4.1. Therapeutic indications

IMBRUVICA in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (IMBRUVICA + R-CHOP) alternating with R-DHAP (or R-DHAOx) without IMBRUVICA, followed by IMBRUVICA monotherapy, is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplantation (ASCT).

IMBRUVICA as a single agent is indicated for the treatment of adult patients with relapsed or refractory MCL.

IMBRUVICA as a single agent or in combination with rituximab or obinutuzumab or venetoclax is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (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

Treatment of adult patients with previously untreated MCL

The recommended dose for the treatment of previously untreated MCL is ibrutinib 560 mg once daily (see Table 1).

Table 1: IMBRUVICA dosing schedule for previously untreated MCL

Treatment

Cycle number

Treatment

IMBRUVICA

Part I*

1, 3, 5

IMBRUVICA in combination with R-CHOP§

On days 1-19

2, 4, 6

R-DHAP#§

Without IMBRUVICA

Part II±

IMBRUVICA

Daily for 24 Months

R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-DHAP= rituximab, dexamethasone, cytarabine, cisplatin.

*6 cycles; each cycle is 21 days.

§ See the Summary of Product Characteristics (SmPC) for dosing information for each medicinal product.

#Interchangeable with R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin)§.

± Treatment should start after recovery of peripheral blood counts. Rituximab may be added as per national treatment guidelines.

Treatment of adult patients with relapsed or refractory MCL

The recommended dose for the treatment of previously treated MCL is ibrutinib 560 mg once daily as a single agent. Treatment with IMBRUVICA as a single agent should continue until disease progression or no longer tolerated by the patient.

CLL and WM

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

Treatment with IMBRUVICA as a single agent or in combination with anti-CD20 therapy should continue until disease progression or no longer tolerated by the patient. In combination with venetoclax for the treatment of CLL, IMBRUVICA should be administered as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of IMBRUVICA plus venetoclax. See the venetoclax Summary of Product Characteristics (SmPC) for full venetoclax dosing information.

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

Dose adjustments

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

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

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

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

Recommended dose modifications for non‑cardiac events are described below:

Events†

Toxicity occurrence

MCL dose modification after recovery

CLL/WM dose modification after recovery

Grade 3 or 4 non-haematological toxicities

Grade 3 or 4 neutropenia with infection or fever

Grade 4 haematological toxicities

First*

restart at 560 mg daily

restart at 420 mg daily

Second

restart at 420 mg daily

restart at 280 mg daily

Third

restart at 280 mg daily

restart at 140 mg daily

Fourth

discontinue IMBRUVICA

discontinue IMBRUVICA

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

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

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

Events

Toxicity occurrence

MCL dose modification after recovery

CLL/WM dose modification after recovery

Grade 2 cardiac failure

First

restart at 420 mg daily

restart at 280 mg daily

Second

restart at 280 mg daily

restart at 140 mg daily

Third

discontinue IMBRUVICA

Grade 3 cardiac arrhythmias

First

restart at 420 mg daily†

restart at 280 mg daily†

Second

discontinue IMBRUVICA

Grade 3 or 4 cardiac failure

Grade 4 cardiac arrhythmias

First

discontinue IMBRUVICA

† Evaluate the benefit-risk before resuming treatment.

Missed dose

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

Special populations

Elderly

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

Renal impairment

No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in IMBRUVICA clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically. Administer IMBRUVICA to patients with severe renal impairment (<30 mL/min creatinine clearance) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).

Hepatic impairment

Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see section 5.2). For patients with mild liver impairment (Child‑Pugh class A), the recommended dose is 280 mg daily. For patients with moderate liver impairment (Child‑Pugh class B), the recommended dose is 140 mg daily. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with severe hepatic impairment (Child‑Pugh class C).

Severe cardiac disease

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

Paediatric population

IMBRUVICA is not recommended for use in children and adolescents aged 0 to 18 years as efficacy has not been established. Currently available data in patients with mature B-cell non-Hodgkin lymphoma are described in sections 4.8, 5.1 and 5.2.

Method of administration

IMBRUVICA should be administered orally once daily with a glass of water approximately at the same time each day. The tablets should be swallowed whole with water and should not be broken or chewed. IMBRUVICA must not be taken with grapefruit juice or Seville oranges (see section 4.5).

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 and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for fever, abnormal liver function tests, neutropenia and infections and appropriate anti‑infective therapy should be instituted as indicated. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

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

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

Hepatic events

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

Cytopenias

Treatment‑emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) were reported in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Interstitial Lung Disease (ILD)

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

Cardiac arrhythmias and cardiac failure

Fatal and serious cardiac arrhythmias and cardiac failure have occurred in patients treated with IMBRUVICA. Patients with advanced age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, or cardiac co-morbidities may be at greater risk of events including sudden fatal cardiac events. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia and cardiac failure have been reported, particularly in patients with acute infections or cardiac risk factors including hypertension, diabetes mellitus, and a previous history of cardiac arrhythmia.

