IMBRUVICA

What it is

IMBRUVICA is ibrutinib , a therapeutic agent for B-cell malignancies. Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys 481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. IMBRUVICA is available as 140 mg capsules and as film-coated tablets in 140 mg, 280 mg, 420 mg and 560 mg strengths. IMBRUVICA should be administered orally once daily with a glass of water at approximately the same time each day. IMBRUVICA can be taken with or without food. The capsules or tablets should be swallowed whole with water.

Approved indications —

Patients with mantle cell lymphoma who have received at least one prior therapy — Adult patients with Waldenström's macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy — Adult patients with Waldenström's macroglobulinaemia in combination with rituximab — Adult patients with previously untreated chronic lymphocytic leukaemia/small lymphocytic lymphoma as a single agent or in combination with rituximab or obinutuzumab or venetoclax — Adult patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma who have received at least one prior therapy as a single agent or in combination with bendamustine and rituximab

Dosing overview

Dose modifications are required for the concomitant use of moderate and strong CYP3A inhibitors as these can increase the exposure of ibrutinib. IMBRUVICA therapy should be withheld for any new onset or worsening Grade 2 cardiac failure, Grade 3 cardiac arrhythmias, Grade ≥ 3 non-haematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 haematological toxicities.

Key safety warnings

Bleeding events have been reported in patients treated with ibrutinib, both with and without thrombocytopenia, including minor bleeding events such as contusion, epistaxis, and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria. Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major bleeding. Fatal and serious cardiac arrhythmias or cardiac failure have occurred in patients treated with IMBRUVICA. Patients with significant 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. Infections, including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections, were observed in patients treated with ibrutinib. Some of these infections have been associated with hospitalisation and death. Cases of hepatitis E, which may be chronic, have occurred in patients treated with ibrutinib. Severe liver toxicity, such as hepatic failure (Grade 3 and 4 elevations in ALT and AST) and drug-induced liver injury, including fatal events, have occurred in the post-marketing setting in patients taking ibrutinib. Hypertension has occurred in patients treated with IMBRUVICA. Hypertension occurred in 18% of 1981 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients.

Contraindications

IMBRUVICA is contraindicated in patients who have known hypersensitivity (such as anaphylactic and anaphylactoid reactions) to ibrutinib or to the excipients in its formulation. Use of preparations containing St. John's Wort is contraindicated in patients treated with IMBRUVICA.

PBS listing

IMBRUVICA is listed on the PBS in four strengths: 280 mg tablets (6 items), 420 mg tablets (6 items), 560 mg tablets (1 item), and 140 mg capsules (6 items). All listings require authority required restriction. Ex-manufacturer prices are: 280 mg A$5194.37, 420 mg A$7791.55, 560 mg A$10388.73, and 140 mg capsules A$7791.55.

Regulatory history

IMBRUVICA was approved on 2015-04-15 for the treatment of patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma who have received at least one prior therapy or as first line in patients with CLL with 17p deletion, and patients with mantle cell lymphoma who have received at least one prior therapy. In March 2017, PBAC recommended the listing for relapsed or refractory chronic lymphocytic leukaemia and relapsed or refractory small lymphocytic lymphoma as monotherapy. In November 2017, PBAC recommended an amendment to allow ibrutinib to be used as first-line therapy for chronic lymphocytic leukaemia in patients with 17p deletion or TP53 mutation. In March 2018, PBAC did not recommend first-line chronic lymphocytic leukaemia or small lymphocytic lymphoma, noting that the clinical claim of superior comparative efficacy and non-inferior safety was accepted but the economic claim of cost-utility analysis was not accepted. Also in March 2018, PBAC recommended an extension of PBS listing for mantle cell lymphoma as an Authority Required benefit. In November 2019, PBAC recommended Authority Required listing for first-line treatment of chronic lymphocytic leukaemia or small lymphocytic lymphoma with 17p chromosome deletions, noting high clinical need and significant improvement in progression-free survival with non-inferior safety. In November 2021, PBAC extended its recommendation for chronic lymphocytic leukaemia and small lymphocytic lymphoma for 12 months. In March 2024, PBAC recommended listing for chronic lymphocytic leukaemia or small lymphocytic lymphoma in combination with venetoclax for previously untreated patients.