 
to 0.8 mg/kg based on tolerability. After confirmed disease progression, patients on chlorambucil were 
able to crossover to ibrutinib.

The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. 
Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an 
ECOG performance status of 2. The study enrolled 269 patients with CLL. At baseline, 45% had 
advanced clinical stage (Rai Stage III or IV), 35% of patients had at least one tumor ≥5 cm, 39% with 
baseline anaemia, 23% with baseline thrombocytopenia, 65% had elevated β2 microglobulin 
>3500 mcg/L, 47% had a CrCL <60 mL/min, 20% of patients presented with del11q, 6% of patients 
presented with del17p/tumor protein 53 (TP53) mutation, and 44% of patients presented with 
unmutated immunoglobulin heavy chain variable region (IGHV).

Progression free survival (PFS) as assessed by IRC according to International Workshop on CLL
(IWCLL) criteria indicated an 84% statistically significant reduction in the risk of death or progression 
in the IMBRUVICA arm. Efficacy results for Study PCYC-1115-CA are shown in Table 4 and the 
Kaplan-Meier curves for PFS and OS are shown in Figures 2 and 3, respectively.

There was a statistically significant sustained platelet or haemoglobin improvement in the ITT 
population in favor of ibrutinib versus chlorambucil. In patients with baseline cytopenias, sustained 
haematologic improvement was: platelets 77.1% versus 42.9%; haemoglobin 84.3% versus 45.5% for 
ibrutinib and chlorambucil respectively.

Table 4: Efficacy results in Study PCYC-1115-CA
Endpoint IMBRUVICA

N=136
Chlorambucil

N=133
PFSa

Number of events (%) 15 (11.0) 64 (48.1)
Median (95% CI), months Not reached 18.9 (14.1, 22.0)
HR (95% CI) 0.161 (0.091, 0.283)
ORRa (CR+PR) 82.4% 35.3%
P-value <0.0001
OSb

Number of deaths (%) 3 (2.2) 17 (12.8)
HR (95% CI) 0.163 (0.048, 0.558)
CI=confidence interval; HR=hazard ratio; CR=complete response; ORR=overall response rate; OS=overall survival; 
PFS=progression-free survival; PR=partial response
a IRC evaluated, median follow-up 18.4 months.
b Median OS not reached for both arms. p<0.005 for OS



15

Figure 2: Kaplan-Meier curve of PFS (ITT Population) in Study PCYC-1115-CA

Figure 3: Kaplan-Meier curve of OS (ITT Population) in Study PCYC-1115-CA

48-month follow-up
With a median follow-up time on study of 48 months in Study PCYC-1115-CA and its extension 
study, an 86% reduction in the risk of death or progression by investigator assessment was observed 
for patients in the IMBRUVICA arm. The median investigator-assessed PFS was not reached in the 
IMBRUVICA arm and was 15 months [95% CI (10.22, 19.35)] in the chlorambucil arm; (HR=0.14 
[95% CI (0.09, 0.21)]). The 4-year PFS estimate was 73.9% in the IMBRUVICA arm and 15.5% in 



16

the chlorambucil arm, respectively. The updated Kaplan-Meier curve for PFS is shown in Figure 4. 
The investigator-assessed ORR was 91.2% in the IMBRUVICA arm versus 36.8% in the chlorambucil 
arm. The CR rate according to IWCLL criteria was 16.2% in the IMBRUVICA arm versus 3.0% in the 
chlorambucil arm. At the time of long-term follow-up, a total of 73 subjects (54.9%) originally 
randomised to the chlorambucil arm subsequently received ibrutinib as cross-over treatment. The 
Kaplan-Meier landmark estimate for OS at 48-months was 85.5% in the IMBRUVICA arm.

The treatment effect of ibrutinib in Study PCYC-1115-CA was consistent across high-risk patients 
with del17p/TP53 mutation, del11q, and/or unmutated IGHV.

Figure 4: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1115-CA with 48 
Months Follow-up

Combination therapy
The safety and efficacy of IMBRUVICA in patients with treatment naïve 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 study 
enrolled patients who were 65 years of age or older or <65 years of age with coexisting medical 
conditions, reduced renal function as measured by creatinine clearance <70 mL/min, or presence of 
del17p/TP53 mutation. Patients (n=229) were randomised 1:1 to receive either IMBRUVICA 420 mg 
daily until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on 
Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1000 mg of 
obinutuzumab on Days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 
5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided 
between day 1 (100 mg) and day 2 (900 mg). 

The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were Caucasian. All 
patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). At baseline, 52% had 
advanced clinical stage (Rai Stage III or IV), 32% of patients had bulky disease (≥5 cm), 44% with 
baseline anaemia, 22% with baseline thrombocytopenia, 28% had a CrCL <60 mL/min, and the 
median Cumulative Illness Rating Score for Geriatrics (CIRS-G) was 4 (range, 0 to 12). At baseline, 
65% of patients presented with CLL/SLL with high risk factors (del17p/TP53 mutation [18%], del11q 
[15%], or unmutated IGHV [54%]). 



17

Progression-free survival (PFS) was assessed by IRC according to IWCLL criteria indicated a 77% 
statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. With a 
median follow-up time on study of 31 months, the median PFS was not reached in the 
IMBRUVICA+obinutuzumab arm and was 19 months in the chlorambucil+obinutuzumab arm. 
Efficacy results for Study PCYC-1130-CA are shown in Table 5 and the Kaplan-Meier curve for PFS 
is shown in Figure 5.

Table 5: Efficacy results in Study PCYC-1130-CA

Endpoint
IMBRUVICA+Obinutuzumab

N=113
Chlorambucil+Obinutuzumab

N=116
Progression Free Survivala

Number of events (%) 24 (21.2) 74 (63.8)
Median (95% CI), months Not reached 19.0 (15.1, 22.1)
HR (95% CI) 0.23 (0.15, 0.37)
Overall Response Ratea

(%)
88.5 73.3

CRb 19.5 7.8
PRc 69.0 65.5
CI=confidence interval; HR=hazard ratio; CR=complete response; PR=partial response.
a IRC evaluated.
b Includes 1 patient in the IMBRUVICA+obinutuzumab arm with a complete response with incomplete 

marrow recovery (CRi).
c PR=PR+nPR. 

Figure 5: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1130-CA

The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population 
(del17p/TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.15 [95% CI (0.09, 0.27)], 
as shown in Table 6. The 2-year PFS rate estimates for the high-risk CLL/SLL population were 78.8% 
[95% CI (67.3, 86.7)] and 15.5% [95% CI (8.1, 25.2)] in the IMBRUVICA+obinutuzumab and 
chlorambucil+obinutuzumab arms, respectively.



18

Table 6: Subgroup Analysis of PFS (Study PCYC-1130-CA)
N Hazard Ratio 95% CI

All subjects 229 0.231 0.145, 0.367
High risk (del17p/TP53/del11q/unmutated IGHV)
Yes 148 0.154 0.087, 0.270
No 81 0.521 0.221, 1.231
Del17p/TP53
Yes 41 0.109 0.031, 0.380
No 188 0.275 0.166, 0.455
FISH
Del17p 32 0.141 0.039, 0.506
Del11q 35 0.131 0.030, 0.573
Others 162 0.302 0.176, 0.520
Unmutated IGHV
Yes 123 0.150 0.084, 0.269
No 91 0.300 0.120, 0.749
Age
<65 46 0.293 0.122, 0.705
≥65 183 0.215 0.125, 0.372
Bulky disease
<5 cm 154 0.289 0.161, 0.521
≥5 cm 74 0.184 0.085, 0.398
Rai stage
0/I/II 110 0.221 0.115, 0.424
III/IV 119 0.246 0.127, 0.477
ECOG per CRF
0 110 0.226 0.110, 0.464
1-2 119 0.239 0.130, 0.438
Hazard ratio based on non-stratified analysis

Any grade infusion-related reactions were observed in 25% of patients treated with 
IMBRUVICA+obinutuzumab and 58% of patients treated with chlorambucil+obinutuzumab. Grade 3 
or higher or serious infusion-related reactions were observed in 3% of patients treated with 
IMBRUVICA+obinutuzumab and 9% of patients treated with chlorambucil+obinutuzumab.

Patients with CLL who received at least one prior therapy
Single agent
The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled 
study and one randomised, controlled study. The open-label, multi-center study (PCYC-1102-CA) 
included 51 patients with relapsed or refractory CLL, who received 420 mg once daily. IMBRUVICA
was administered until disease progression or unacceptable toxicity. The median age was 68 years 
(range: 37 to 82 years), median time since diagnosis was 80 months, and median number of prior 
treatments was 4 (range: 1 to 12 treatments), including 92.2% with a prior nucleoside analog, 98.0% 
with prior rituximab, 86.3% with a prior alkylator, 39.2% with prior bendamustine and 19.6% with 
prior ofatumumab. At baseline, 39.2% of patients had Rai Stage IV, 45.1% had bulky disease (≥5 cm), 
35.3% had deletion 17p and 31.4% had deletion 11q.

ORR was assessed according to the 2008 IWCLL criteria by investigators and IRC. At a median 
duration follow up of 16.4 months, the ORR by IRC for the 51 relapsed or refractory patients was 
64.7% (95% CI: 50.1%; 77.6%), all PRs. The ORR including PR with lymphocytosis was 70.6%.
Median time to response was 1.9 months. The DOR ranged from 3.9 to 24.2+ months. The median 
DOR was not reached.