Appropriate clinical evaluation of cardiac history and function should be performed prior to initiating IMBRUVICA. Patients should be carefully monitored during treatment for signs of clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g., ECG, echocardiogram), as indicated for patients in whom there are cardiovascular concerns.

For patients with relevant risk factors for cardiac events, carefully assess benefit/risk before initiating treatment with IMBRUVICA; alternative treatment may be considered.

In patients who develop signs and/or symptoms of ventricular tachyarrhythmia, IMBRUVICA should be temporarily discontinued and a thorough clinical benefit/risk assessment should be performed before possibly restarting therapy.

In patients with preexisting atrial fibrillation requiring anticoagulant therapy, alternative treatment options to IMBRUVICA should be considered. In patients who develop atrial fibrillation on therapy with IMBRUVICA a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to IMBRUVICA are non‑suitable, tightly controlled treatment with anticoagulants should be considered.

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

Cerebrovascular accidents

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

Tumour lysis syndrome

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

Non‑melanoma skin cancer

Non‑melanoma skin cancers were reported more frequently in patients treated with IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non‑melanoma skin cancer.

Hypertension

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

Haemophagocytic lymphohistiocytosis (HLH)

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

Drug‑drug interactions

Co‑administration of strong or moderate CYP3A4 inhibitors with IMBRUVICA may lead to increased ibrutinib exposure and consequently a higher risk for toxicity. On the contrary, co‑administration of CYP3A4 inducers may lead to decreased IMBRUVICA exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of IMBRUVICA with strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers should be avoided whenever possible and co‑administration should only be considered when the potential benefits clearly outweigh the potential risks. Patients should be closely monitored for signs of IMBRUVICA toxicity if a CYP3A4 inhibitor must be used (see sections 4.2 and 4.5). If a CYP3A4 inducer must be used, closely monitor patients for signs of IMBRUVICA lack of efficacy.

Women of childbearing potential

Women of childbearing potential must use a highly effective method of contraception while taking IMBRUVICA (see section 4.6).

Excipients with known effect

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

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

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, nefazodone, cobicistat, voriconazole and posaconazole) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the IMBRUVICA dose to 140 mg for the duration of the inhibitor use or withhold IMBRUVICA temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).

Moderate CYP3A4 inhibitors

In patients with B‑cell malignancies taking IMBRUVICA with food, co‑administration of the CYP3A4 inhibitor erythromycin increased Cmax by 3.4‑fold and AUC by 3.0‑fold. If a moderate CYP3A4 inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone and dronedarone) is indicated, reduce IMBRUVICA dose to 280 mg for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).

Mild CYP3A4 inhibitors

Simulations using fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by <2‑fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.

Co‑administration of grapefruit juice, containing CYP3A4 inhibitors, in eight healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by approximately 4‑ and 2‑fold, respectively. Grapefruit and Seville oranges should be avoided during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).

Agents that may decrease ibrutinib plasma concentrations

Administration of IMBRUVICA with inducers of CYP3A4 can decrease ibrutinib plasma concentrations.

Co‑administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (Cmax and AUC) of ibrutinib by 92 and 90%, respectively. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin). Preparations containing St. John's Wort are contraindicated during treatment with IMBRUVICA, as efficacy may be reduced. Consider alternative agents with less CYP3A4 induction. If the benefit outweighs the risk and a strong or moderate CYP3A4 inducer must be used, monitor patient closely for lack of efficacy (see sections 4.3 and 4.4). Mild inducers may be used concomitantly with IMBRUVICA, however, patients should be monitored for potential lack of efficacy.

Ibrutinib has a pH dependent solubility, with lower solubility at higher pH. A lower Cmax was observed in fasted healthy subjects administered a single 560 mg dose of ibrutinib after taking omeprazole at 40 mg once daily for 5 days (see section 5.2). There is no evidence that the lower Cmax would have clinical significance, and medicinal products that increase stomach pH (e.g., proton pump inhibitors) have been used without restrictions in the pivotal clinical studies.

Agents that may have their plasma concentrations altered by ibrutinib

Ibrutinib is a P‑gp and breast cancer resistance protein (BCRP) inhibitor in vitro. As no clinical data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal P‑gp and BCRP after a therapeutic dose. To minimise the potential for an interaction in the GI tract, oral narrow therapeutic range, P‑gp or BCRP substrates such as digoxin or methotrexate should be taken at least 6 hours before or after IMBRUVICA. Ibrutinib may also inhibit BCRP in the liver and increase the exposure of medicinal products that undergo BCRP‑mediated hepatic efflux, such as rosuvastatin.

