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 ibrutinib. Ibrutinib may also inhibit BCRP in the liver and increase the exposure of medicinal products that undergo BCRP-mediated hepatic efflux, such as rosuvastatin.

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

Co-administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (C_max 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 ibrutinib, 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. Mild inducers may be used concomitantly with ibrutinib, however, patients should be monitored for potential lack of efficacy.

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

No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in ibrutinib 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 ibrutinib 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.

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

Strong CYP3A4 inhibitors increase the exposure of ibrutinib.

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.

Co-administration of ketoconazole, a very strong CYP3A4 inhibitor, in 18 fasted healthy subjects, increased exposure (C_max 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 ibrutinib with food, co-administration of the strong CYP3A4 inhibitor voriconazole increased C_max 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 ibrutinib dose to 140 mg for the duration of the inhibitor use or withhold ibrutinib temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed.

Moderate CYP3A4 inhibitors increase the exposure of ibrutinib.

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

In patients with B-cell malignancies taking ibrutinib with food, co-administration of the
CYP3A4 inhibitor erythromycin increased C_max 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 ibrutinib dose to 280 mg for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed.

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.

Use of either anticoagulants or medicinal products that inhibit platelet function (antiplatelet agents) concomitantly with ibrutinib 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 ibrutinib. Monitor for signs and symptoms of bleeding.

Warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib.

Fatal and serious cardiac arrhythmias and cardiac failure have occurred in patients treated with ibrutinib. 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 ibrutinib. 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 ibrutinib; alternative treatment may be considered.

In patients who develop signs and/or symptoms of ventricular tachyarrhythmia, ibrutinib 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 ibrutinib should be considered. In patients who develop atrial fibrillation on therapy with ibrutinib a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to ibrutinib are non-suitable, tightly controlled treatment with anticoagulants should be considered.

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

Supplements such as fish oil and vitamin E preparations should be avoided in co-administration with ibrutinib.

Ibrutinib should not be used during pregnancy. There are no data from the use of ibrutinib in pregnant women. Studies in animals have shown reproductive toxicity.

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 ibrutinib.

Women of child-bearing potential/Contraception in females

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

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). No human data on the effects of ibrutinib on fertility are available.

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

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

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 ¾ 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 ibrutinib 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 2. Patients treated for MCL in clinical studies received ibrutinib at 560 mg once daily and patients treated for CLL or WM in clinical studies received ibrutinib at 420 mg once daily. All patients in clinical studies received ibrutinib until disease progression or no longer tolerated, except for studies with ibrutinib in combination with venetoclax where patients received fixed duration treatment (Studies CLL3011 and PCYC-1142-CA). The median duration of ibrutinib 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 1. Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies^†:

^† 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 ibrutinib arm) treated with ibrutinib in the phase 3 TRIANGLE study. Patients received ibrutinib at 560 mg once daily according to the TRIANGLE treatment schedule. The median treatment duration was 28.5 months in the ibrutinib arm.

Table 2. Adverse reactions reported in the ibrutinib arm of the TRIANGLE Study^†:

^† 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 ibrutinib 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 ibrutinib 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 ibrutinib arm.

Elderly

Of the 1 981 patients treated with ibrutinib, 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 ibrutinib.

Long-term safety

The safety data from long-term treatment with ibrutinib over 5 years from 1 284 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106) were analysed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 70% and 52% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for WM was 47 months (range, 0.3 to 61 months) with 78% and 46% of patients receiving treatment for more than 2 years and 4 years, respectively. The overall known safety profile of ibrutinib-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 ibrutinib 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. No new adverse reactions were observed in this study.