A randomised, multi-center, open-label phase 3 study of IMBRUVICA versus ofatumumab 
(PCYC-1112-CA) was conducted in patients with relapsed or refractory CLL. Patients (n=391) were 
randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable 



19

toxicity, or ofatumumab for up to 12 doses (300/2,000 mg). Fifty-seven patients randomised to 
ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 
67 years (range: 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline 
ECOG performance status of 0 or 1. The median time since diagnosis was 91 months and the median 
number of prior treatments was 2 (range: 1 to 13 treatments). At baseline, 58% of patients had at least 
one tumour ≥5 cm. Thirty-two percent of patients had deletion 17p (with 50% of patients having 
deletion 17p/TP53 mutation), 24% had 11q deletion, and 47% of patients had unmutated IGHV.

Progression free survival (PFS) as assessed by an IRC according to IWCLL criteria indicated a 78% 
statistically significant reduction in the risk of death or progression for patients in the IMBRUVICA 
arm. Analysis of OS demonstrated a 57% statistically significant reduction in the risk of death for 
patients in the IMBRUVICA arm. Efficacy results for Study PCYC-1112-CA are shown in Table 7.

Table 7: Efficacy results in patients with CLL (Study PCYC-1112-CA)
Endpoint IMBRUVICA

N=195
Ofatumumab

N=196
Median PFS Not reached 8.1 months

HR=0.215 [95% CI: 0.146; 0.317]
OSa HR=0.434 [95% CI: 0.238; 0.789]b

HR=0.387 [95% CI: 0.216; 0.695]c

ORRd, e (%) 42.6 4.1
ORR including PR with 
lymphocytosisd (%)

62.6 4.1

HR=hazard ratio; CI=confidence interval; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PR=partial response
a Median OS not reached for both arms. p<0.005 for OS.
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 8).

Table 8: Subgroup analysis of PFS (Study PCYC-1112-CA)
N Hazard Ratio 95% CI

All subjects 391 0.210 (0.143; 0.308)
Del17P
Yes 127 0.247 (0.136; 0.450)
No 264 0.194 (0.117; 0.323)
Refractory disease to purine analog
Yes 175 0.178 (0.100; 0.320)
No 216 0.242 (0.145; 0.404)
Age
<65 152 0.166 (0.088; 0.315)
≥65 239 0.243 (0.149; 0.395)
Number of prior lines
<3 198 0.189 (0.100; 0.358)
≥3 193 0.212 (0.130; 0.344)
Bulky disease
<5 cm 163 0.237 (0.127; 0.442)
≥5 cm 225 0.191 (0.117; 0.311)
Hazard ratio based on non-stratified analysis



20

The Kaplan-Meier curve for PFS is shown in Figure 6.

Figure 6: 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 7. 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. 



21

Figure 7: 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, multicenter, 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 9.

Table 9: Efficacy Results in patients with CLL (Study CLL3001)

Endpoint
IMBRUVICA+BR

N=289
Placebo+BR

N=289
PFSa

Median (95% CI), months
Not reached 13.3 (11.3, 13.9)

HR=0.203 [95% CI: 0.150, 0.276]
ORRb % 82.7 67.8
OSc HR=0.628 [95% CI: 0.385, 1.024]
CI=confidence interval; HR=hazard ratio; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival
a IRC evaluated.
b IRC evaluated, ORR (complete response, complete response with incomplete marrow recovery, nodular partial 

response, partial response).
c Median OS not reached for both arms.



22

WM
Single agent
The safety and efficacy of IMBRUVICA in WM (IgM-excreting lymphoplasmacytic lymphoma) were
evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median 
age was 63 years (range: 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a 
baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the 
median number of prior treatments was 2 (range: 1 to 11 treatments). At baseline, the median serum 
IgM value was 3.5 g/dL, and 60% of patients were anaemic (haemoglobin ≤11 g/dL or 6.8 mmol/L).

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable 
toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR 
were assessed using criteria adopted from the Third International Workshop of WM. Responses to 
IMBRUVICA are shown in Table 10.

Table 10: ORR and DOR in patients with WM
Total (N=63)

ORR (%) 87.3
95% CI (%) (76.5, 94.4)
VGPR (%) 14.3
PR (%) 55.6
MR (%) 17.5
Median DOR months (range) NR (0.03+, 18.8+)
CI=confidence interval; DOR=duration of response; NR=not reached; MR=minor response; PR=partial response; 
VGPR=very good partial response; ORR=MR+PR+VGPR
Median follow-up time on study=14.8 months

The median time to response was 1.0 month (range: 0.7-13.4 months).
Efficacy results were also assessed by an IRC demonstrating an ORR of 83%, with a 11% VGPR rate 
and a 51% PR rate.

Combination therapy
The safety and efficacy of IMBRUVICA in WM were further evaluated in patients with 
treatment-naïve or previously treated WM in a randomised, 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 randomised 1:1 to receive either IMBRUVICA 420 mg 
daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. 
Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) 
followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).

The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. 
Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients 
had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 
55% of patients were previously treated. The median time since diagnosis was 52.6 months 
(treatment-naïve patients=6.5 months and previously treated patients=94.3 months). Among 
previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). 
At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were 
anaemic (haemoglobin ≤11 g/dL 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.



23

Table 11: Efficacy results in Study PCYC-1127-CA

Endpoint
IMBRUVICA+R

N=75
Placebo+R

N=75
Progression Free Survivala

Number of events (%) 14 (18.7) 42 (56.0)
Median (95% CI), months Not reached 20.3 (13.7, 27.6)
HR (95% CI) 0.20 (0.11, 0.38)
TTnT
Median (95% CI), months Not reached 18.1 (11.1, NE)
HR (95% CI) 0.1 (0.04, 0.23)
Best Overall Response (%)
CR 2.7 1.3
VGPR 22.7 4.0
PR 46.7 26.7
MR 20.0 14.7
Overall Response Rate (CR, 
VGPR, PR, MR)b (%)

92.0 46.7

Median duration of overall 
response, months (range)

Not reached (1.9+, 36.4+) 24.8 (1.9, 30.3+)

Response Rate (CR, VGPR, PR)b

(%)
72.0 32.0

Median duration of response, 
months (range)

Not reached (1.9+, 36.4+) 21.2 (4.6, 25.8)

Rate of Sustained Haemoglobin 
Improvementb, c (%)

73.3 41.3

CI=confidence interval; CR=complete response; HR=hazard ratio; MR=minor response; NE=not estimable; 
PR=partial response; R=Rituximab; TTnT=time to next treatment; VGPR=very good partial response
a IRC evaluated.
b p-value associated with response rate was <0.0001.
c Defined as increase of ≥2 g/dL over baseline regardless of baseline value, or an increase to >11 g/dL with 

a ≥0.5 g/dL improvement if baseline was ≤11 g/dL.
Median follow-up time on study=26.5 months.



24

Figure 8: 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.

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.

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).

5.2 Pharmacokinetic properties

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



25

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.
After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 
90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the faeces 
and <10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the 
radiolabeled excretion product in faeces and none in urine.

Special populations
Elderly
Population pharmacokinetics indicated that age does not significantly influence ibrutinib clearance 
from the circulation.

Paediatric population
No pharmacokinetic studies were performed with IMBRUVICA in patients under 18 years of age.

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

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

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

Renal impairment
Ibrutinib has minimal renal clearance; urinary excretion of metabolites is <10% of the dose. No 
specific studies have been conducted to date in subjects with impaired renal function. There are no 
data in patients with severe renal impairment or patients on dialysis (see section 4.2).

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 (AUClast) 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 



26

to 3.3% in plasma from matched healthy controls within this study. The corresponding increase in 
unbound ibrutinib exposure (AUCunbound, 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 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).

5.3 Preclinical safety data

The following adverse effects were seen in studies of 13-weeks duration in rats and dogs. Ibrutinib 
was found to induce gastrointestinal effects (soft faeces/diarrhoea and/or inflammation) and lymphoid 
depletion in rats and dogs with a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day in 
both species. Based on mean exposure (AUC) at the 560 mg/day clinical dose, AUC ratios were 
2.6 and 21 at the NOAEL in male and female rats, and 0.4 and 1.8 at the NOAEL in male and female 
dogs, respectively. Lowest Observed Effect Level (LOEL) (60 mg/kg/day) margins in the dog are 
3.6-fold (males) and 2.3-fold (females). In rats, moderate pancreatic acinar cell atrophy (considered 
adverse) was observed at doses of ≥100 mg/kg in male rats (AUC exposure margin of 2.6-fold) and 
not observed in females at doses up to 300 mg/kg/day (AUC exposure margin of 21.3-fold). Mildly 
decreased trabecular and cortical bone was seen in female rats administered ≥100 mg/kg/day (AUC 
exposure margin of 20.3-fold). All gastrointestinal, lymphoid and bone findings recovered following 
recovery periods of 6-13 weeks. Pancreatic findings partially recovered during comparable reversal 
periods.

Juvenile toxicity studies have not been conducted.

Carcinogenicity/genotoxicity
Ibrutinib was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse at oral doses up 
to 2000 mg/kg/day with an exposure margin of approximately 23 (males) to 37 (females) times the 
human AUC of ibrutinib at a dose of 560 mg daily.
Ibrutinib has no genotoxic properties when tested in bacteria, mammalian cells or in mice.

Reproductive toxicity
In pregnant rats, ibrutinib at a dose of 80 mg/kg/day was associated with increased post-implantation 
loss and increased visceral (heart and major vessels) malformations and skeletal variations with an
exposure margin 14 times the AUC found in patients at a daily dose of 560 mg. At a dose of 
≥40 mg/kg/day, ibrutinib was associated with decreased foetal weights (AUC ratio of ≥5.6 as 
compared to daily dose of 560 mg in patients). Consequently the foetal NOAEL was 10 mg/kg/day 
(approximately 1.3 times the AUC of ibrutinib at a dose of 560 mg daily) (see section 4.6).

