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

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

INCELL 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.

INCELL 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. INCELL in combination with rituximab is indicated for the treatment of adult patients with WM.

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

Posology

MCL

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

CLL and WM

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

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

When administering INCELL in combination with anti-CD20 therapy, it is recommended to administer INCELL 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.

INCELL 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), INCELL 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.

Recommended dose modifications are described below:

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 INCELL 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 INCELL 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 INCELL toxicity and follow dose modification guidance as needed. It is not recommended to administer INCELL to patients with severe hepatic impairment (Child-Pugh class C).

Severe cardiac disease

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

Paediatric population

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

Method of administration

INCELL 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. INCELL must not be taken with grapefruit juice or Seville oranges (see section 4.5).

Bleeding-related events

There have been reports of bleeding events in patients treated with INCELL, 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 INCELL. Use of either anticoagulants or medicinal products that inhibit platelet function (antiplatelet agents)

concomitantly with INCELL 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 INCELL. Monitor for signs and symptoms of bleeding.

Supplements such as fish oil and vitamin E preparations should be avoided.

INCELL 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 INCELL. A high number of circulating lymphocytes (>400,000/mcL) may confer increased risk. Consider temporarily withholding INCELL. 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 INCELL treatment. Disease status and spleen size should be carefully monitored (e.g. clinical examination, ultrasound) when INCELL 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 INCELL. Some of these infections have been associated with hospitalisation and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for fever, abnormal liver function tests, neutropenia and infections and appropriate anti-infective therapy should be instituted as indicated. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

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

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

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

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

Interstitial Lung Disease (ILD)

Cases of ILD have been reported in patients treated with INCELL. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt INCELL and manage ILD appropriately. If symptoms persist, consider the risks and benefits of INCELL 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 INCELL. 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, INCELL 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 INCELL should be considered. In patients who develop atrial fibrillation on therapy with INCELL a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to INCELL are non-suitable, tightly controlled treatment with anticoagulants should be considered.

Patients should be monitored for signs and symptoms of cardiac failure during INCELL treatment. In some of these cases cardiac failure resolved or improved after INCELL 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 INCELL, with and without concomitant atrial fibrillation and/or hypertension. Among cases with reported latency, the initiation of treatment with INCELL 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 INCELL 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 INCELL 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 INCELL. Hepatitis B virus (HBV) status should be established before initiating treatment with INCELL. 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 INCELL (see section 4.8). Regularly monitor blood pressure in patients treated with INCELL and initiate or adjust antihypertensive medication throughout treatment with INCELL as appropriate.

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH (including fatal cases) have been reported in patients treated with INCELL. 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 INCELL 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 INCELL exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of INCELL 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 INCELL 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 INCELL lack of efficacy.

Women of childbearing potential

Women of childbearing potential must use a highly effective method of contraception while taking INCELL (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.

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4). Agents that may increase ibrutinib plasma concentrations

Concomitant use of INCELL 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 INCELL 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 INCELL dose to 140 mg for the duration of the inhibitor use or withhold INCELL 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 INCELL 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 INCELL 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 INCELL treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).

Agents that may decrease ibrutinib plasma concentrations

Administration of INCELL 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 INCELL, 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 INCELL, 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 INCELL. 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.

Pregnancy category D

Women of child-bearing potential/Contraception in females

Based on findings in animals, INCELL may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking INCELL and for up to 3 months after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking INCELL and for three months after stopping treatment.

Pregnancy

INCELL should not be used during pregnancy. There are no data from the use of INCELL 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 INCELL.

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.

INCELL has minor influence on the ability to drive and use machines.

Fatigue, dizziness and asthenia have been reported in some patients taking INCELL and should be considered when assessing a patient's ability to drive or operate machines.

A.  Summary of the safety profile

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

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

B.  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.

C.  Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 1552 patients treated with INCELL for B-cell malignancies, 6% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, thrombocytopenia, haemorrhage, neutropenia, rash, and arthralgia. Adverse reactions leading to dose reduction occurred in approximately 8% of patients.

Elderly

Of the 1552 patients treated with INCELL, 52% were 65 years of age or older. Grade 3 or higher pneumonia (12% of patients age ≥65 versus 5% of patients <65 years) and thrombocytopenia (12% of patients age ≥65 years versus 6% of patients <65 years) occurred more frequently among elderly patients treated with INCELL.

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 INCELL 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 INCELL-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%.

D.  Paediatric population

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

E.  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 INCELL 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 INCELL 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 INCELL toxicity and follow dose modification guidance as needed. It is not recommended to administer INCELL to patients with severe hepatic impairment (Child-Pugh class C).

Severe cardiac disease

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

To report any side effect(s):

 Saudi Arabia

There are limited data on the effects of INCELL 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 INCELL. Patients who ingested more than the recommended dose should be closely monitored and given appropriate supportive treatment.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EL01. Mechanism of action

Ibrutinib is a potent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL. BTK's pivotal role in signalling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

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 INCELL. This effect has also been observed in about one third of patients with relapsed or refractory MCL treated with INCELL. 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 INCELL 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 INCELL.

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 INCELL 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.

INCELL 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 INCELL are shown in Table 2.

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 INCELL was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age.

The safety and efficacy of INCELL 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 INCELL 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.

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

CLL

Patients previously untreated for CLL Single agent

A randomised, multicenter, open-label phase 3 study (PCYC-1115-CA) of INCELL 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 INCELL 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 INCELL 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.

