Prescribing information For Healthcare Professionals Only

IMBRUVICA®

140mg Hard Capsules and 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 hard capsules
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 obinutuzumab 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 (1 tablet or 4 capsules). CLL and WM – 420 mg (1 tablet or 3 capsules) as single agent or in combination (refer to SmPC). Concomitant moderate CYP3A4 inhibitors – reduce dose to 280mg. Withhold IMBRUVICA therapy for any new onset/worsening grade ≥ 3 non-haematological toxicity, grade ≥ 3 neutropenia with infection/fever, or grade 4 haematological toxicities. Re-initiate when toxicities resolved to grade 1 or baseline. If toxicities recur, reduce dose by 140mg. A second dose reduction of 140mg may be be considered if needed. Discontinue IMBRUVICA if toxicities persist/recur following two dose reductions.
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.
Infections: infections seen, some resulting in hospitalisation and death; monitor for fever, 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. 
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 arrhythmia: atrial fibrillation/flutter and ventricular tachyarrhythmia reported. Atrial fibrillation/flutter reported particularly in patients with cardiac risk factors/hypertension/acute infections/previous history of atrial fibrillation; Periodic clinical monitoring; consider ECG if arrhythmic symptoms or new onset dyspnoea, dizziness or fainting develop; 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 when pre-existing atrial fibrillation requiring anticoagulant therapy or high risk of thromboembolic disease; where no suitable alternatives to IMBRUVICA, consider tightly controlled treatment with anticoagulants.
Viral reactivation: hepatitis B reactivation reported; establish HBV status before starting treatment; if positive HBV consult specialist physician; if positive hepatitis B serology, consult a liver disease expert before starting treatment and monitor/manage to prevent hepatitis B reactivation.

 


Tumour lysis syndrome: cases reported. Monitor at risk patients closely, take precautions.
Non-melanoma skin cancer: cases reported; monitor patients. 
Hypertension: Monitor BP regularly, treat as appropriate.
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, headache, haemorrhage, bruising, hypertension, diarrhoea, vomiting, stomatitis, nausea, constipation, rash, arthralgia, musculoskeletal pain, pyrexia, oedema peripheral, muscle spasms. 
Common: Sepsis, urinary tract infection, sinusitis, non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, febrile neutropenia, leukocytosis, interstitial lung disease, lymphocytosis, tumour lysis syndrome, hyperuricaemia, peripheral neuropathy, dizziness, vision blurred, atrial fibrillation, epistaxis, petechiae, urticaria, erythema, onychoclasis.
Other side effects: Hepatitis B reactivation, leukostasis syndrome, hepatic failure, panniculitis, Stevens-Johnson syndrome, angioedema, ventricular tachyarrhythmia, subdural haematoma, fungal infections (Cryprococcal, Pneumocystis, Aspergillus).

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; if using hormonal contraceptives, add barrier method. 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). Ibrutinib may inhibit intestinal CYP3A4 and thus increase exposure of some CYP3A4 substrates sensitive to gut CYP3A metabolism; caution with narrow therapeutic range oral CYP3A4 substrates (e.g. dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus, tacrolimus). Ibrutinib is a weak CYP2B6 inducer and may affect expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR) (e.g. CYP2C9, CYP2C19, UGT1A1, MRP2). Exposure to substrates of CYP2B6 (e.g. efavirenz, bupropion) and co-regulated enzymes may be reduced with ibrutinib.

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 bottles 90 capsules EU/1/14/945/001 £4,599
140mg bottles 120 capsules EU/1/14/945/002 £6,132
140mg blister pack 28 tablets EU/1/14/945/007 £1,430.80
280mg blister pack 28 tablets EU/1/14/945/009 £2,861.60
420mg blister pack 28 tablets EU/1/14/945/011 £4,292.40
560mg blister pack 28 tablets EU/1/14/945/012 £5,723.20

MARKETING AUTHORISATION HOLDER: 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: September 2019

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