In pregnant rabbits, ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal 
malformations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with 
increased post-implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15 mg/kg/day 
(approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560 mg 
daily and 2.8 times the exposure in patients with CLL or WM receiving ibrutinib dose 420 mg per 
day). Consequently the foetal NOAEL was 5 mg/kg/day (approximately 0.7 times the AUC of 
ibrutinib at a dose of 560 mg daily) (see section 4.6).

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 (HED 16 mg/kg/day).



27

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Croscarmellose sodium
Magnesium stearate
Microcrystalline cellulose
Sodium lauril sulfate (E487)

Capsule shell
Gelatin
Titanium dioxide (E171)

Printing ink
Shellac
Black iron oxide (E172)
Propylene glycol (E1520)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

HDPE bottles with a child-resistant polypropylene closure.

Each carton contains one bottle of either 90 or 120 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/001 (90 hard capsules)
EU/1/14/945/002 (120 hard capsules)



28

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 October 2014
Date of latest renewal: 25 June 2019

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


29

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

IMBRUVICA 140 mg film-coated tablets
Each film-coated tablet contains 140 mg of ibrutinib.

Excipients with known effect
Each 140 mg film-coated tablet contains 28 mg of lactose monohydrate.

IMBRUVICA 280 mg film-coated tablets
Each film-coated tablet contains 280 mg of ibrutinib.

Excipients with known effect
Each 280 mg film-coated tablet contains 56 mg of lactose monohydrate.

IMBRUVICA 420 mg film-coated tablets
Each film-coated tablet contains 420 mg of ibrutinib.

Excipients with known effect
Each 420 mg film-coated tablet contains 84 mg of lactose monohydrate.

IMBRUVICA 560 mg film-coated tablets
Each film-coated tablet contains 560 mg of ibrutinib.

Excipients with known effect
Each 560 mg film-coated tablet contains 112 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

IMBRUVICA 140 mg film-coated tablets
Yellow-green to green round tablets (9 mm), debossed with “ibr” on one side and “140” on the other 
side.

IMBRUVICA 280 mg film-coated tablets
Purple oblong tablets (15 mm in length and 7 mm in width), debossed with “ibr” on one side and 
“280” on the other side.

IMBRUVICA 420 mg film-coated tablets
Yellow-green to green oblong tablets (17.5 mm in length and 7.4 mm in width), debossed with “ibr” 
on one side and “420” on the other side.

IMBRUVICA 560 mg film-coated tablets
Yellow to orange oblong tablets (19 mm in length and 8.1 mm in width), debossed with “ibr” on one 
side and “560” on the other side.



30

4. CLINICAL PARTICULARS

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

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, either as a single agent or in combination, is 420 mg 
once daily (for details of the combination regimen, 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 therapies, it is recommended to 
administer IMBRUVICA prior to rituximab or obinutuzumab 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 ≥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), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity 
reoccurs, the once daily dose should be reduced by 140 mg. A second reduction of dose by 140 mg 
may be considered as needed. If these toxicities persist or recur following two dose reductions, 
discontinue the medicinal product.



31

Recommended dose modifications are described below:

Toxicity 
occurrence

MCL dose modification after 
recovery

CLL/WM dose modification after 
recovery

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

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
The safety and efficacy of IMBRUVICA in children and adolescents aged 0 to 18 years have not been 
established. No data are available.

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).

4.3 Contraindications

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.



32

4.4 Special warnings and precautions for use

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, 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.



33

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 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. 

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 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 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.

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, 



34

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.

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).

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

4.5 Interaction with other medicinal products and other forms of interaction

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, nefazodon, 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).



35

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 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 



36

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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile
The safety profile is based on pooled data from 1200 patients treated with IMBRUVICA in three 
phase 2 clinical studies and six 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, haemorrhage (e.g., 
bruising), neutropenia, musculoskeletal pain, nausea, and thrombocytopenia. The most common
grade 3/4 adverse reactions (≥5%) were neutropenia, pneumonia, and thrombocytopenia.

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.

Table 1: 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*

16
18
14

10
1
3

Common Sepsis*#

Urinary tract infection
Sinusitis*

5
10
10

4
2
1

Uncommon Cryptococcal infections* <1 0

Pneumocystis infections* # 1 1



37

Aspergillus infections* 1 <1

Hepatitis B reactivation@ # <1 <1

Neoplasms benign and 
malignant (incl cysts 
and polyps)

Common Non-melanoma skin cancer*

Basal cell carcinoma
Squamous cell carcinoma

6
3
2

1
<1
<1

Blood and lymphatic 
system disorders

Very common Neutropenia
Thrombocytopenia

30
21

26
10

Common Febrile neutropenia
Leukocytosis
Lymphocytosis

5
2
1

5
1
1

Rare Leukostasis syndrome <1 <1
Immune system 
disorders

Common Interstitial lung disease*,#,a 2 <1

Metabolism and 
nutrition disorders

Common Tumour lysis syndromea

Hyperuricaemia

1
8

1
2

Nervous system 
disorders

Very common Headache 13 1
Common Peripheral neuropathy*,a

Dizziness

5
9

<1
0

Uncommon Cerebrovascular accident a, #

Transient ischaemic attacka

Ischaemic stroke a, #

<1
1

<1

<1
<1
<1

Eye disorders Common Vision blurred 7 0
Cardiac disorders Common Cardiac failurea,*

Atrial fibrillation

2
7

1
4

Uncommon Ventricular 
tachyarrhythmia*,a,b

1 <1

Vascular disorders Very common Haemorrhage*#

Bruising*

Hypertension*

31
22
12

1
1
5

Common Epistaxis
Petechiae

8
7

<1
0

Uncommon Subdural haematoma# 1 1

Gastrointestinal 
disorders

Very common Diarrhoea
Vomiting
Stomatitis*

Nausea
Constipation

39
13
12
25
16

3
<1
1
1

<1

Hepatobiliary disorders Uncommon Hepatic failure*,a # <1 <1

Skin and subcutaneous 
tissue disorders

Very common Rash* 31 3

Common Urticariaa

Erythemaa

Onychoclasisa

1
2
3

<1
0
0

Uncommon Angioedemaa <1 <1

Panniculitis*,a

Neutrophilic dermatoses*, a
1

<1
0

<1

Not known Stevens-Johnson syndromea Not known Not known

Musculoskeletal and 
connective tissue 
disorders

Very common Arthralgia
Muscle spasms
Musculoskeletal pain*

14
14
30

1
<1
3

General disorders and 
administration site 
conditions

Very common Pyrexia
Oedema peripheral

20
15

2
1

† Frequencies are rounded to the nearest integer.
* Includes multiple adverse reaction terms.
# Includes events with fatal outcome.
@ Lower level term (LLT) used for selection.
a Spontaneous reports from post-marketing experience.
b Frequency calculated from monotherapy clinical studies.



38

Description of selected adverse reactions
Discontinuation and dose reduction due to adverse reactions
Of the 1200 patients treated with IMBRUVICA for B-cell malignancies, 5% discontinued treatment 
primarily due to adverse reactions. These included pneumonia, atrial fibrillation, haemorrhage, and 
thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 7% of 
patients.

Elderly
Of the 1200 patients treated with IMBRUVICA, 64% were 65 years of age or older. Grade 3 or higher 
pneumonia occurred more frequently among elderly patients treated with IMBRUVICA (12% of 
patients age ≥65 versus 7% of patients <65 years of age).

Long-term safety
The long-term safety data over 5 years from 1178 patients (treatment-naïve CLL/SLL n = 162, 
relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370) treated with 
IMBRUVICA were 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%.

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.

4.9 Overdose

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE27.

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.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


39

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
The effect of ibrutinib on the QTc interval was evaluated in 20 healthy male and female subjects in a 
randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic 
dose of 1,680 mg, ibrutinib did not prolong the QTc interval to any clinically relevant extent. The 
largest upper bound of the 2-sided 90% CI for the baseline adjusted mean differences between 
ibrutinib and placebo was below 10 ms. In this same study, a concentration dependent shortening in 
the QTc interval was observed (-5.3 ms [90% CI: -9.4, -1.1] at a Cmax of 719 ng/mL following the 
supratherapeutic dose of 1,680 mg).

Clinical efficacy and safety
MCL
The safety and efficacy of IMBRUVICA in patients with relapsed or refractory MCL were evaluated 
in a single open-label, multi-center phase 2 study (PCYC-1104-CA) of 111 patients. The median age 
was 68 years (range: 40 to 84 years), 77% were male and 92% were Caucasian. Patients with Eastern 
Cooperative Oncology Group (ECOG) performance status of 3 or greater were excluded from the 
study. The median time since diagnosis was 42 months, and median number of prior treatments was 
3 (range: 1 to 5 treatments), including 35% with prior high-dose chemotherapy, 43% with prior 
bortezomib, 24% with prior lenalidomide, and 11% with prior autologous or allogeneic stem cell 
transplant. At baseline, 39% of patients had bulky disease (≥5 cm), 49% had high-risk score by 
Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal 
and/or bone marrow involvement) at screening.

IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable 
toxicity. Tumour response was assessed according to the revised International Working Group (IWG) 
for non-Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in this study was 
investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 2.

Table 2: ORR and DOR in patients with relapsed or refractory MCL (Study 
PCYC-1104-CA)

Total
N=111

ORR (%) 67.6
95% CI (%) (58.0; 76.1)
CR (%) 20.7
PR (%) 46.8
Median DOR (CR+PR) (months) 17.5 (15.8, NR)
Median time to initial response, months (range) 1.9 (1.4-13.7)
Median time to CR, months (range) 5.5 (1.7-11.5)



40

CI=confidence interval; CR=complete response; DOR=duration of response; ORR=overall response rate; PR=partial 
response; NR=not reached

The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an 
ORR of 69%, with a 21% complete response (CR) rate and a 48% partial response (PR) rate. The IRC 
estimated median DOR was 19.6 months.