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 INCELL arm. The median investigator-assessed PFS was not reached in the INCELL 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 INCELL 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 INCELL arm versus 36.8% in the chlorambucil arm. The CR rate according to IWCLL criteria was 16.2% in the INCELL 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 INCELL 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 INCELL in patients with previously untreated CLL/SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (PCYC-1130-CA) of INCELL 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 INCELL 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 INCELL arm. With a median follow-up time on study of 31 months, the median PFS was not reached in the INCELL+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.

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 INCELL+obinutuzumab and chlorambucil+obinutuzumab arms, respectively.

Any grade infusion-related reactions were observed in 25% of patients treated with INCELL+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 INCELL+obinutuzumab and 9% of patients treated with chlorambucil+obinutuzumab.

The safety and efficacy of INCELL in patients with previously untreated CLL or SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (E1912) of INCELL in combination with rituximab (IR) versus standard fludarabine, cyclophosphamide, and rituximab (FCR) chemo-immunotherapy. The study enrolled previously untreated patients with CLL or SLL who were 70 years or younger. Patients with del17p were excluded from the study. Patients (n=529) were randomised 2:1 to receive either IR or FCR. INCELL was administered at a dose of 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of 250 mg/m2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the IR arm and in Cycle 1 for the FCR arm and was administered at a dose of 50 mg/m2  on Day 1 of the first cycle, 325 mg/m2  on Day 2 of the first cycle, and 500 mg/m2  on Day 1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.

The median age was 58 years (range, 28 to 70 years), 67% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1 (98%) or 2 (2%). At baseline, 43% of patients presented

with Rai Stage III or IV, and 59% of patients presented with CLL/SLL with high risk factors (TP53 mutation [6%], del11q [22%], or unmutated IGHV [53%]).

With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 7. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria, and OS are shown in Figures 6 and 7, respectively.

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

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

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

Patients with CLL who received at least one prior therapy Single agent

The safety and efficacy of INCELL 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. INCELL 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 INCELL versus ofatumumab (PCYC-1112-CA) was conducted in patients with relapsed or refractory CLL. Patients (n=391) were randomised 1:1 to receive either INCELL 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 INCELL. 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 INCELL arm. Analysis of

OS demonstrated a 57% statistically significant reduction in the risk of death for patients in the INCELL arm. Efficacy results for Study PCYC-1112-CA are shown in Table 9.

The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Table 10).

The Kaplan-Meier curve for PFS is shown in Figure 8.

Figure 8: 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 INCELL arm. The median investigator-assessed PFS according to IWCLL criteria was 44.1 months [95% CI (38.47, 56.18)] in the INCELL 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 9. The investigator-assessed ORR in the INCELL 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 INCELL 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 INCELL arm.

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

Figure 9: 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 INCELL in patients previously treated for CLL were further evaluated in a randomised, multicenter, double-blinded phase 3 study of INCELL in combination with BR versus placebo+BR (Study CLL3001). Patients (n=578) were randomised 1:1 to receive either INCELL 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 INCELL 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 11.

WM

Single agent

The safety and efficacy of INCELL 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).

INCELL 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 INCELL are shown in Table 12.

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 INCELL in WM were further evaluated in patients with treatment-naïve or previously treated WM in a randomised, multicenter, double-blinded phase 3 study of INCELL in combination with rituximab versus placebo in combination with rituximab (PCYC-1127-CA). Patients (n=150) were randomised 1:1 to receive either INCELL 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 INCELL arm. Efficacy results for Study PCYC-1127-CA are shown in Table 13 and the Kaplan-Meier curve for PFS is shown in Figure 10. PFS hazard ratios for treatment-naïve patients, previously treated patients, and patients with or without MYD88 L265P mutations were consistent with the PFS hazard ratio for the ITT population.

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

Grade 3 or 4 infusion-related reactions were observed in 1% of patients treated with INCELL+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 INCELL+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 INCELL. 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 INCELL in all subsets of the paediatric population in MCL, CLL and lymphoplasmacytic lymphoma (LPL) (for information on paediatric use, see section 4.2).

Absorption

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

Pharmacokinetics of ibrutinib does not significantly differ in patients with different B-cell malignancies. Ibrutinib exposure increases with doses up to 840 mg. The steady state AUC observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 ng h/mL. Administration of ibrutinib in fasted condition resulted in approximately 60% of exposure (AUClast ) as compared to either 30 minutes before, 30 minutes after (fed condition) or 2 hours after a high fat breakfast.

Ibrutinib has a pH dependent solubility, with lower solubility at higher pH. In fasted healthy subjects administered a single 560 mg dose of ibrutinib after taking omeprazole at 40 mg once daily for 5 days, compared to ibrutinib alone, geometric mean ratios (90% CI) were 83% (68-102%), 92% (78-110%), and 38% (26-53%) for AUC0-24 , AUClast , and Cmax , respectively.

Distribution

Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1,000 ng/mL. The apparent volume of distribution at steady state (Vd, ss /F) was approximately 10,000 L.

Metabolism

Ibrutinib is metabolised primarily by CYP3A4 to produce a dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Involvement of CYP2D6 in the metabolism of ibrutinib appears to be minimal.

Therefore, no precautions are necessary in patients with different CYP2D6 genotypes. Elimination

Apparent clearance (CL/F) is approximately 1,000 L/h. The half-life of ibrutinib is 4 to 13 hours.

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 INCELL 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 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).

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).

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