Ibrutinib

Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec kinase family. BTK 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 mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukaemia (CLL).

Mechanism of Action

• Covalent binding: ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the active site of BTK. This gives sustained inhibition of the enzyme and prevents phosphorylation of downstream substrates such as PLC-γ.
• B-cell signalling: signalling through the B-cell surface receptors activates the pathways needed for B-cell trafficking, chemotaxis and adhesion. Preclinical studies showed that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo, and cell migration and substrate adhesion in vitro.
• Combination with venetoclax: in preclinical tumour models, ibrutinib with venetoclax increased apoptosis and antitumour activity compared with either medicine alone. BTK inhibition increases the dependence of CLL cells on the survival protein BCL-2, which venetoclax inhibits.
• Lymphocytosis: when treatment starts, a reversible rise in lymphocyte counts (an increase of 50% or more from baseline and an absolute count above 5,000/µL), often with shrinking lymph nodes, occurs in about three quarters of patients with CLL and about one third of patients with relapsed or refractory MCL. This is a pharmacodynamic effect and should not be taken as progressive disease in the absence of other clinical findings.

Pharmacokinetics

• Absorption: rapid; median time to peak 1 to 2 hours. Absolute bioavailability is only 2.9% on an empty stomach and doubles with a meal; taken fasted, exposure was about 60% of that with food. Exposure increases with doses up to 840 mg, and the steady-state AUC at 560 mg is 953 ± 705 ng·h/mL. Solubility falls at higher pH; omeprazole lowered the peak concentration in fasted volunteers, but medicines that raise gastric pH were used without restriction in the pivotal studies.
• Distribution: reversible binding to human plasma proteins is 97.3% in vitro, and the apparent volume of distribution at steady state is about 10,000 L.
• Metabolism: mainly by CYP3A4, producing a dihydrodiol metabolite whose inhibitory activity against BTK is about 15 times lower than that of ibrutinib. CYP2D6 plays a minimal role.
• Elimination: apparent clearance is about 1,000 L/h and the half-life 4 to 13 hours. After a radiolabelled dose, about 90% of the radioactivity was excreted within 168 hours, 80% in faeces and under 10% in urine. Unchanged ibrutinib made up about 1% of the faecal radioactivity and none of the urinary.
• Special populations: age, sex and body weight have no significant effect on clearance; there are too few data to assess race. Renal clearance is minimal, but there are no data in severe renal impairment or dialysis. In hepatic impairment, exposure (AUClast) rose on average 2.7-fold in mild (Child-Pugh A), 8.2-fold in moderate (Child-Pugh B) and 9.8-fold in severe (Child-Pugh C) impairment.

Ibrutinib is indicated in adults for:

Mantle cell lymphoma (MCL)

• Previously untreated MCL: in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) alternating with R-DHAP (or R-DHAOx) without ibrutinib, followed by ibrutinib monotherapy, in patients who would be eligible for autologous stem cell transplantation (ASCT).
• Relapsed or refractory MCL: as a single agent.

Chronic lymphocytic leukaemia (CLL)

• Previously untreated CLL: as a single agent or in combination with rituximab, obinutuzumab or venetoclax.
• CLL after at least one prior therapy: as a single agent or in combination with bendamustine and rituximab (BR).

Waldenström’s macroglobulinaemia (WM)

• WM: as a single agent in patients who have received at least one prior therapy, or as first-line treatment in patients unsuitable for chemo-immunotherapy.
• WM with rituximab: in combination with rituximab.

• Hypersensitivity to ibrutinib or to any of the excipients.
• Use of preparations containing St John’s wort.

The most commonly occurring adverse reactions (20% or more) were diarrhoea, neutropenia, musculoskeletal pain, haemorrhage (for example bruising), rash, nausea, thrombocytopenia, arthralgia and upper respiratory tract infection. The most common grade 3 or 4 reactions (5% or more) were neutropenia, lymphocytosis, thrombocytopenia, hypertension and pneumonia. The frequencies below are pooled from 1,981 patients with B-cell malignancies in four phase 2 and eight randomised phase 3 studies, plus post-marketing experience; the median duration of treatment was 14.7 months. In the pooled table diarrhoea occurred in 47% of patients, neutropenia in 39%, musculoskeletal pain in 36%, haemorrhage in 35% and rash in 34%. Patients with previously untreated MCL in the TRIANGLE study (265 on ibrutinib, median treatment 28.5 months) are reported separately in the SmPC.

Very common (≥1/10): pneumonia, upper respiratory tract infection, skin infection; neutropenia, thrombocytopenia, lymphocytosis; dizziness, headache; haemorrhage, bruising, hypertension; diarrhoea, vomiting, stomatitis, nausea, constipation, dyspepsia; rash; arthralgia, muscle spasms, musculoskeletal pain; pyrexia, peripheral oedema; increased blood creatinine.