The overall response to IMBRUVICA was independent of prior treatment including bortezomib and 
lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age.

The safety and efficacy of IMBRUVICA were demonstrated in a randomised phase 3, open-label, 
multicenter study including 280 patients with MCL who received at least one prior therapy (Study 
MCL3001). Patients were randomised 1:1 to receive either IMBRUVICA orally at 560 mg once daily 
for 21 days or temsirolimus intravenously at 175 mg on Days 1, 8, 15 of the first cycle followed by 
75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until 
disease progression or unacceptable toxicity. The median age was 68 years (range, 34; 88 years), 74% 
were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median 
number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high-dose 
chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell 
transplant. At baseline, 53% of patients had bulky disease (≥5 cm), 21% had high-risk score by 
Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening.

Progression-free survival (PFS) was assessed by IRC according to the revised International Working 
Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. Efficacy results for Study MCL3001 are 
shown in Table 3 and the Kaplan-Meier curve for PFS in Figure 1.

Table 3: Efficacy Results in patients with relapsed or refractory MCL (Study MCL3001)
Endpoint IMBRUVICA

N=139
Temsirolimus

N=141
PFSa

Median PFS (95% CI), (months)
14.6 (10.4, NE) 6.2 (4.2, 7.9)

HR=0.43 [95% CI: 0.32, 0.58]
ORR (%) 71.9 40.4
p-value p<0.0001
NE=not estimable; HR=hazard ratio; CI=confidence interval; ORR=overall response rate; PFS=progression-free survival
a IRC evaluated.

A smaller proportion of patients treated with ibrutinib experienced a clinically meaningful worsening 
of lymphoma symptoms versus temsirolimus (27% versus 52%) and time to worsening of symptoms 
occurred more slowly with ibrutinib versus temsirolimus (HR 0.27, p<0.0001).



41

Figure 1: Kaplan-Meier curve of PFS (ITT Population) in Study MCL3001

CLL
Patients previously untreated for CLL
Single agent
A randomised, multicenter, open-label phase 3 study (PCYC-1115-CA) of IMBRUVICA versus 
chlorambucil was conducted in patients with treatment-naïve CLL who were 65 years of age or older. 
Patients between 65 and 70 years of age were required to have at least one comorbidity that precluded 
the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab. 
Patients (n=269) were randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease 
progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on days 1 and 
15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases 
up to 0.8 mg/kg based on tolerability. After confirmed disease progression, patients on chlorambucil 
were able to crossover to ibrutinib.

The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. 
Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an 
ECOG performance status of 2. The study enrolled 269 patients with CLL. At baseline, 45% had 
advanced clinical stage (Rai Stage III or IV), 35% of patients had at least one tumor ≥5 cm, 39% with 
baseline anaemia, 23% with baseline thrombocytopenia, 65% had elevated β2 microglobulin 
>3500 mcg/L, 47% had a CrCL<60 mL/min, 20% of patients presented with del11q, 6% of patients 
presented with del17p/tumor protein 53 (TP53) mutation, and 44% of patients presented with 
unmutated immunoglobulin heavy chain variable region (IGHV).

Progression free survival (PFS) as assessed by IRC according to International Workshop on CLL 
(IWCLL) criteria indicated an 84% statistically significant reduction in the risk of death or progression 
in the IMBRUVICA arm. Efficacy results for Study PCYC-1115-CA are shown in Table 4 and the 
Kaplan-Meier curves for PFS and OS are shown in Figures 2 and 3, respectively.



42

There was a statistically significant sustained platelet or haemoglobin improvement in the ITT 
population in favor of ibrutinib versus chlorambucil. In patients with baseline cytopenias, sustained 
haematologic improvement was: platelets 77.1% versus 42.9%; haemoglobin 84.3% versus 45.5% for 
ibrutinib and chlorambucil respectively.

Table 4: Efficacy results in Study PCYC-1115-CA
Endpoint IMBRUVICA

N=136
Chlorambucil

N=133
PFSa

Number of events (%) 15 (11.0) 64 (48.1)
Median (95% CI), months Not reached 18.9 (14.1, 22.0)
HR (95% CI) 0.161 (0.091, 0.283)
ORRa (CR+PR) 82.4% 35.3%
P-value <0.0001
OSb

Number of deaths (%) 3 (2.2) 17 (12.8)
HR (95% CI) 0.163 (0.048, 0.558)
CI=confidence interval; HR=hazard ratio; CR=complete response; ORR=overall response rate; OS=overall survival; 
PFS=progression-free survival; PR=partial response
a IRC evaluated, median follow-up 18.4 months.
b Median OS not reached for both arms. p<0.005 for OS

Figure 2: Kaplan-Meier curve of PFS (ITT Population) in Study PCYC-1115-CA



43

Figure 3: Kaplan-Meier curve of OS (ITT Population) in Study PCYC-1115-CA

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

The treatment effect of ibrutinib in Study PCYC-1115-CA was consistent across high-risk patients 
with del17p/TP53 mutation, del11q, and/or unmutated IGHV.



44

Figure 4: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1115-CA with 48 
Months Follow-up

Combination therapy
The safety and efficacy of IMBRUVICA in patients with treatment naïve 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 study 
enrolled patients who were 65 years of age or older or <65 years of age with coexisting medical 
conditions, reduced renal function as measured by creatinine clearance <70 mL/min, or presence of 
del17p/TP53 mutation. Patients (n=229) were randomised 1:1 to receive either IMBRUVICA 420 mg 
daily until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on 
Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1000 mg of 
obinutuzumab on Days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 
5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided 
between day 1 (100 mg) and day 2 (900 mg). 

The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were Caucasian. All 
patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). At baseline, 52% had 
advanced clinical stage (Rai Stage III or IV), 32% of patients had bulky disease (≥5 cm), 44% with 
baseline anaemia, 22% with baseline thrombocytopenia, 28% had a CrCL <60 mL/min, and the 
median Cumulative Illness Rating Score for Geriatrics (CIRS-G) was 4 (range, 0 to 12). At baseline, 
65% of patients presented with CLL/SLL with high risk factors (del17p/TP53 mutation [18%], del11q 
[15%], or unmutated IGHV [54%]). 

Progression-free survival (PFS) was assessed by IRC according to IWCLL criteria indicated a 77% 
statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. With a 
median follow-up time on study of 31 months, the median PFS was not reached in the 
IMBRUVICA+obinutuzumab arm and was 19 months in the chlorambucil+obinutuzumab arm. 
Efficacy results for Study PCYC-1130-CA are shown in Table 5 and the Kaplan-Meier curve for PFS 
is shown in Figure 5.



45

Table 5: Efficacy results in Study PCYC-1130-CA

Endpoint
IMBRUVICA+Obinutuzumab

N=113
Chlorambucil+Obinutuzumab

N=116
Progression Free Survivala

Number of events (%) 24 (21.2) 74 (63.8)
Median (95% CI), months Not reached 19.0 (15.1, 22.1)
HR (95% CI) 0.23 (0.15, 0.37)
Overall Response Ratea

(%)
88.5 73.3

CRb 19.5 7.8
PRc 69.0 65.5
CI=confidence interval; HR=hazard ratio; CR=complete response; PR=partial response.
a IRC evaluated.
b Includes 1 patient in the IMBRUVICA+obinutuzumab arm with a complete response with incomplete 

marrow recovery (CRi).
c PR=PR+nPR. 

Figure 5: Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1130-CA

The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population 
(del17p/TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.15 [95% CI (0.09, 0.27)], 
as shown in Table 6. The 2-year PFS rate estimates for the high-risk CLL/SLL population were 78.8% 
[95% CI (67.3, 86.7)] and 15.5% [95% CI (8.1, 25.2)] in the IMBRUVICA+obinutuzumab and 
chlorambucil+obinutuzumab arms, respectively.

Table 6: Subgroup Analysis of PFS (Study PCYC-1130-CA)
N Hazard Ratio 95% CI

All subjects 229 0.231 0.145, 0.367
High risk (del17p/TP53/del11q/unmutated IGHV)
Yes 148 0.154 0.087, 0.270
No 81 0.521 0.221, 1.231
Del17p/TP53
Yes 41 0.109 0.031, 0.380
No 188 0.275 0.166, 0.455



46

FISH
Del17p 32 0.141 0.039, 0.506
Del11q 35 0.131 0.030, 0.573
Others 162 0.302 0.176, 0.520
Unmutated IGHV
Yes 123 0.150 0.084, 0.269
No 91 0.300 0.120, 0.749
Age
<65 46 0.293 0.122, 0.705
≥65 183 0.215 0.125, 0.372
Bulky disease
<5 cm 154 0.289 0.161, 0.521
≥5 cm 74 0.184 0.085, 0.398
Rai stage
0/I/II 110 0.221 0.115, 0.424
III/IV 119 0.246 0.127, 0.477
ECOG per CRF
0 110 0.226 0.110, 0.464
1-2 119 0.239 0.130, 0.438
Hazard ratio based on non-stratified analysis

Any grade infusion-related reactions were observed in 25% of patients treated with 
IMBRUVICA+obinutuzumab and 58% of patients treated with chlorambucil+obinutuzumab. Grade 3
or higher or serious infusion-related reactions were observed in 3% of patients treated with 
IMBRUVICA+obinutuzumab and 9% of patients treated with chlorambucil+obinutuzumab.

