iBRUtinib

iBRUtinib

COMMON TRADE NAME(S):   Imbruvica®

• Chronic lymphocytic leukemia (CLL)
• Waldenstrom macroglobulinemia (WM)
• Mantle cell lymphoma (MCL)
• Marginal zone lymphoma (MZL)
• Chronic graft vs. host disease (cGVHD)
   

Refer to the product monograph for a full list and details of approved indications.

• Diffuse large B cell lymphoma (DLBCL)

Emetogenic Potential:  

The following adverse effects were reported in a phase 3 study of ibrutinib 420 mg in previously untreated patients with CLL or SLL. It also includes severe or life-threatening adverse effects from other sources or post-marketing.

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for ibrutinib include lymphocytosis, diarrhea, musculoskeletal pain, fatigue, cough, dyspnea, nausea, vomiting, rash, edema (limbs), dry eye and constipation.

Atrial fibrillation, atrial flutter, heart failure, and arrhythmias (including fatal events) were reported, particularly in patients with cardiac risk factors, hypertension, diabetes, acute infection, and a previous history of cardiac arrhythmias.

Cerebrovascular accident, transient ischemic attack, and ischemic stroke (including fatalities) have been reported, with and without concomitant atrial fibrillation and/or hypertension; causality with ibrutinib has not been established.

In the pooled safety database, grade 3 or 4 hypertension has occurred with a median time to onset of 6 months. Increased incidence has been observed over time while on treatment with ibrutinib.

Transient lymphocytosis (≥ 50% increase from baseline) was observed in most CLL patients treated with ibrutinib with a median time to onset of 1 to 2 weeks and a median time to resolution of 12 to 14 weeks. When given in combination with obinutuzumab or in combination with bendamustine and rituximab, the incidences were lower and median times to resolution were shorter. The increase in lymphocytes may be related to a pharmacodynamic effect of BTK inhibition and should not be considered progressive disease in the absence of other clinical signs. 

Rare cases of leukostasis have occurred within two to three weeks of starting treatment and included intracranial hemorrhage, lethargy, gait instability and headache. Risk increases in patients with circulating lymphocytes > 400,000/microlitre.

BTK is expressed in platelets and ibrutinib inhibits collagen-induced platelet aggregation in vitro. Major hemorrhage has been reported, including subdural hematoma and deaths. Patients > 65 years of age, receiving concomitant antiplatelet or anticoagulant drugs, with a history of bleeding disorders, thrombocytopenia or leukocytosis, or who have had recent strokes or intracranial hemorrhage are at increased risk and should be monitored closely.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported.

Cases of hepatitis B viral reactivation have also been reported, although causality has not been established.

• Patients who have a hypersensitivity to this drug or any components of the formulation.
   

• Do not use ibrutinib in patients with moderate or severe hepatic impairment due to ↑ risk of coagulopathy and bleeding. Patients with AST/ALT ≥ 3 x ULN were excluded from clinical trials.

• Avoid concomitant use of ibrutinib with strong CYP3A inhibitors due to ↑ ibrutinib exposure.

• Exercise caution in patients at risk of bleeding, including those receiving anticoagulants or medications that inhibit platelet function. A higher risk for major bleeding was observed with anticoagulant than with antiplatelet agents. Patients on warfarin or other vitamin K antagonists and those with a history of recent stroke or intracranial hemorrhage were excluded from clinical trials.  Patients with congenital bleeding conditions have not been studied.

• Exercise caution in patients with cardiac risk factors, hypertension, pre-existing conduction system abnormalities, history of arrhythmias/atrial fibrillation or acute infection.

• Transient lymphocytosis has been observed in patients treated with ibrutinib and should not be considered progressive disease in the absence of other clinical findings.

• Patients should use caution when driving or operating a vehicle or potentially dangerous machinery due to fatigue, dizziness and asthenia.
   

• Genotoxicity: No
  
• Clastogenicity: No
  
• Fetotoxicity: Probable
  

  • Ibrutinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.

  • Women who use hormonal contraception should add a barrier method. Male patients should use a condom and not donate sperm during treatment, and for at least 3 months after the last dose.

• Excretion into breast milk: Unknown
  
  • Breastfeeding is not recommended during treatment and for 1 week after the last dose.
• Fertility effects: Unknown
  

Ibrutinib is primarily metabolized by CYP3A.

In vitro, ibrutinib is an inhibitor of P-gp and BCRP transporters and a weak inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 enzymes. Inhibition or induction of CYP450 enzymes by ibrutinib or its metabolites is unlikely to result in clinically significant drug interactions with CYP450 substrates.

In vitro, ibrutinib is a substrate of OCT2; administration of P-gp or other major transporter inhibitors is unlikely to lead to clinically relevant interactions.

Co-administration with grapefruit juice increased exposure. Grapefruit and Seville oranges should be avoided during treatment.

No dose adjustment is required when used with mild CYP3A4 inhibitors.

Concomitant medications that ↑ stomach pH (e.g., proton pump inhibitors) were permitted in the pivotal clinical trials.

 *Resume previous ibrutinib dose after inhibitor discontinuation.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Exceptional Access Program (EAP Website)

• iBRUtinib - For patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to specific criteria.
• iBRUtinib - For relapsed and refractory Mantle Cell Lymphoma, according to clinical criteria

Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-2437.

Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23.

Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11.

Prescribing Information: Imbruvica (ibrutinib). Pharmacyclics Inc., December 2020.

Product Monograph: Imbruvica (ibrutinib). Janssen Inc. June 29, 2022.

Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015 Apr 9;372(15):1430-40.

Wang ML, Rule S, Martin P, Goy A, Auer R, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013 Aug 8;369(6):507-16.

February 2023 Updated adverse effects and dose modification sections