Common (≥1/100 to <1/10): sepsis, urinary tract infection, sinusitis; non-melanoma skin cancer (including basal cell and squamous cell carcinoma); febrile neutropenia, leukocytosis; interstitial lung disease; hyperuricaemia; peripheral neuropathy; blurred vision; cardiac failure, atrial fibrillation; epistaxis, petechiae; urticaria, erythema, onychoclasis (nail breakage); acute kidney injury.

Uncommon (≥1/1,000 to <1/100): cryptococcal, Pneumocystis and Aspergillus infections; hepatitis B reactivation; tumour lysis syndrome; cerebrovascular accident, transient ischaemic attack, ischaemic stroke; eye haemorrhage, uveitis; ventricular tachyarrhythmia, cardiac arrest; subdural haematoma; hepatic failure; angioedema, panniculitis, neutrophilic dermatosis, pyogenic granuloma, cutaneous vasculitis.

Rare (≥1/10,000 to <1/1,000): leukostasis syndrome, Stevens-Johnson syndrome.

Events with a fatal outcome were reported for pneumonia, sepsis, Pneumocystis infection, hepatitis B reactivation, interstitial lung disease, haemorrhage, cardiac failure, ventricular tachyarrhythmia, cerebrovascular accident and ischaemic stroke, subdural haematoma, hepatic failure and acute kidney injury. Major bleeding, infections, progressive multifocal leukoencephalopathy, cardiac arrhythmias and cerebrovascular events are described under Special Instructions.

Ibrutinib is metabolised mainly by CYP3A4, so strong and moderate inhibitors raise its exposure and inducers lower it.

• Strong CYP3A4 inhibitors (ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, voriconazole, posaconazole): should be avoided. Ketoconazole raised ibrutinib peak concentration 29-fold and AUC 24-fold; voriconazole raised them 6.7-fold and 5.7-fold; clarithromycin was predicted to raise AUC 14-fold. If the benefit outweighs the risk and a strong inhibitor must be used, ibrutinib is reduced to 140 mg for the duration of use or withheld temporarily (7 days or less), with close monitoring for toxicity.
• Moderate CYP3A4 inhibitors (fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone): erythromycin raised peak concentration 3.4-fold and AUC 3.0-fold. The ibrutinib dose is reduced to 280 mg for the duration of use.
• Mild CYP3A4 inhibitors (azithromycin, fluvoxamine): AUC is predicted to rise by less than 2-fold. No dose adjustment is needed, but the patient is monitored for toxicity.
• CYP3A4 inducers: rifampicin lowered ibrutinib peak concentration by 92% and AUC by 90%. Strong or moderate inducers (for example carbamazepine, rifampicin, phenytoin) should be avoided; if one must be used, the patient is monitored closely for lack of efficacy. Mild inducers may be used with monitoring. St John’s wort is contraindicated.
• Grapefruit and Seville oranges: grapefruit juice raised ibrutinib peak concentration about 4-fold and AUC about 2-fold. Both should be avoided.
• Gastric acid-reducing medicines: omeprazole lowered the peak concentration in fasted healthy volunteers, but there is no evidence of clinical significance and proton pump inhibitors were used without restriction in the pivotal studies.
• Anticoagulants and antiplatelet agents: they raise the risk of major bleeding, more so with anticoagulants. Warfarin and other vitamin K antagonists should not be given with ibrutinib. Fish oil and vitamin E supplements should be avoided.
• P-gp and BCRP substrates: ibrutinib inhibits P-gp and BCRP in vitro. Oral narrow-range substrates such as digoxin or methotrexate should be taken at least 6 hours before or after ibrutinib. Ibrutinib may also raise the exposure of medicines that undergo BCRP-mediated efflux in the liver, such as rosuvastatin.
• Venetoclax: in CLL studies, venetoclax exposure was about 1.8-fold higher (AUC) with ibrutinib than with venetoclax alone.
• No clinically relevant effect: ibrutinib did not meaningfully change the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel), or of probe substrates of CYP3A4 and CYP2B6.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicinal products. The capsules or film-coated tablets are swallowed whole with a glass of water, once daily at about the same time each day. Capsules must not be opened, broken or chewed, and tablets must not be broken or chewed. Ibrutinib must not be taken with grapefruit juice or Seville oranges. When it is given on the same day as an anti-CD20 antibody, ibrutinib is taken first.

Recommended Dose

The film-coated tablets come in strengths of 140 mg, 280 mg, 420 mg and 560 mg, which cover every dose level on this page, and the milligram doses are the same as for the capsules. The capsule counts in brackets apply to the capsules only.

