Ibrutinib

Serious (and some fatal) cardiac arrhythmias have occurred with therapy, including grade 3 or greater atrial fibrillation and flutter and grade 3 or greater ventricular tachyarrhythmias. Cardiac events have occurred particularly in patients with cardiac risk factors, hypertension, infections (acute), or with a history of arrhythmias. Monitor periodically for clinical symptoms of cardiac arrhythmias (eg, palpitations, light-headedness, syncope, chest pain); an ECG should be performed if symptoms or new-onset dyspnea develop. Manage arrhythmias appropriately; for persistent events, evaluate the risk-benefit of ibrutinib treatment and dose modification.

May cause dizziness, fatigue, and/or weakness, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

Diarrhea has been commonly observed; maintain adequate hydration.

Grade 3 and 4 neutropenia, thrombocytopenia, and anemia occurred commonly during clinical studies in patients who received single-agent ibrutinib for B-cell malignancies. Monitor blood counts monthly or as clinically necessary. Lymphocytosis (≥50% increase from baseline) may occur upon therapy initiation, generally within the first few weeks of therapy. The increase in lymphocytes is temporary, and resolves by a median of 8 weeks (mantle cell lymphoma) or 14 weeks (chronic lymphocytic leukemia). Some patients who developed lymphocytosis (lymphocytes >400,000/mcL) have developed intracranial hemorrhage, lethargy, headache, and gait instability (some cases may have been associated with disease progression). Monitor for leukostasis, particularly in patients experiencing a rapid increase in lymphocytes to >400,000/mcL.

Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], GI bleeding, hematuria, and postprocedural bleeding) have occurred; some events were fatal. Bleeding events of any grade, including bruising and petechiae have occurred in approximately half of patients receiving ibrutinib. Monitor for signs of bleeding. Patients receiving concurrent antiplatelet or anticoagulant treatment may have an increased risk for bleeding. Evaluate the risk-benefit of withholding ibrutinib for 3 to 7 days prior to and after surgery, depending on the procedure type and risk of bleeding.

Hypertension has been reported with ibrutinib therapy. The median onset of hypertension was 4.6 months (range: 0.03 to 22 months). Monitor for new onset hypertension or hypertension that is not adequately controlled after treatment initiation. May require antihypertensive therapy or adjustment of existing antihypertensive regimen.

Serious infections (some fatal) have been observed, including bacterial, viral, and fungal infections. Cases of Pneumocystis jirovecii pneumonia (PCP) have also been reported (Ahn 2016). Monitor and evaluate for fever and other signs/symptoms of infection and manage appropriately. Consider prophylaxis (according to standard of care) for patients at increased risk for opportunistic infections.

Progressive multifocal encephalopathy (PML) has been observed; evaluate for symptoms and manage appropriately.

Renal failure has been reported with use; some cases were fatal. Clinical trials report serum creatinine increases of up to 3 times ULN; monitor renal function periodically and maintain hydration.

Patients treated with ibrutinib have developed second primary malignancies, including skin cancers and other carcinomas. Evaluate for sign/symptoms of malignancy during treatment.

Tumor lysis syndrome has been reported (rare); increased uric acid levels have been observed, including grade 4 elevations. Assess risk for tumor lysis syndrome (eg, high tumor burden); monitor closely in patients at risk and manage appropriately. Disease related concerns:

Ibrutinib is hepatically metabolized, and exposure is increased in patients with hepatic dysfunction. Dosage adjustment is recommended in patients with mild or moderate (Child-Pugh class A or B) impairment; avoid use in patients with severe (Child-Pugh class C) impairment. Monitor closely for toxicity.

While ibrutinib is minimally excreted by the kidney and exposure is not affected in patients with mild to moderate impairment, renal failure has been observed in studies. Use with caution in patients with pre-existing renal impairment; has not been studied in those with severe impairment or in patients on dialysis. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Hyperviscosity may require plasmapheresis prior to or during ibrutinib treatment in patients with Waldenström macroglobulinemia; adjustment of ibrutinib dose due to plasmapheresis is not necessary. Other warnings/precautions:

A retrospective analysis of a phase 3 efficacy trial in previously treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma evaluated the effect of dose intensity on progression-free survival (PFS) and overall response rate (ORR). A higher dose intensity was associated with longer median PFS and a higher ORR; optimal outcomes were achieved in patients with sustained adherence to a 420 mg/day dosing schedule (Barr 2017).