Patients with CLL who received at least one prior therapy
Single agent
The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled 
study and one randomised, controlled study. The open-label, multi-center study (PCYC-1102-CA) 
included 51 patients with relapsed or refractory CLL, who received 420 mg once daily. IMBRUVICA 
was administered until disease progression or unacceptable toxicity. The median age was 68 years 
(range: 37 to 82 years), median time since diagnosis was 80 months, and median number of prior 
treatments was 4 (range: 1 to 12 treatments), including 92.2% with a prior nucleoside analog, 98.0% 
with prior rituximab, 86.3% with a prior alkylator, 39.2% with prior bendamustine and 19.6% with 
prior ofatumumab. At baseline, 39.2% of patients had Rai Stage IV, 45.1% had bulky disease (≥5 cm), 
35.3% had deletion 17p and 31.4% had deletion 11q.

ORR was assessed according to the 2008 IWCLL criteria by investigators and IRC. At a median 
duration follow up of 16.4 months, the ORR by IRC for the 51 relapsed or refractory patients was 
64.7% (95% CI: 50.1%; 77.6%), all PRs. The ORR including PR with lymphocytosis was 70.6%. 
Median time to response was 1.9 months. The DOR ranged from 3.9 to 24.2+ months. The median 
DOR was not reached.

A randomised, multi-center, open-label phase 3 study of IMBRUVICA versus ofatumumab 
(PCYC-1112-CA) was conducted in patients with relapsed or refractory CLL. Patients (n=391) were 
randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable 
toxicity, or ofatumumab for up to 12 doses (300/2,000 mg). Fifty-seven patients randomised to 
ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 
67 years (range: 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline 
ECOG performance status of 0 or 1. The median time since diagnosis was 91 months and the median 
number of prior treatments was 2 (range: 1 to 13 treatments). At baseline, 58% of patients had at least 
one tumour ≥5 cm. Thirty-two percent of patients had deletion 17p (with 50% of patients having 
deletion 17p/TP53 mutation), 24% had 11q deletion, and 47% of patients had unmutated IGHV.

Progression free survival (PFS) as assessed by an IRC according to IWCLL criteria indicated a 78% 
statistically significant reduction in the risk of death or progression for patients in the IMBRUVICA 



47

arm. Analysis of OS demonstrated a 57% statistically significant reduction in the risk of death for 
patients in the IMBRUVICA arm. Efficacy results for Study PCYC-1112-CA are shown in Table 7.

Table 7: Efficacy results in patients with CLL (Study PCYC-1112-CA)
Endpoint IMBRUVICA

N=195
Ofatumumab

N=196
Median PFS Not reached 8.1 months

HR=0.215 [95% CI: 0.146; 0.317]
OSa HR=0.434 [95% CI: 0.238; 0.789]b

HR=0.387 [95% CI: 0.216; 0.695]c

ORRd, e (%) 42.6 4.1
ORR including PR with 
lymphocytosisd (%)

62.6 4.1

HR=hazard ratio; CI=confidence interval; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PR=partial response
a Median OS not reached for both arms. p<0.005 for OS.
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 8).

Table 8: Subgroup analysis of PFS (Study PCYC-1112-CA)
N Hazard Ratio 95% CI

All subjects 391 0.210 (0.143; 0.308)
Del17P
Yes 127 0.247 (0.136; 0.450)
No 264 0.194 (0.117; 0.323)
Refractory disease to purine analog
Yes 175 0.178 (0.100; 0.320)
No 216 0.242 (0.145; 0.404)
Age
<65 152 0.166 (0.088; 0.315)
≥65 239 0.243 (0.149; 0.395)
Number of prior lines
<3 198 0.189 (0.100; 0.358)
≥3 193 0.212 (0.130; 0.344)
Bulky disease
<5 cm 163 0.237 (0.127; 0.442)
≥5 cm 225 0.191 (0.117; 0.311)
Hazard ratio based on non-stratified analysis



48

The Kaplan-Meier curve for PFS is shown in Figure 6.

Figure 6: 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 7. 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.



49

Figure 7: 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, multicenter, 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 9.

Table 9: Efficacy Results in patients with CLL (Study CLL3001) 

Endpoint
IMBRUVICA+BR

N=289
Placebo+BR

N=289
PFSa

Median (95% CI), months
Not reached 13.3 (11.3, 13.9)

HR=0.203 [95% CI: 0.150, 0.276]
ORRb % 82.7 67.8
OSc HR=0.628 [95% CI: 0.385, 1.024]
CI=confidence interval; HR=hazard ratio; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival
a IRC evaluated.
b IRC evaluated, ORR (complete response, complete response with incomplete marrow recovery, nodular partial 

response, partial response).
c Median OS not reached for both arms.



50

WM
Single agent
The safety and efficacy of IMBRUVICA in WM (IgM-excreting lymphoplasmacytic lymphoma) were 
evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median 
age was 63 years (range: 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a 
baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the 
median number of prior treatments was 2 (range: 1 to 11 treatments). At baseline, the median serum 
IgM value was 3.5 g/dL, and 60% of patients were anaemic (haemoglobin ≤11 g/dL or 6.8 mmol/L).

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable 
toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR 
were assessed using criteria adopted from the Third International Workshop of WM. Responses to 
IMBRUVICA are shown in Table 10.

Table 10: ORR and DOR in patients with WM
Total (N=63)

ORR (%) 87.3
95% CI (%) (76.5, 94.4)
VGPR (%) 14.3
PR (%) 55.6
MR (%) 17.5
Median DOR months (range) NR (0.03+, 18.8+)
CI=confidence interval; DOR=duration of response; NR=not reached; MR=minor response; PR=partial response; 
VGPR=very good partial response; ORR=MR+PR+VGPR
Median follow-up time on study=14.8 months

The median time to response was 1.0 month (range: 0.7-13.4 months).
Efficacy results were also assessed by an IRC demonstrating an ORR of 83%, with a 11% VGPR rate 
and a 51% PR rate.

Combination therapy
The safety and efficacy of IMBRUVICA in WM were further evaluated in patients with treatment-
naïve or previously treated WM in a randomised, 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 randomised 1:1 to receive either IMBRUVICA 420 mg 
daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. 
Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) 
followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).

The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. 
Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients 
had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 
55% of patients were previously treated. The median time since diagnosis was 52.6 months (treatment-
naïve patients=6.5 months and previously treated patients=94.3 months). Among previously treated 
patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the 
median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were anaemic 
(haemoglobin ≤11 g/dL 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.



51

Table 11: Efficacy results in Study PCYC-1127-CA

Endpoint
IMBRUVICA+R

N=75
Placebo+R

N=75
Progression Free Survivala

Number of events (%) 14 (18.7) 42 (56.0)
Median (95% CI), months Not reached 20.3 (13.7, 27.6)
HR (95% CI) 0.20 (0.11, 0.38)
TTnT
Median (95% CI), months Not reached 18.1 (11.1, NE)
HR (95% CI) 0.1 (0.04, 0.23)
Best Overall Response (%)
CR 2.7 1.3
VGPR 22.7 4.0
PR 46.7 26.7
MR 20.0 14.7
Overall Response Rate (CR, 
VGPR, PR, MR)b (%)

92.0 46.7

Median duration of overall 
response, months (range)

Not reached (1.9+, 36.4+) 24.8 (1.9, 30.3+)

Response Rate (CR, VGPR, PR)b

(%)
72.0 32.0

Median duration of response, 
months (range)

Not reached (1.9+, 36.4+) 21.2 (4.6, 25.8)

Rate of Sustained Haemoglobin 
Improvementb, c (%)

73.3 41.3

CI=confidence interval; CR=complete response; HR=hazard ratio; MR=minor response; NE=not estimable; 
PR=partial response; R=Rituximab; TTnT=time to next treatment; VGPR=very good partial response
a IRC evaluated.
b p-value associated with response rate was <0.0001.
c Defined as increase of ≥2 g/dL over baseline regardless of baseline value, or an increase to >11 g/dL with 

a ≥0.5 g/dL improvement if baseline was ≤11 g/dL.
Median follow-up time on study=26.5 months.



52

Figure 8: 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.

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.

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).

5.2 Pharmacokinetic properties

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



53

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.
After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 
90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the faeces 
and <10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the 
radiolabeled excretion product in faeces and none in urine.

Special populations
Elderly
Population pharmacokinetics indicated that age does not significantly influence ibrutinib clearance 
from the circulation.

Paediatric population
No pharmacokinetic studies were performed with IMBRUVICA in patients under 18 years of age.

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

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

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

Renal impairment
Ibrutinib has minimal renal clearance; urinary excretion of metabolites is <10% of the dose. No 
specific studies have been conducted to date in subjects with impaired renal function. There are no 
data in patients with severe renal impairment or patients on dialysis (see section 4.2).

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 (AUClast) 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 



54

to 3.3% in plasma from matched healthy controls within this study. The corresponding increase in 
unbound ibrutinib exposure (AUCunbound, 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 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).

5.3 Preclinical safety data

The following adverse effects were seen in studies of 13-weeks duration in rats and dogs. Ibrutinib 
was found to induce gastrointestinal effects (soft faeces/diarrhoea and/or inflammation) and lymphoid 
depletion in rats and dogs with a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day in 
both species. Based on mean exposure (AUC) at the 560 mg/day clinical dose, AUC ratios were 
2.6 and 21 at the NOAEL in male and female rats, and 0.4 and 1.8 at the NOAEL in male and female 
dogs, respectively. Lowest Observed Effect Level (LOEL) (60 mg/kg/day) margins in the dog are 
3.6-fold (males) and 2.3-fold (females). In rats, moderate pancreatic acinar cell atrophy (considered 
adverse) was observed at doses of ≥100 mg/kg in male rats (AUC exposure margin of 2.6-fold) and 
not observed in females at doses up to 300 mg/kg/day (AUC exposure margin of 21.3-fold). Mildly 
decreased trabecular and cortical bone was seen in female rats administered ≥100 mg/kg/day (AUC 
exposure margin of 20.3-fold). All gastrointestinal, lymphoid and bone findings recovered following 
recovery periods of 6-13 weeks. Pancreatic findings partially recovered during comparable reversal 
periods.