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

In a drug interaction study in patients with B-cell malignancies, a single 560 mg dose of ibrutinib did not have a clinically meaningful effect on the exposure of the CYP3A4 substrate midazolam. In the same study, 2 weeks of treatment with ibrutinib at 560 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the CYP2B6 substrate bupropion.

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.

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

Tabulated list of adverse reactions

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

Summary for B-cell malignancies

The safety profile is based on pooled data from 1,981 patients treated with IMBRUVICA in four phase 2 clinical studies and eight randomised phase 3 studies and from post‑marketing experience. The TRIANGLE study data is not included in the pooled data and presented separately in Table 3. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated, except for studies with IMBRUVICA in combination with venetoclax where patients received fixed duration treatment (Studies CLL3011 and PCYC-1142-CA). The median duration of IMBRUVICA treatment across the pooled dataset was 14.7 months. The median duration of treatment for CLL/SLL was 14.7 months (up to 52 months); MCL was 11.7 months (up to 28 months); WM was 21.6 months (up to 37 months).

Table 2: Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies†

System organ class

Frequency

(All grades)

Adverse reactions

All Grades (%)

Grade ≥3 (%)

Infections and infestations

Very common

Pneumonia*#

Upper respiratory tract infection

Skin infection*

12

21

15

7

1

2

Common

Sepsis*#

Urinary tract infection

Sinusitis*

3

9

9

3

1

1

Uncommon

Cryptococcal infections*

Pneumocystis infections* #

Aspergillus infections*

Hepatitis B reactivation@ #

<1

<1

<1

<1

0

<1

<1

<1

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common

Non‑melanoma skin cancer*

Basal cell carcinoma

Squamous cell carcinoma

5

3

1

1

<1

<1

Blood and lymphatic system disorders

Very common

Neutropenia*

Thrombocytopenia*

Lymphocytosis*

39

29

15

31

8

11

Common

Febrile neutropenia

Leukocytosis

4

4

4

4

Rare

Leukostasis syndrome

<1

<1

Immune system disorders

Common

Interstitial lung disease*,#

2

<1

Metabolism and nutrition disorders

Common

Hyperuricaemia

9

1

Uncommon

Tumour lysis syndrome

1

1

Nervous system disorders

Very common

Dizziness

Headache

12

19

<1

1

Common

Peripheral neuropathy*

7

<1

Uncommon

Cerebrovascular accident #

Transient ischaemic attack

Ischaemic stroke #

<1

<1

<1

<1

<1

<1

Eye disorders

Common

Vision blurred

6

0

Uncommon

Eye haemorrhage‡

Uveitis*

<1

<1

0

0

Cardiac disorders

Common

Cardiac failure*, #

Atrial fibrillation

2

8

1

4

Uncommon

Ventricular tachyarrhythmia*,#

Cardiac arrest#

1

<1

<1

<1

Vascular disorders

Very common

Haemorrhage*#

Bruising*

Hypertension*

35

27

18

1

<1

8

Common

Epistaxis

Petechiae

9

7

<1

0

Uncommon

Subdural haematoma#

1

<1

Gastrointestinal disorders

Very common

Diarrhoea

Vomiting

Stomatitis*

Nausea

Constipation

Dyspepsia

47

15

17

31

16

11

4

1

1

1

<1

<1

Hepatobiliary disorders

Uncommon

Hepatic failure*, #

<1

<1

Skin and subcutaneous tissue disorders

Very common

Rash*

34

3

Common

Urticaria

Erythema

Onychoclasis

1

3

4

<1

<1

0

Uncommon

Angioedema

Panniculitis*

Neutrophilic dermatoses*

Pyogenic granuloma

Cutaneous vasculitis

<1

<1

<1

<1

<1

<1

<1

<1

0

0

Rare

Stevens‑Johnson syndrome

<1

<1

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Muscle spasms

Musculoskeletal pain*

24

15

36

2

<1

3

Renal and urinary disorders

Common

Acute kidney injury#

<2

<1

General disorders and administration site conditions

Very common

Pyrexia

Oedema peripheral

19

16

1

1

Investigations

Very common

Blood creatinine increased

10

<1

† Frequencies are rounded to the nearest integer.

* Includes multiple adverse reaction terms.

‡ In some cases associated with loss of vision.

# Includes events with fatal outcome.

@ Lower level term (LLT) used for selection.

