IMBRUVICA

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Posology MCL Treatment of adult patients with previously untreated MCL The recommended dose for the treatment of previously untreated MCL is ibrutinib 560 mg once daily (see Table 1).

Table 1:

IMBRUVICA dosing schedule for previously untreated MCL Treatment Cycle number Treatment IMBRUVICA 1, 3, 5 IMBRUVICA in combination with R- CHOP§ On days 1-19Part I* 2, 4, 6 R-DHAP#§ Without IMBRUVICA Part II± IMBRUVICA Daily for 24 Months R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-DHAP= rituximab, dexamethasone, cytarabine, cisplatin.

*6 cycles; each cycle is 21 days. §See the Summary of Product Characteristics (SmPC) for dosing information for each medicinal product. #Interchangeable with R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin)§. ± Treatment should start after recovery of peripheral blood counts.

Rituximab may be added as per national treatment guidelines. Treatment of adult patients with relapsed or refractory MCL The recommended dose for the treatment of previously treated MCL is ibrutinib 560 mg once daily as a single agent.

Treatment with IMBRUVICA as a single agent should continue until disease progression or no longer tolerated by the patient. 1). Treatment with IMBRUVICA as a single agent or in combination with anti-CD20 therapy 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.

When administering IMBRUVICA in combination with anti-CD20 therapy, it is recommended to administer IMBRUVICA prior to anti-CD20 therapy when given on the same day. 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. IMBRUVICA therapy should be withheld for any new onset or worsening grade 2 cardiac failure, grade 3 cardiac arrhythmias, grade ≥3 non-haematological toxicity, grade 3 or greater neutropenia with infection or fever, or grade 4 haematological toxicities.

, bruising), rash, nausea, thrombocytopenia, arthralgia, and upper respiratory tract infection. The most common grade 3/4 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 IMBRUVICA 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 3.

Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated, except for studies with IMBRUVICA in combination with venetoclax where patients received fixed duration treatment (Studies CLL3011 and PCYC-1142-CA).

7 months. 6 months (up to 37 months).

Table 2:

Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies† System organ class Frequency (All grades) Adverse reactions All Grades (%) Grade ≥3 (%) Very common Pneumonia*# Upper respiratory tract infection Skin infection* 12 21 15 7 1 2 Common Sepsis*# Urinary tract infection Sinusitis* 3 9 9 3 1 1 Cryptococcal infections* <1 0 Pneumocystis infections* # <1 <1 Aspergillus infections* <1 <1 Infections and infestations Uncommon Hepatitis B reactivation@ # <1 <1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Non-melanoma skin cancer* Basal cell carcinoma Squamous cell carcinoma 5 3 1 1 <1 <1 Very common Neutropenia* Thrombocytopenia* Lymphocytosis* 39 29 15 31 8 11 Common Febrile neutropenia Leukocytosis 4 4 4 4 Blood and lymphatic system disorders Rare Leukostasis syndrome <1 <1 Immune system disorders Common Interstitial lung disease*,# 2 <1 Common Hyperuricaemia 9 1Metabolism and nutrition disorders Uncommon Tumour lysis syndrome 1 1 Very common Dizziness Headache 12 19 <1 1 Common Peripheral neuropathy* 7 <1 Nervous system disorders Uncommon Cerebrovascular accident # Transient ischaemic attack Ischaemic stroke # <1 <1 <1 <1 <1 <1 Common Vision blurred 6 0Eye disorders Uncommon Eye haemorrhage‡ Uveitis* <1 <1 0 0 Common Cardiac failure*, # Atrial fibrillation 2 8 1 4 Cardiac disorders Uncommon Ventricular tachyarrhythmia*,# Cardiac arrest# 1 <1 <1 <1 Very common Haemorrhage*# Bruising* Hypertension* 35 27 18 1 <1 8 Common Epistaxis Petechiae 9 7 <1 0 Vascular disorders Uncommon Subdural haematoma# 1 <1 Gastrointestina l disorders Very common Diarrhoea Vomiting Stomatitis* Nausea Constipation Dyspepsia 47 15 17 31 16 11 4 1 1 1 <1 <1 Hepatobiliary disorders Uncommon Hepatic failure*, # <1 <1 Very common Rash* 34 3 Common Urticaria Erythema Onychoclasis 1 3 4 <1 <1 0 Uncommon Angioedema Panniculitis* Neutrophilic dermatoses* Pyogenic granuloma Cutaneous vasculitis <1 <1 <1 <1 <1 <1 <1 <1 0 0 Skin and subcutaneous tissue disorders Rare Stevens-Johnson syndrome <1 <1 Musculoskeleta l and connective tissue disorders Very common Arthralgia Muscle spasms Musculoskeletal pain* 24 15 36 2 <1 3 Renal and urinary disorders Common Acute kidney injury# <2 <1 General disorders and administration site conditions Very common Pyrexia Oedema peripheral 19 16 1 1 Investigations Very common Blood creatinine increased 10 <1 † Frequencies are rounded to the nearest integer.

Bleeding-related events There have been reports of bleeding events in patients treated with IMBRUVICA, 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 IMBRUVICA. Use of either anticoagulants or medicinal products that inhibit platelet function (antiplatelet agents) concomitantly with IMBRUVICA 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 IMBRUVICA. Monitor for signs and symptoms of bleeding.

Supplements such as fish oil and vitamin E preparations should be avoided. IMBRUVICA 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 IMBRUVICA. A high number of circulating lymphocytes (>400,000/mcL) may confer increased risk.

Consider temporarily withholding IMBRUVICA. 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 IMBRUVICA treatment.

g. clinical examination, ultrasound) when IMBRUVICA 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 IMBRUVICA.

1. Use of preparations containing St. John’s Wort is contraindicated in patients treated with IMBRUVICA.