Juvenile toxicity studies have not been conducted.

Carcinogenicity/genotoxicity
Ibrutinib was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse at oral doses up 
to 2000 mg/kg/day with an exposure margin of approximately 23 (males) to 37 (females) times the 
human AUC of ibrutinib at a dose of 560 mg daily.
Ibrutinib has no genotoxic properties when tested in bacteria, mammalian cells or in mice.

Reproductive toxicity
In pregnant rats, ibrutinib at a dose of 80 mg/kg/day was associated with increased post-implantation 
loss and increased visceral (heart and major vessels) malformations and skeletal variations with an 
exposure margin 14 times the AUC found in patients at a daily dose of 560 mg. At a dose of 
≥40 mg/kg/day, ibrutinib was associated with decreased foetal weights (AUC ratio of ≥5.6 as 
compared to daily dose of 560 mg in patients). Consequently the foetal NOAEL was 10 mg/kg/day 
(approximately 1.3 times the AUC of ibrutinib at a dose of 560 mg daily) (see section 4.6).

In pregnant rabbits, ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal 
malformations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with 
increased post-implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15 mg/kg/day 
(approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560 mg 
daily and 2.8 times the exposure in patients with CLL or WM receiving ibrutinib dose 420 mg per 
day). Consequently the foetal NOAEL was 5 mg/kg/day (approximately 0.7 times the AUC of 
ibrutinib at a dose of 560 mg daily) (see section 4.6).

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 (HED 16 mg/kg/day).



55

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Colloidal anhydrous silica
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Povidone
Sodium lauril sulfate (E487)

Film-coat
IMBRUVICA 140 mg film-coated tablets and IMBRUVICA 420 mg film-coated tablets
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Black iron oxide (E172)
Yellow iron oxide (E172)

IMBRUVICA 280 mg film-coated tablets
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Black iron oxide (E172)
Red iron oxide (E172)

IMBRUVICA 560 mg film-coated tablets
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Polyvinyl chloride (PVC) laminated with polychlorotrifluoroethylene (PCTFE)/aluminium blister of 
14 film-coated tablets in a cardboard wallet. Each carton contains (28 film-coated tablets) 2 wallets.

Polyvinyl chloride (PVC) laminated with polychlorotrifluoroethylene (PCTFE)/aluminium blister of 
10 film-coated tablets in a cardboard wallet. Each carton contains (30 film-coated tablets) 3 wallets.



56

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

IMBRUVICA 140 mg film-coated tablets
EU/1/14/945/007 – 28 tablets (2 wallet packs of 14)
EU/1/14/945/008 – 30 tablets (3 wallet packs of 10)

IMBRUVICA 280 mg film-coated tablets
EU/1/14/945/009 – 28 tablets (2 wallet packs of 14)
EU/1/14/945/010 – 30 tablets (3 wallet packs of 10)

IMBRUVICA 420 mg film-coated tablets
EU/1/14/945/011 – 28 tablets (2 wallet packs of 14)
EU/1/14/945/005 – 30 tablets (3 wallet packs of 10)

IMBRUVICA 560 mg film-coated tablets
EU/1/14/945/012 – 28 tablets (2 wallet packs of 14)
EU/1/14/945/006 – 30 tablets (3 wallet packs of 10)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 October 2014
Date of latest renewal: 25 June 2019

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


57

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT



58

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

IMBRUVICA Hard Capsules
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

IMBRUVICA Film-Coated Tablets
Janssen-Cilag SpA
Via C. Janssen,
Loc. Borgo S. Michele,
04100 Latina,
Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.



59

ANNEX III

LABELLING AND PACKAGE LEAFLET



60

A. LABELLING



61

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON 140 MG CAPSULE

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg hard capsules
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 140 mg of ibrutinib

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

90 hard capsules
120 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



62

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/001 (90 hard capsules)
EU/1/14/945/002 (120 hard capsules)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 140 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



63

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL 140 MG CAPSULE

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg capsules
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 140 mg of ibrutinib

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

90 capsules
120 capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



64

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/001 (90 hard capsules)
EU/1/14/945/002 (120 hard capsules)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



65

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 140 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 140 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets
30 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



66

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/007 (28 tablets)
EU/1/14/945/008 (30 tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 140 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



67

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 140 MG TABLET (28 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 140 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday

Oral use

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



68

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/007

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 140 mg



69

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



70

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 140 MG TABLET (30 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 140 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

10 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

When you take a tablet, fill in the day of the week or the date in the space provided.

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



71

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/008

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 140 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



72

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 140 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 140 mg tablets
ibrutinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



73

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 280 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 280 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 280 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets
30 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



74

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/009 (28 tablets)
EU/1/14/945/010 (30 tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 280 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



75

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 280 MG TABLET (28 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 280 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 280 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday

Oral use

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



76

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/009

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 280 mg



77

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



78

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 280 MG TABLET (30 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 280 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 280 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

10 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

When you take a tablet, fill in the day of the week or the date in the space provided.

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



79

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/010

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 280 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



80

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 280 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 280 mg tablets
ibrutinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



81

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 420 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 420 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 420 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets
30 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



82

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/011 (28 tablets)
EU/1/14/945/005 (30 tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 420 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



83

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 420 MG TABLET (28 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 420 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 420 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday

Oral use

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



84

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/011

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 420 mg

17. UNIQUE IDENTIFIER – 2D BARCODE



85

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



86

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 420 MG TABLET (30 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 420 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 420 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

10 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

When you take a tablet, fill in the day of the week or the date in the space provided.

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



87

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 420 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



88

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 420 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 420 mg tablets
ibrutinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



89

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 560 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 560 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 560 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets
30 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



90

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/012 (28 tablets)
EU/1/14/945/006 (30 tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 560 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



91

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 560 MG TABLET (28 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 560 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 560 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday

Oral use

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



92

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 560 mg



93

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



94

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

WALLET 560 MG TABLET (30 days)

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 560 mg film-coated tablets
ibrutinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 560 mg of ibrutinib

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

10 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

When you take a tablet, fill in the day of the week or the date in the space provided.

HOW TO TAKE IMBRUVICA
Use as directed by your physician.
Take IMBRUVICA tablet by mouth, at about the same time each day, with a glass of water.
Swallow the tablet whole. Do not break or chew.
If you miss a dose of IMBRUVICA, take it as soon as you remember on the same day. Do not take 
extra doses to make up the missed dose.

Flip open the pack. Push tablet through from other side.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



95

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Dispose of unused medicines as per local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/945/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Imbruvica 560 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



96

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 560 MG TABLET

1. NAME OF THE MEDICINAL PRODUCT

IMBRUVICA 560 mg tablets
ibrutinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



97

B. PACKAGE LEAFLET



98

Package leaflet: Information for the patient

IMBRUVICA 140 mg hard capsules
ibrutinib

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IMBRUVICA is and what it is used for
2. What you need to know before you take IMBRUVICA
3. How to take IMBRUVICA
4. Possible side effects
5. How to store IMBRUVICA
6. Contents of the pack and other information

1. What IMBRUVICA is and what it is used for

What IMBRUVICA is
IMBRUVICA is an anticancer medicine that contains the active substance ibrutinib. It belongs to a 
class of medicines called protein kinase inhibitors.

What IMBRUVICA is used for
It is used to treat the following blood cancers in adults:
 Mantle cell lymphoma (MCL), a type of cancer affecting the lymph nodes, when the disease has 

come back or has not responded to treatment.
 Chronic lymphocytic leukaemia (CLL) a type of cancer affecting white blood cells called 

lymphocytes that also involves the lymph nodes. IMBRUVICA is used in patients who have not 
previously been treated for CLL or when the disease has come back or has not responded to 
treatment.

 Waldenström’s macroglobulinaemia (WM), a type of cancer affecting white blood cells called 
lymphocytes. It is used in patients who have not previously been treated for WM or when the 
disease has come back or has not responded to treatment or in patients for whom chemotherapy
given together with an antibody is not a suitable therapy.

How IMBRUVICA works
In MCL, CLL and WM, IMBRUVICA works by blocking Bruton's tyrosine kinase, a protein in the 
body that helps these cancer cells grow and survive. By blocking this protein, IMBRUVICA helps kill 
and reduce the number of cancer cells. It also slows down the worsening of the cancer.

2. What you need to know before you take IMBRUVICA

Do not take IMBRUVICA
 if you are allergic to ibrutinib or any of the other ingredients of this medicine (listed in 

section 6)
 if you are taking a herbal medicine called St. John’s Wort, used for depression. If you are not 

sure about this, talk to your doctor, pharmacist or nurse before taking this medicine.



99

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking IMBRUVICA:
 if you have ever had unusual bruising or bleeding or are on any medicines or supplements that 

increase your risk of bleeding (see section “Other medicines and IMBRUVICA”)
 if you have irregular heart beat or have a history of irregular heart beat or severe heart failure, or 

if you feel any of the following: shortness of breath, weakness, dizziness, light-headedness, 
fainting or near fainting, chest pain or swollen legs

 if you have liver or kidney problems
 if you have high blood pressure
 if you have recently had any surgery, especially if this might affect how you absorb food or 

medicines from your stomach or gut
 if you are planning to have any surgery– your doctor may ask you to stop taking IMBRUVICA

for a short time (3 to 7 days) before and after your surgery.
 if you have ever had or might now have a hepatitis B infection. This is because IMBRUVICA 

could cause hepatitis B to become active again, which can be fatal. Patients will be carefully 
checked by their doctor for signs of this infection before treatment is started.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking this medicine.

