IBRU

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

Other Supportive Care:

Doses should be modified according to the protocol by which the patient is being treated.

Patients who require anticoagulant treatment should not start ibrutinib until stable coagulation is achieved.

Ibrutinib should be held 3-7 days pre- and post-surgery depending on the surgery type and risk of bleeding; restart at physician discretion.

Ibrutinib may be affected by CYP3A inducers and inhibitors; see Drug Interaction section for dose adjustments.

Dose Modifications for Non-cardiac toxicity:

*Do not restart until hematological and non-hematological toxicities resolve to ≤ grade 1 or baseline.

Dose Modifications for Cardiac toxicity:

*Do not restart until heart failure resolves to ≤ grade 1 or baseline.
**Consider risk vs. benefit before restarting treatment.

Ibrutinib is metabolized in the liver and increased exposure is seen in patients with hepatic impairment.  The risk of bleeding increases in moderate to severe hepatic impairment.
 

Ibrutinib has minimal renal clearance.
 

No dose adjustment required. No difference in effectiveness of ibrutinib was observed for patients with B-cell malignancies > 65 years of age compared to younger patients. Steady state drug levels are higher in the elderly, but no starting dosage adjustment is required. Patients > 65 years of age reported more frequent grade 3 or higher adverse events (including fatal events), as well as thrombocytopenia, pneumonia, hypertension, urinary tract infection, and atrial fibrillation.

Refer to ibrutinib drug monograph(s) for additional details of adverse effects.

Refer to ibrutinib drug monograph(s) for additional details.

• For strong CYP3A inhibitors, avoid concomitant use due to ↑ ibrutinib exposure; if unavoidable short term (≤ 7 days), hold* ibrutinib for duration of inhibitor use.

• For moderate CYP3A inhibitors (excluding voriconazole), reduce* ibrutinib dose to 280 mg daily for duration of inhibitor use due to ↑ ibrutinib exposure.

• For voriconazole, reduce* ibrutinib dose to 140 mg for duration of inhibitor use due to ↑ ibrutinib exposure.

• For strong CYP3A inducers, avoid concomitant use due to ↓ ibrutinib exposure.

• Caution with the concurrent use of ibrutinib and anticoagulants or drugs that inhibit platelet function. If anticoagulation is required, consider temporary hold of ibrutinib until stable anticoagulation achieved.

• Avoid supplements that may inhibit platelet aggregation (e.g. fish oil, flaxseed, vitamin E).

• PGP substrates (e.g. verapamil, digoxin) and BRCP substrates (e.g. methotrexate) with narrow therapeutic range must be taken ≥ 6 hours before or after the ibrutinib dose. BCRP substrates may require dose reduction.
   

*Resume previous dose of ibrutinib after strong or moderate CYP3A inhibitor discontinuation.
 

Refer to ibrutinib drug monograph(s) for additional details.

Administration

• Administer ibrutinib with or without food.

• Swallow whole with a glass of water. Do not open, break or chew capsules.

• Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during ibrutinib treatment.

• If a dose of ibrutinib is missed, patient may take it as soon as possible on the same day and return to the scheduled time the next day. Patient should not take an extra dose to make up for a missed dose.

• Store at room temperature (15-30^oC).
   

Contraindications

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

Warnings/Precautions

• 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.
   

Pregnancy/Lactation

• 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.

• Breastfeeding is not recommended during treatment and for 1 week after the last dose.

• Fertility effects: Unknown

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.

Recommended Clinical Monitoring

Outpatient prescription for home administration

Ibrutinib drug monograph, Ontario Health (Cancer Care Ontario).

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.