Prescribing information For Healthcare Professionals Only

IMBRUVICA®

140mg, 280mg, 420mg and 560mg Film-coated Tablets

PRESCRIBING INFORMATION

ACTIVE INGREDIENT:

Ibrutinib

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

The IMBRUVICA® SmPCs are available at:

Please click the following product name to access the full SmPC
IMBRUVICA® 140 mg film-coated tablets

INDICATIONS: 

As a single agent for adults with relapsed or refractory mantle cell lymphoma (MCL). As a single agent or in combination with rituximab or obinutuzumab or venetoclax for adults with chronic lymphocytic leukaemia (CLL) who are previously untreated. As a single agent or in combination with bendamustine and rituximab (BR) for adults with CLL who have received ≥ one prior therapy. As a single agent for adults with Waldenström’s macroglobulinaemia (WM), who have received ≥ one prior therapy or first line in patients unsuitable for chemo immunotherapy. In combination with rituximab for adults with WM.

DOSAGE & ADMINISTRATION:

Adults: Orally, once daily, swallowed whole with water. MCL – 560 mg. CLL and WM – 420 mg as single agent or in combination (refer to SmPC). Treatment with IMBRUVICA should continue until disease progression or no longer tolerated by the patient. In combination with venetoclax for the treatment of CLL, IMBRUVICA should be administered as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of IMBRUVICA plus venetoclax. See the venetoclax Summary of Product Characteristics (SmPC) for full venetoclax dosing information. Concomitant strong CYP3A4 inhibitors – reduce dose to 140 mg (or withhold IMBRUVICA for up to 7 days). Concomitant moderate CYP3A4 inhibitors – reduce to 280 mg. Withhold IMBRUVICA therapy for any new onset/worsening grade 2 cardiac failure, grade 3 cardiac arrhythmias, grade ≥ 3 non-haematological toxicity, grade ≥ 3 neutropenia with infection/fever, or grade 4 haematological toxicities. Refer to SmPC/DHPC for further information on dose modification and discontinuation recommendations for non-cardiac and cardiac events. 
Children: Safety/efficacy not established ≤ 18 years old.
Elderly: No dose adjustment required.
Renal impairment: Mild/moderate - no dose adjustment. Severe – no data; consider benefit/risk and monitor closely. No data with dialysis.
Hepatic impairment: Mild (Child-Pugh class A) – 280mg daily; moderate (Child-Pugh class B) – 140mg daily; severe (Child-Pugh class C) – not recommended. Monitor for toxicities.
Severe cardiac disease: No clinical data.

CONTRAINDICATIONS:

Hypersensitivity to active substance/excipients. St. John’s Wort preparations.

SPECIAL WARNINGS & PRECAUTIONS: 

Bleeding-related events: minor and major events reported, some fatal. Do not use with warfarin or other vitamin K antagonists. Risk of major bleeding increased with use of anticoagulants and antiplatelet agents. Monitor for signs, symptoms of bleeding. Avoid fish oil and vitamin E preparations. Withhold IMBRUVICA ≥ 3 to 7 days pre/post-surgery. 
Leukostasis: cases reported; consider temporary withhold of IMBRUVICA; monitor closely, give supportive care.
Splenic rupture: cases reported following treatment discontinuation, monitor disease status and spleen size when treatment is interrupted or ceased.
Infections: infections seen, some resulting in hospitalisation and death; monitor for fever, abnormal liver function tests, neutropenia and infections and give anti-infective therapy. Consider prophylaxis in increased risk patients. Invasive fungal infections have been associated with fatal outcomes.
Progressive Multifocal Leukoencephalopathy (PML): including fatal cases, reported with prior or concomitant immunosuppressive therapy; monitor for new/worsening neurological, cognitive or behavioural signs/symptoms; if suspected, suspend treatment until PML excluded; if in doubt refer to neurologist for diagnostic tests. 
Hepatic events: Cases of hepatotoxicity, hepatitis B reactivation, and cases of hepatitis E, which may be chronic, have occurred in patients treated with IMBRUVICA. Hepatic failure, including fatal events, also occurred. Assess liver function and viral hepatitis status before initiating treatment. Patients should be periodically monitored for changes in liver function parameters during treatment. Viral load and serological testing for infectious hepatitis should be performed per local medical guidelines as clinically indicated. For patients diagnosed with hepatic events, consider consulting a liver disease expert for management. 
Cytopenias: treatment-emergent grade 3/4 cytopenias reported; monitor complete blood counts monthly.
Interstitial Lung Disease (ILD): cases reported; monitor patients for pulmonary symptoms of ILD; interrupt IMBRUVICA and manage ILD if symptoms develop; if symptoms persist, consider risk/benefit of IMBRUVICA treatment and follow dose modification guidelines. 
Cardiac arrhythmias and cardiac failure: Fatal and serious cardiac arrhythmias and cardiac failure have occurred in patients treated with IMBRUVICA. Patients of advanced age, Eastern Cooperative Oncology (ECOG) performance status ≥2, or with cardiac co-morbidities may be at greater risk of events including sudden fatal cardiac events. Atrial fibrillation/flutter, ventricular tachyarrhythmia and cardiac failure have been reported, particularly in patients with acute infections or cardiac risk factors including hypertension/ diabetes mellitus and a previous history of cardiac arrhythmia. Appropriate clinical evaluation of cardiac history and function should be performed prior to initiating IMBRUVICA. Patients should be carefully monitored during treatment for signs of clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g., ECG, echocardiogram), as indicated for patients in whom there are cardiovascular concerns. For patients with relevant risk factors for cardiac events, carefully assess benefit/risk before initiating treatment with IMBRUVICA; alternative treatment may be considered. If signs/symptoms of ventricular tachyarrhythmia develop, temporarily discontinue IMBRUVICA and carry out thorough clinical benefit/risk assessment before considering restarting; consider alternative to IMBRUVICA. In patients with pre-existing atrial fibrillation requiring anticoagulant therapy or high risk of thromboembolic disease consider alternative treatment options to IMBRUVICA; where no suitable alternatives to IMBRUVICA exist, consider tightly controlled treatment with anticoagulants. Patients should be monitored at baseline and periodically for signs and symptoms of cardiac failure during IMBRUVICA treatment. In some of these cases cardiac failure resolved or improved after IMBRUVICA withdrawal or dose reduction. 