When taking IMBRUVICA, tell your doctor immediately if you notice or someone notices in you: 
memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare but 
serious brain infection which can be fatal (Progressive Multifocal Leukoencephalopathy or PML).

Tell your doctor immediately if you notice or someone notices in you: sudden numbness or weakness 
in the limbs (especially on one side of the body), sudden confusion, trouble speaking or understanding 
speech, sight loss, difficulty walking, loss of balance or lack of coordination, sudden severe headache 
with no known cause. These may be signs and symptoms of stroke.

Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the left rib 
cage or at the tip of your left shoulder (these may be symptoms of rupture of the spleen) after you stop 
taking IMBRUVICA.

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.

Tests and check-ups before and during treatment
Tumour lysis syndrome (TLS): Unusual levels of chemicals in the blood caused by the fast breakdown 
of cancer cells have happened during treatment of cancer and sometimes even without treatment. This 
may lead to changes in kidney function, abnormal heartbeat, or seizures. Your doctor or another
healthcare provider may do blood tests to check for TLS.

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



100

Children and adolescents
IMBRUVICA should not be used in children and adolescents. This is because it has not been studied 
in these age groups.

Other medicines and IMBRUVICA
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription, herbal medicines and 
supplements. This is because IMBRUVICA may affect the way some other medicines work. Also 
some other medicines can affect the way IMBRUVICA works.

IMBRUVICA may make you bleed more easily. This means you should tell your doctor if you take 
other medicines that increase your risk of bleeding. This includes:
 acetyl salicylic acid and non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen or 

naproxen
 blood thinners such as warfarin, heparin or other medicines for blood clots
 supplements that may increase your risk of bleeding such as fish oil, vitamin E or flaxseed.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking IMBRUVICA.

Also tell your doctor if you take any of the following medicines – The effects of IMBRUVICA or 
other medicines may be influenced if you take IMBRUVICA together with any of the following
medicines:
 medicines called antibiotics to treat bacterial infections – clarithromycin, telithromycin, 

ciprofloxacin, erythromycin or rifampicin
 medicines for fungal infections – posaconazole, ketoconazole, itraconazole, fluconazole or 

voriconazole
 medicines for HIV infection – ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, 

atazanavir, or fosamprenavir
 medicines to prevent nausea and vomiting associated with chemotherapy - aprepitant
 medicines for depression - nefazodon
 medicines called kinase inhibitors for treatment of other cancers – crizotinib or imatinib
 medicines called calcium channel blockers for high blood pressure or chest pain – diltiazem or

verapamil
 medicines called statins to treat high cholesterol - rosuvastatin
 heart medicines/anti-arrhythmics – amiodarone or dronedarone
 medicines to prevent seizures or to treat epilepsy, or medicines to treat a painful condition of the 

face called trigeminal neuralgia – carbamazepine or phenytoin.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking IMBRUVICA.

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

IMBRUVICA with food
Do not take IMBRUVICA with grapefruit or Seville oranges (bitter oranges) – this includes 
eating them, drinking the juice or taking a supplement that might contain them. This is because it can 
increase the amount of IMBRUVICA in your blood.

Pregnancy and breast-feeding
Do not get pregnant while you are taking this medicine. IMBRUVICA should not be used during 
pregnancy. There is no information about the safety of IMBRUVICA in pregnant women.



101

Women of childbearing age must use a highly effective method of birth control during and up to three 
months after receiving IMBRUVICA, to avoid becoming pregnant while being treated with 
IMBRUVICA. 

 Tell your doctor immediately if you become pregnant.
 Do not breast-feed while you are taking this medicine.

Driving and using machines
You may feel tired or dizzy after taking IMBRUVICA, which may affect your ability to drive or use 
any tools or machines.

IMBRUVICA contains sodium
IMBRUVICA contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’.

3. How to take IMBRUVICA

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure.

How much to take
Mantle cell lymphoma (MCL)
The recommended dose of IMBRUVICA is four capsules (560 mg) once a day.

Chronic lymphocytic leukaemia (CLL)/Waldenström’s macroglobulinaemia (WM)
The recommended dose of IMBRUVICA is three capsules (420 mg) once a day.

Your doctor may adjust your dose.

Taking this medicine
 Take the capsules orally (by mouth) with a glass of water.
 Take the capsules about the same time each day.
 Swallow the capsules whole. Do not open, break or chew them.

If you take more IMBRUVICA than you should
If you take more IMBRUVICA than you should, talk to a doctor or go to a hospital straight away. 
Take the capsules and this leaflet with you.

If you forget to take IMBRUVICA
 If you miss a dose, it can be taken as soon as possible on the same day with a return to the 

normal schedule the following day.
 Do not take a double dose to make up for a forgotten dose.
 If you are not sure, talk to your doctor, pharmacist or nurse about when to take your next dose.

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

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:



102

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
 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
 swollen hands, ankles or feet
 high blood pressure.

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



103

 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 dysfunction 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).

Rare (may affect up to 1 in 1,000 people)
 severely increased white blood cell count that may cause cells to clump together.

Not known (frequency cannot be estimated from available data)
 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 the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store IMBRUVICA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and bottle label after EXP. 
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What IMBRUVICA contains
 The active substance is ibrutinib. Each hard capsule contains 140 mg of ibrutinib.
 The other ingredients are:

- capsule content: croscarmellose sodium, magnesium stearate, microcrystalline cellulose 
and sodium lauril sulfate (E487)

- capsule shell: gelatin and titanium dioxide (E171)
- printing ink: shellac, black iron oxide (E172), and propylene glycol (E1520).

What IMBRUVICA looks like and contents of the pack
IMBRUVICA are white opaque, hard capsules marked with “ibr 140 mg” in black ink on one side.
The capsules are provided in a plastic bottle with a child resistant polypropylene closure. Each bottle 
contains either 90 or 120 capsules. Each pack contains one bottle.

Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


104

Turnhoutseweg 30
B-2340 Beerse
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD.
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.:+48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800



105

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel.: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800 688 777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tel: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu/


106

Package leaflet: Information for the patient

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

ibrutinib

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IMBRUVICA is and what it is used for
2. What you need to know before you take IMBRUVICA
3. How to take IMBRUVICA
4. Possible side effects
5. How to store IMBRUVICA
6. Contents of the pack and other information

1. What IMBRUVICA is and what it is used for

What IMBRUVICA is
IMBRUVICA is an anticancer medicine that contains the active substance ibrutinib. It belongs to a 
class of medicines called protein kinase inhibitors.

What IMBRUVICA is used for
It is used to treat the following blood cancers in adults:
 Mantle cell lymphoma (MCL), a type of cancer affecting the lymph nodes, when the disease has 

come back or has not responded to treatment.
 Chronic lymphocytic leukaemia (CLL) a type of cancer affecting white blood cells called 

lymphocytes that also involves the lymph nodes. IMBRUVICA is used in patients who have not 
previously been treated for CLL or when the disease has come back or has not responded to 
treatment.

 Waldenström’s macroglobulinaemia (WM), a type of cancer affecting white blood cells called 
lymphocytes. It is used in patients who have not previously been treated for WM or when the 
disease has come back or has not responded to treatment or in patients for whom chemotherapy
given together with an antibody is not a suitable therapy.

How IMBRUVICA works
In MCL, CLL and WM, IMBRUVICA works by blocking Bruton's tyrosine kinase, a protein in the 
body that helps these cancer cells grow and survive. By blocking this protein, IMBRUVICA helps kill 
and reduce the number of cancer cells. It also slows down the worsening of the cancer.

2. What you need to know before you take IMBRUVICA

Do not take IMBRUVICA
 if you are allergic to ibrutinib or any of the other ingredients of this medicine (listed in 

section 6)



107

 if you are taking a herbal medicine called St. John’s Wort, used for depression. If you are not 
sure about this, talk to your doctor, pharmacist or nurse before taking this medicine.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking IMBRUVICA:
 if you have ever had unusual bruising or bleeding or are on any medicines or supplements that 

increase your risk of bleeding (see section “Other medicines and IMBRUVICA”)
 if you have irregular heart beat or have a history of irregular heart beat or severe heart failure, or 

if you feel any of the following: shortness of breath, weakness, dizziness, light-headedness, 
fainting or near fainting, chest pain or swollen legs

 if you have liver or kidney problems
 if you have high blood pressure
 if you have recently had any surgery, especially if this might affect how you absorb food or 

medicines from your stomach or gut
 if you are planning to have any surgery– your doctor may ask you to stop taking IMBRUVICA 

for a short time (3 to 7 days) before and after your surgery.
 if you have ever had or might now have a hepatitis B infection. This is because IMBRUVICA 

could cause hepatitis B to become active again, which can be fatal. Patients will be carefully 
checked by their doctor for signs of this infection before treatment is started.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking this medicine.

When taking IMBRUVICA, tell your doctor immediately if you notice or someone notices in you: 
memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare but 
serious brain infection which can be fatal (Progressive Multifocal Leukoencephalopathy or PML).

Tell your doctor immediately if you notice or someone notices in you: sudden numbness or weakness 
in the limbs (especially on one side of the body), sudden confusion, trouble speaking or understanding 
speech, sight loss, difficulty walking, loss of balance or lack of coordination, sudden severe headache 
with no known cause. These may be signs and symptoms of stroke.

Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the left rib 
cage or at the tip of your left shoulder (these may be symptoms of rupture of the spleen) after you stop 
taking IMBRUVICA.

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.

