Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice

Abstract

Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated CLL patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers). Although the ibrutinib starting dose was changed in 18 patients on CYP3A interacting medications, no difference in 18-month progression-free survival or rate of ibrutinib discontinuation was observed in patients who were not. In routine clinical practice, 2 of 3 CLL patients commencing ibrutinib are on a concomitant medication with potential to influence ibrutinib metabolism. Formal medication review by a pharmacist should be considered in all patients initiating ibrutinib.

Ibrutinib‐associated bleeding: pathogenesis, management and risk reduction strategies

“…There are limited data describing physician and patient awareness of the bleeding risks associated with ibrutinib. One group performed a medication review of 96 CLL patients beginning ibrutinib and found that 64% of the patients were concurrently taking medications that increased the risk of ibrutinib toxicity, including CYP3A4 inhibitors carbamazepine, rifampin and rifabutin . When beginning ibrutinib, 9% of patients were taking an anticoagulant and 30% were on aspirin .…”

“…One group performed a medication review of 96 CLL patients beginning ibrutinib and found that 64% of the patients were concurrently taking medications that increased the risk of ibrutinib toxicity, including CYP3A4 inhibitors carbamazepine, rifampin and rifabutin . When beginning ibrutinib, 9% of patients were taking an anticoagulant and 30% were on aspirin . The data showed that 10% of the patients had clinically significant bleeding, with 4% (four patients, one on enoxaparin, two on an SSRI and one on a NSAID) requiring hospitalization .…”

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

“…Major bleeding was classified according to the Common Terminology Criteria for Adverse Events and included the following: (1) grade $3 (n 5 8), [1][2][3]15,16,28,30,31 (2) grade $2 (n 5 3), 4,26,29 (3) reason for drug discontinuation (n 5 2), 5,27 and (4) bleeding requiring hospitalization (n 5 1). 24 In addition, 3 studies did not report a definition of major bleeding; one of these studies 17 reported 10 events, including 1 resulting in death and 3 leading to drug discontinuation. In the 4 RCTs reporting on major bleeding, 1,3,6 (Figure 2).…”

“…Thirteen articles reported on the incidence of overall bleeding 6,8,[15][16][17][18][19][20][21][22][23][24][25] with a pooled annual incidence of any bleeding of 20.8 per 100 patient-years (95% confidence interval [CI], 19.1-22.1) in ibrutinibtreated patients. Two RCTs 6,15 compared the incidence of overall bleeding between ibrutinib and an alternative therapy ( Figure 1).…”

How I treat CLL patients with ibrutinib

“…Consumption of grapefruit and Seville oranges, as well as some supplements, also alter exposure of CYP3A4 metabolized drugs like ibrutinib. A recent study from the Mayo Clinic found that 64% of 118 CLL patients treated with ibrutinib were on medications that could increase toxicity through drug interactions, the majority of which were antiplatelet medications, but 18% were drug interactions through CYP3A 38 . Thus a careful medication review prior to ibrutinib prescription is important to avoid AEs like one reported with co-administration with the moderate CYP3A4 inhibitor verapamil 39 .…”