Cerebrovascular accidents: Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported in patients treated with IMBRUVICA, with and without concomitant atrial fibrillation and/or hypertension; monitor regularly. 
Tumour lysis syndrome (TLS): cases reported. Monitor at risk patients closely, take precautions.
Non-melanoma skin cancer: cases reported; monitor patients. 
Hypertension: Monitor BP regularly, treat as appropriate.
Haemophagocytic lymphohistiocytosis (HLH): cases reported including fatal cases; inform patients of HLH symptoms.
Drug-drug interactions: Strong/moderate CYP3A4 inhibitors may increase ibrutinib exposure; CYP3A4 inducers may decrease ibrutinib exposure; avoid strong inhibitors, and strong/moderate inducers, of CYP3A4 where possible; if not monitor closely for toxicities/lack of efficacy.                                  

 

SIDE EFFECTS:

Very common: Pneumonia#, upper respiratory tract infection, skin infection, neutropenia, thrombocytopenia, lymphocytosis, hyperuricaemia, dizziness, headache, haemorrhage#, bruising, hypertension, diarrhoea, vomiting, stomatitis, nausea, constipation, dyspepsia, rash, arthralgia, musculoskeletal pain, pyrexia, oedema peripheral, muscle spasms, blood creatinine increased.
Common: Sepsis#, urinary tract infection, sinusitis, non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, febrile neutropenia, leukocytosis, interstitial lung disease#, hyperuricaemia, peripheral neuropathy, vision blurred, cardiac failure#, atrial fibrillation, epistaxis, petechiae, urticaria, erythema, onychoclasis, acute kidney injury#

Uncommon: cryptococcal infections, pneumocystis infections#, aspergillus infections, hepatitis B reactivation#, tumour lysis syndrome, cerebrovascular accident#, transient ischaemic attack, ischaemic stroke#, eye haemorrhage including some cases associated with loss of vision, ventricular tachyarrhythmia#, cardiac arrest#, subdural haematoma#, hepatic failure#, angioedema, panniculitis, neutrophilic dermatoses, pyogenic granuloma.
Rare: leukostasis syndrome, Stevens-Johnson syndrome 
(# includes events with fatal outcome)

Refer to SmPC for other side effects.

PREGNANCY:

Women of child-bearing potential must use highly effective contraceptive measures during and for 3 months after stopping treatment. Not to be used during pregnancy.

LACTATION:

Discontinue breast-feeding during treatment.

INTERACTIONS:

CYP3A4 inhibitors: 

Strong: Avoid where possible or reduce IMBRUVICA dose (or withhold for ≤ 7 days) and monitor closely; e.g. ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, voriconazole, posaconazole
Moderate: Avoid where possible or reduce IMBRUVICA dose and monitor closely; e.g. erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone. Avoid grapefruit and Seville oranges. 
Mild: No dose adjustment required; monitor closely.

CYP3A4 inducers
Strong/moderate: Avoid or monitor closely for lack of efficacy; e.g. carbamazepine, rifampicin, phenytoin.
Mild: may be used; monitor for lack of efficacy. 

Potential interactions: Oral narrow therapeutic range P‑gp or breast cancer resistance protein (BCRP) substrates (e.g. digoxin, methotrexate) should be taken ≥ 6 h before/after IMBRUVICA. Ibrutinib may inhibit BCRP in the liver and so increase exposure of drugs undergoing BCRP-mediated hepatic efflux (e.g. rosuvastatin).

Refer to SmPC for full details of interactions.

LEGAL CATEGORY: POM

PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S) & BASIC NHS COSTS

PRESENTATIONS PACK SIZES MARKETING AUTHORISATION
NUMBER(S)
BASIC NHS COSTS
140mg blister pack 28 tablets EU/1/14/945/007
PLGB 00242/0688
£1,430.80
280mg blister pack 28 tablets EU/1/14/945/009
PLGB 00242/0689
£2,861.60
420mg blister pack 28 tablets EU/1/14/945/011
PLGB 00242/0690
£4,292.40
560mg blister pack 28 tablets EU/1/14/945/012
PLGB 00242/0691
£5,723.20

MARKETING AUTHORISATION HOLDER: 
Great-Britain (PLGB): Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK
Northern Ireland (EU): Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. 

Prescribing information last revised: October 2023

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