• Previously untreated mantle cell lymphoma: 560 mg (four capsules) once daily. Part I consists of six 21-day cycles: ibrutinib is taken on days 1–19 of cycles 1, 3 and 5 together with R-CHOP, while cycles 2, 4 and 6 contain R-DHAP (or R-DHAOx) without ibrutinib. In Part II ibrutinib is taken daily for 24 months, starting after recovery of peripheral blood counts; rituximab may be added according to national treatment guidelines. The doses of the combination medicines are in their own SmPCs.
• Relapsed or refractory mantle cell lymphoma: 560 mg (four capsules) once daily as a single agent, until disease progression or until the patient can no longer tolerate it.
• CLL and Waldenström’s macroglobulinaemia: 420 mg (three capsules) once daily, as a single agent or in combination, until disease progression or until the patient can no longer tolerate it.
• CLL with venetoclax: ibrutinib alone for 3 cycles (1 cycle is 28 days), followed by 12 cycles of ibrutinib plus venetoclax; see the venetoclax SmPC for its dosing.

Dose Adjustments

Ibrutinib is withheld for any new or worsening grade 2 cardiac failure, grade 3 cardiac arrhythmia, grade 3 or higher non-haematological toxicity, grade 3 or higher neutropenia with infection or fever, or grade 4 haematological toxicity. Once the toxicity has resolved to grade 1 or baseline, ibrutinib is restarted at the dose shown below.

• Non-cardiac events (grade 3 or 4 non-haematological toxicity, grade 3 or 4 neutropenia with infection or fever, grade 4 haematological toxicity): first occurrence, restart at 560 mg daily (MCL) or 420 mg daily (CLL/WM); second, 420 mg (MCL) or 280 mg (CLL/WM); third, 280 mg (MCL) or 140 mg (CLL/WM); fourth, stop ibrutinib. On restarting, the same or a lower dose may be chosen after a benefit–risk evaluation, and if the toxicity recurs the daily dose is reduced by 140 mg.
• Grade 2 cardiac failure: first occurrence, restart at 420 mg (MCL) or 280 mg (CLL/WM); second, 280 mg (MCL) or 140 mg (CLL/WM); third, stop ibrutinib.
• Grade 3 cardiac arrhythmia: first occurrence, restart at 420 mg (MCL) or 280 mg (CLL/WM) after evaluating the benefit–risk; second, stop ibrutinib.
• Grade 3 or 4 cardiac failure, or grade 4 cardiac arrhythmia: stop ibrutinib.
• Moderate CYP3A4 inhibitors: reduce to 280 mg once daily (two capsules).
• Strong CYP3A4 inhibitors: reduce to 140 mg once daily (one capsule) or withhold for up to 7 days.

Special Populations

• Elderly (65 years and older): no specific dose adjustment.
• Renal impairment: no adjustment for mild or moderate impairment (creatinine clearance above 30 mL/min); hydration is maintained and serum creatinine monitored periodically. In severe impairment (below 30 mL/min) ibrutinib is given only if the benefit outweighs the risk, with close monitoring for toxicity. There are no data in severe impairment or dialysis.
• Hepatic impairment: mild impairment (Child-Pugh A), 280 mg daily (two capsules); moderate impairment (Child-Pugh B), 140 mg daily (one capsule). Patients are monitored for signs of toxicity. Ibrutinib is not recommended in severe impairment (Child-Pugh C).
• Severe cardiac disease: patients with severe cardiovascular disease were excluded from the clinical studies.
• Children and adolescents: ibrutinib is not recommended from 0 to 18 years because efficacy has not been established.

Missed Dose

A missed dose can be taken as soon as possible on the same day, returning to the normal schedule the next day. Extra capsules or tablets are not taken to make up for a missed dose.

Bleeding-Related Events

Bleeding has been reported with and without thrombocytopenia. It includes minor events (bruising, nosebleeds, petechiae) and major events, some fatal, such as gastrointestinal bleeding, intracranial haemorrhage and blood in the urine. Warfarin and other vitamin K antagonists should not be given with ibrutinib. Anticoagulants and antiplatelet agents increase the risk of major bleeding (higher with anticoagulants), so their benefit and risk should be weighed and patients monitored for bleeding. Fish oil and vitamin E preparations should be avoided. Ibrutinib should be held for at least 3 to 7 days before and after surgery, depending on the type of surgery and the bleeding risk. Patients with a congenital bleeding disorder have not been studied.

Leukostasis

Leukostasis has been reported. A high number of circulating lymphocytes (above 400,000/µL) may increase the risk. Temporary withholding of ibrutinib should be considered; patients are monitored closely and given supportive care such as hydration or cytoreduction as indicated.

Splenic Rupture

Splenic rupture has been reported after ibrutinib was stopped. Disease status and spleen size should be monitored when treatment is interrupted or ended, and a patient with pain in the left upper abdomen or at the shoulder tip should be evaluated for splenic rupture.