Tests and check-ups before and during treatment
Tumour lysis syndrome (TLS): Unusual levels of chemicals in the blood caused by the fast breakdown 
of cancer cells have happened during treatment of cancer and sometimes even without treatment. This 
may lead to changes in kidney function, abnormal heartbeat, or seizures. Your doctor or another
healthcare provider may do blood tests to check for TLS.

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



108

Children and adolescents
IMBRUVICA should not be used in children and adolescents. This is because it has not been studied 
in these age groups.

Other medicines and IMBRUVICA
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription, herbal medicines and 
supplements. This is because IMBRUVICA may affect the way some other medicines work. Also 
some other medicines can affect the way IMBRUVICA works.

IMBRUVICA may make you bleed more easily. This means you should tell your doctor if you take 
other medicines that increase your risk of bleeding. This includes:
 acetyl salicylic acid and non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen or 

naproxen
 blood thinners such as warfarin, heparin or other medicines for blood clots
 supplements that may increase your risk of bleeding such as fish oil, vitamin E or flaxseed.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking IMBRUVICA.

Also tell your doctor if you take any of the following medicines – The effects of IMBRUVICA or 
other medicines may be influenced if you take IMBRUVICA together with any of the following
medicines:
 medicines called antibiotics to treat bacterial infections – clarithromycin, telithromycin, 

ciprofloxacin, erythromycin or rifampicin
 medicines for fungal infections – posaconazole, ketoconazole, itraconazole, fluconazole or 

voriconazole
 medicines for HIV infection – ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, 

atazanavir, or fosamprenavir
 medicines to prevent nausea and vomiting associated with chemotherapy - aprepitant
 medicines for depression - nefazodon
 medicines called kinase inhibitors for treatment of other cancers – crizotinib or imatinib
 medicines called calcium channel blockers for high blood pressure or chest pain – diltiazem or

verapamil
 medicines called statins to treat high cholesterol - rosuvastatin
 heart medicines/anti-arrhythmics – amiodarone or dronedarone
 medicines to prevent seizures or to treat epilepsy, or medicines to treat a painful condition of the 

face called trigeminal neuralgia – carbamazepine or phenytoin.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking IMBRUVICA.

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

IMBRUVICA with food
Do not take IMBRUVICA with grapefruit or Seville oranges (bitter oranges) – this includes 
eating them, drinking the juice or taking a supplement that might contain them. This is because it can 
increase the amount of IMBRUVICA in your blood.

Pregnancy and breast-feeding
Do not get pregnant while you are taking this medicine. IMBRUVICA should not be used during 
pregnancy. There is no information about the safety of IMBRUVICA in pregnant women.



109

Women of childbearing age must use a highly effective method of birth control during and up to three 
months after receiving IMBRUVICA, to avoid becoming pregnant while being treated with 
IMBRUVICA. 

 Tell your doctor immediately if you become pregnant.
 Do not breast-feed while you are taking this medicine.

Driving and using machines
You may feel tired or dizzy after taking IMBRUVICA, which may affect your ability to drive or use 
any tools or machines.

IMBRUVICA contains lactose
IMBRUVICA contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

IMBRUVICA contains sodium
IMBRUVICA contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’.

3. How to take IMBRUVICA

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure.

How much to take
Mantle cell lymphoma (MCL)
The recommended dose of IMBRUVICA is 560 mg once a day.

Chronic lymphocytic leukaemia (CLL)/Waldenström’s macroglobulinaemia (WM)
The recommended dose of IMBRUVICA is 420 mg once a day.

Your doctor may adjust your dose.

Taking this medicine
 Take the tablets orally (by mouth) with a glass of water.
 Take the tablets about the same time each day.
 Swallow the tablets whole. Do not break or chew them.

If you take more IMBRUVICA than you should
If you take more IMBRUVICA than you should, talk to a doctor or go to a hospital straight away. 
Take the tablets and this leaflet with you.

If you forget to take IMBRUVICA
 If you miss a dose, it can be taken as soon as possible on the same day with a return to the 

normal schedule the following day.
 Do not take a double dose to make up for a forgotten dose.
 If you are not sure, talk to your doctor, pharmacist or nurse about when to take your next dose.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.



110

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
 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
 swollen hands, ankles or feet
 high blood pressure.

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



111

 confusion, headache with slurred speech or feeling faint – these could be signs of serious 
internal bleeding in your brain

 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 dysfunction 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).

Rare (may affect up to 1 in 1,000 people)
 severely increased white blood cell count that may cause cells to clump together.

Not known (frequency cannot be estimated from available data)
 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 the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store IMBRUVICA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month.

This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What IMBRUVICA contains
 The active substance is ibrutinib.

- IMBRUVICA 140 mg film-coated tablets: Each tablet contains 140 mg of ibrutinib.
- IMBRUVICA 280 mg film-coated tablets: Each tablet contains 280 mg of ibrutinib.
- IMBRUVICA 420 mg film-coated tablets: Each tablet contains 420 mg of ibrutinib.
- IMBRUVICA 560 mg film-coated tablets: Each tablet contains 560 mg of ibrutinib.

 The other ingredients are:
 Tablet core: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate (see 

section 2 “IMBRUVICA contains lactose”), magnesium stearate, microcrystalline cellulose, 
povidone, sodium lauril sulfate (E487).

 Tablet film-coat: polyvinyl alcohol, macrogol, talc, titanium dioxide (E171);
IMBRUVICA 140 mg and IMBRUVICA 420 mg film-coated tablets also contain black iron 
oxide (E172) and yellow iron oxide (E172);
IMBRUVICA 280 mg film-coated tablets also contain black iron oxide (E172) and red iron 
oxide (E172);
IMBRUVICA 560 mg film-coated tablets also contain red iron oxide (E172) and yellow iron 
oxide (E172).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


112

What IMBRUVICA looks like and contents of the pack
IMBRUVICA 140 mg film-coated tablets
Yellow-green to green round (9 mm) tablets, written with “ibr” on one side and “140” on the other 
side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard wallets of 14 film-coated 
tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 10 
film-coated tablets each.

IMBRUVICA 280 mg film-coated tablets
Purple oblong (15 mm in length and 7 mm in width), written with “ibr” on one side and “280” on the 
other side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard wallets of 14 film-coated 
tablets each. Each 30 day carton contains 30 film-coated tablets in 3 cardboard wallets of 
10 film-coated tablets each.

IMBRUVICA 420 mg film-coated tablets
Yellow-green to green oblong tablets (17.5 mm in length and 7.4 mm in width), written with “ibr” on 
one side and “420” on the other side. Each 28 day carton contains 28 film-coated tablets in 2 
cardboard wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 
3 cardboard wallets of 10 film-coated tablets each.

IMBRUVICA 560 mg film-coated tablets
Yellow to orange oblong tablets (19 mm in length and 8.1 mm in width), written with “ibr” on one 
side and “560” on the other side. Each 28 day carton contains 28 film-coated tablets in 2 cardboard 
wallets of 14 film-coated tablets each. Each 30 day carton contains 30 film-coated tablets in 3 
cardboard wallets of 10 film-coated tablets each.

Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen-Cilag SpA
Via C. Janssen,
Loc. Borgo S. Michele,
04100 Latina,
Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858



113

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD.
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.:+48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel.: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800 688 777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tel: +46 8 626 50 00
jacse@its.jnj.com



114

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu/


115

ANNEX IV

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



116

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for ibrutinib, the scientific 
conclusions of the CHMP are as follows: 

In view of the available data on splenic rupture following discontinuation of ibrutinib treatment and 
considering the seriousness of this condition, a plausible temporal relationship and mechanism of 
action, the prescribers should be warned about the possibility of splenic rupture occurrence after 
ibrutinib discontinuation. 

Considering the large number of cases reporting events related to cardiac failure/decreased LVEF -
total of 839 cases, of which 2 cases with positive dechallenge and rechallenge and 14 cases of positive 
dechallenge in which heart failure resolved or improved after ibrutinib withdrawal or decreasing the 
dose as well as literature findings (two literature case reports of cardiac failure which reported positive 
dechallenge to ibrutinib and one literature case of cardiac failure possibly related to ibrutinib) and 
plausible mechanism of action, a causal relationship between ibrutinib and cardiac failure is at least a 
reasonable possibility. The PRAC concluded that the product information of ibrutinib should be 
amended accordingly. 

Based on plausible mechanism of action, the absence of neutrophilic dermatoses events with the 
comparator in the RCT and 7 cases identified from the MAH’s global safety database with positive 
dechallenge including one also with positive rechallenge; of which 4 were biopsy confirmed and had 
no alternate explanation for the events, a causal relationship between ibrutinib and the events of 
neutrophilic dermatosis, acute febrile neutrophilic dermatosis and pyoderma gangrenosum is a 
reasonable possibility. The PRAC concluded that the product information of ibrutinib should be 
amended in order to add these 3 events under the grouped term, neutrophilic dermatoses, as a new 
ADR in the product information.  

Twenty five cases were identified in MAH’s safety database coded to PTs Haemophagocytic 
lymphohistiocytosis (HLH) or Macrophage activation, of which 2 cases were identified as cases of 
interest in which patients had classic symptoms and laboratory findings consistent with HLH and had 
fatal outcome, one report of HLH of clinical trial database in ibrutinib pool and publication in 
scientific literature in which a plausible biological mechanism is proposed. Considering the 
seriousness of this condition with often fatal outcome, there is a need to warn clinicians and patients. 
The PRAC concluded that the product information of product ibrutinib should be amended 
accordingly.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for ibrutinib the CHMP is of the opinion that the benefit-risk 
balance of the medicinal product containing ibrutinib is unchanged subject to the proposed changes to 
the product information.

The CHMP recommends that the terms of the marketing authorisation should be varied.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)