As part of its advice on safety-related aspects to other European Medicines Agency (EMA) committees, the Pharmacovigilance Risk Assessment Committee (PRAC) discussed at its meeting held from August 30, 2021, to September 2, 2021, direct healthcare professional communication (DHPC) containing important safety information for ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)

Following the PRAC meeting, the EMA informs healthcare professionals about a new safety signal of sudden or cardiac death with ibrutinib when used in combination with rituximab (Rituxan®; Genentech/Biogen; sold by Roche as MabThera® in Europe) and angiotensin-converting enzyme (ACE) inhibitors. The safety signal was recognized following a review of the findings of a clinical study.

Interim analyses
Ibrutinib is used for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinaemia.

An interim analysis of the clinical study suggested that the risk of sudden or cardiac death in patients on an ACE inhibitor when entering the study was increased in patients randomized to ibrutinib and rituximab, compared to those randomized to fludarabine, cyclophosphamide, and rituximab.

Precautionary measure
While the PRAC is reviewing the signal, as a precautionary measure, for patients with CLL currently receiving ibrutinib plus rituximab together with an ACE inhibitor, the PRAC advises healthcare professionals to reconsider the treatment strategy.

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For patients with CLL on ACE-inhibitors who have not yet started treatment with ibrutinib plus rituximab, the treatment strategy should be reconsidered before commencing ibrutinib. Also, patients should not stop taking ibrutinib or ACE inhibitors without first consulting their healthcare professional and should talk to their healthcare professional if they have questions or concerns.

The PRAC will communicate final conclusions and recommendations as soon as the evaluation has been completed.

The DHPC for ibrutinib will be forwarded to EMA’s Committee for Medicinal Products for Human Use (CHMP). Following the CHMP decision, the DHPC will be disseminated to healthcare professionals by the marketing authorization holder, according to an agreed communication plan, and published on EMA’s website and in national registers in EU Member States.

Highlights of prescribing information (US)
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) [Perscription Inform]
Rituximab (Rituxan®; Genentech/Biogen; sold by Roche as MabThera® in Europe) [Prescribing Information][Summary of Product Characteristics]

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