Infections

Infections, including sepsis, neutropenic sepsis and bacterial, viral or fungal infections, have occurred, some leading to hospitalisation or death; most patients with fatal infections also had neutropenia. Patients are monitored for fever, abnormal liver tests, neutropenia and infection, and prophylaxis according to standard of care should be considered in those at higher risk of opportunistic infections. Invasive fungal infections (aspergillosis, cryptococcosis, Pneumocystis jirovecii infection), some fatal, have been reported. Cases of progressive multifocal leukoencephalopathy (PML), including fatal ones, have been reported in the context of prior or concomitant immunosuppressive therapy. PML should be considered in patients with new or worsening neurological, cognitive or behavioural signs or symptoms, and treatment is suspended until it is excluded.

Hepatic Events

Hepatotoxicity, hepatitis B reactivation and hepatitis E (which may be chronic) have occurred, as has hepatic failure, including fatal events. Liver function and viral hepatitis status are assessed before starting, and liver tests are monitored periodically during treatment.

Cytopenias

Grade 3 or 4 neutropenia, thrombocytopenia and anaemia have been reported during treatment. A complete blood count is checked monthly.

Interstitial Lung Disease

Interstitial lung disease has been reported. Patients are monitored for pulmonary symptoms; if they develop, ibrutinib is interrupted and the condition managed, and the benefit and risk of continuing are reconsidered if symptoms persist.

Cardiac Arrhythmias and Cardiac Failure

Fatal and serious cardiac arrhythmias and cardiac failure have occurred. Advanced age, ECOG performance status of 2 or more, and cardiac comorbidity may add to the risk. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia and cardiac failure were reported, particularly with acute infections or cardiac risk factors such as hypertension, diabetes mellitus and a history of arrhythmia. Cardiac history and function are evaluated before starting, and patients are monitored for clinical deterioration. In patients with relevant risk factors the benefit and risk should be assessed carefully and alternative treatment may be considered. If ventricular tachyarrhythmia signs or symptoms appear, ibrutinib is stopped temporarily and the benefit and risk reassessed. In patients with pre-existing atrial fibrillation that needs anticoagulation, alternatives to ibrutinib should be considered; if atrial fibrillation develops on treatment, the risk of thromboembolic disease should be assessed thoroughly.

Cerebrovascular Accidents

Cerebrovascular accident, transient ischaemic attack and ischaemic stroke, including fatal cases, have occurred, with or without atrial fibrillation or hypertension. Where the latency was reported, onset was more than 1 month after starting in 78% of cases and more than 6 months in 44%, so regular monitoring is needed.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported. Patients with a high tumour burden before treatment are at risk and are monitored closely.

Non-Melanoma Skin Cancer

Non-melanoma skin cancer was reported more often with ibrutinib than with comparators in pooled phase 3 studies. Patients are monitored for its appearance.

Hypertension

Hypertension has occurred. Blood pressure is checked regularly, and antihypertensive medicine is started or adjusted during treatment as appropriate.

Haemophagocytic Lymphohistiocytosis

Cases of haemophagocytic lymphohistiocytosis (HLH), including fatal cases, have been reported. It is a life-threatening syndrome of excessive immune activation, with fever, enlarged liver and spleen, high triglycerides, high ferritin and low blood counts. Patients should know the symptoms, and anyone with early signs needs immediate evaluation.

Interacting Medicines

Strong CYP3A4 inhibitors and strong or moderate CYP3A4 inducers should be avoided whenever possible and used together with ibrutinib only if the benefit clearly outweighs the risk, with monitoring for toxicity or lack of efficacy.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception while taking ibrutinib and for 3 months after stopping.
• Pregnancy: ibrutinib may cause foetal harm based on animal findings and should not be used in pregnancy. There are no data in pregnant women. Women should avoid becoming pregnant while taking it and for up to 3 months afterwards.
• Breastfeeding: it is not known whether ibrutinib or its metabolites pass into human milk, and a risk to the breastfed child cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: no effects on fertility or reproduction were seen in male or female rats up to the highest dose tested (100 mg/kg/day, human equivalent 16 mg/kg/day). There are no human data.

Sodium

Each capsule contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

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

Imbruvica capsules and film-coated tablets do not require any special storage conditions. The capsules are supplied in HDPE bottles with a child-resistant polypropylene closure; each carton contains one bottle of 90 or 120 hard capsules, and not all pack sizes may be marketed. Keep out of the sight and reach of children.

3 years for both the capsules and the film-coated tablets. Do not use after the expiry date stated on the pack.

Prescription only (Rx), subject to restricted medical prescription: treatment is started and supervised by a physician experienced in the use of anticancer medicinal products. Ibrutinib is taken at home as a capsule or tablet, so it is supplied to the patient or to the treating clinic on prescription.