Summary for patients with previously untreated MCL who were eligible for ASCT

The safety profile is based on data from 265 patients (in the IMBRUVICA arm) treated with IMBRUVICA in the phase 3 TRIANGLE study. Patients received IMBRUVICA at 560 mg once daily according to the TRIANGLE treatment schedule (see section 5.1). The median treatment duration was 28.5 months in the IMBRUVICA arm.

Table 3: Adverse reactions reported in the IMBRUVICA arm of the TRIANGLE Study†

N=265

System Organ Class

Frequency

(All Grades)

Adverse Reactions

All Grades (%)

Grade ≥3 (%)

Infections and infestations

Very common

Pneumonia* #

16

9

Skin infection*

12

3

Common

Upper respiratory tract infection

6

<1

Sepsis*

2

2

Urinary tract infection

6

<1

Sinusitis*

6

1

Uncommon

Aspergillus infections*

1

<1

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common

Non-Melanoma skin cancer*

1

<1

Basal cell carcinoma

1

<1

Blood and lymphatic system disorders

Very common

Thrombocytopenia*

69

61

Neutropenia*

63

60

Febrile neutropenia

14

14

Common

Leukocytosis

3

1

Immune system disorders

Common

Interstitial lung disease*

5

1

Metabolism and nutrition disorders

Common

Hyperuricaemia

8

3

Tumour lysis syndrome*

3

3

Nervous system disorders

Very common

Peripheral neuropathy*

35

3

Headache

11

1

Common

Dizziness

6

<1

Uncommon

Transient ischaemic attack

1

0

Eye disorders

Uncommon

Vision blurred

1

0

Eye haemorrhage

<1

0

Cardiac disorders

Common

Atrial fibrillation

10

4

Cardiac failure*

2

0

Vascular disorders

Very common

Haemorrhage*

14

2

Hypertension*

14

5

Common

Bruising*

8

1

Epistaxis

6

1

Petechiae

3

0

Gastrointestinal disorders

Very common

Nausea

32

4

Diarrhoea

28

5

Vomiting

18

4

Stomatitis*

11

2

Constipation

17

<1

Common

Dyspepsia

8

0

Skin and subcutaneous tissue disorders

Very common

Rash*

23

2

Common

Erythema

5

0

Onychoclasis

2

0

Uncommon

Urticaria

<1

0

Angioedema

1

0

Cutaneous vasculitis

<1

0

Panniculitis*

1

0

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain*

19

2

Common

Muscle spasms

9

1

Arthralgia

8

1

Renal and urinary disorders

Very common

Acute kidney injury

11

5

General disorders and administration site conditions

Very common

Pyrexia

22

2

Common

Oedema peripheral

5

0

Investigations

Very common

Blood creatinine increased

16

1

† Frequencies are rounded to the nearest integer.

* Terms required grouping.

# Includes events with fatal outcome.

Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 1,981 patients treated with IMBRUVICA for B‑cell malignancies, 6% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, neutropenia, rash, thrombocytopenia, and haemorrhage. Adverse reactions leading to dose reduction occurred in approximately 8% of patients. In the phase 3 TRIANGLE study involving 265 patients with previously untreated MCL who were eligible for ASCT treatment discontinuation due to adverse reactions was observed in 13% in the IMBRUVICA arm. These included neutropenia, pneumonia, atrial fibrillation, acute kidney injury, diarrhoea, rash, and interstitial lung disease. Adverse reactions leading to dose reduction occurred in approximately 12% in the IMBRUVICA arm.

Elderly

Of the 1,981 patients treated with IMBRUVICA, 50% were 65 years of age or older. Grade 3 or higher pneumonia (11% of patients age ≥65 versus 4% of patients <65 years) and thrombocytopenia (11% of patients age ≥65 years versus 5% of patients <65 years) occurred more frequently among elderly patients treated with IMBRUVICA.

Long-term safety

The safety data from long-term treatment with IMBRUVICA over 5 years from 1284 patients (treatment-naïve CLL/SLL n = 162, relapsed/refractory CLL/SLL n = 646, relapsed/refractory MCL n = 370, and WM n=106) were analysed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 70% and 52% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for WM was 47 months (range, 0.3 to 61 months) with 78% and 46% of patients receiving treatment for more than 2 years and 4 years, respectively. The overall known safety profile of IMBRUVICA-exposed patients remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0‑1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%.

Paediatric population

The safety assessment is based on data from a phase 3 study of IMBRUVICA in combination with either a rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone (RICE) regimen, or a rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) regimen, as background therapy or background therapy alone in paediatric and young adult patients (aged 3 to 19 years) with relapsed or refractory mature B-cell non-Hodgkin lymphoma (see section 5.1). No new adverse reactions were observed in this study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.