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IBRU

Cancer Type: Hematologic, Lymphoma - Non-Hodgkin's Low Grade  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    iBRUtinib - For relapsed and refractory Mantle Cell Lymphoma, according to clinical criteria
A - Regimen Name

IBRU Regimen
Ibrutinib


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's Low Grade

Mantle cell lymphoma


Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL). 


Supplementary Public Funding

iBRUtinib
Exceptional Access Program (iBRUtinib - For relapsed and refractory Mantle Cell Lymphoma, according to clinical criteria) (EAP Website)

 
B - Drug Regimen

iBRUtinib
560 mg PO Daily

(Outpatient prescription in multiples of 140 mg capsules)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Consider prophylaxis for patients at an increased risk for opportunistic infections.

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

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered. Patients who require anticoagulant treatment should not start ibrutinib until they are stable on their anticoagulant. Do not use warfarin or other vitamin K antagonists concomitantly with ibrutinib.

Dosage with toxicity

Toxicity Occurrence Dose modification after recovery (starting dose = 560 mg)
First Restart at 560 mg daily
Second Restart at 420 mg daily
Third Restart at 280 mg daily
Fourth Discontinue

 

 

 

 

 

Toxicity
Ibrutinib dose
Grade 4 ANC > 7 days OR
Grade ≥3 neutropenia with infection or fever OR Grade 4 platelets or thrombocytopenic bleeding
Hold until ≤ grade 1, restart at dose indicated above
Grade 3 or 4 non-hematologic toxicity (despite appropriate treatment)
Hold until ≤ grade 1, restart at dose indicated above
Major hemorrhage
Discontinue
Lymphocytes > 400,000/mcL
Consider temporary hold. Monitor closely for signs of leukostasis and manage patient appropriately.
New onset or inadequately controlled hypertension Initiate or adjust antihypertensive treatment as appropriate
Persistent atrial fibrillation
Consider risk vs. benefit of continuing treatment
Surgery
Hold 3-7 days pre and post-surgery depending on the surgery type and risk of bleeding, restart at physician discretion
Concomitant usage of CYP3A inhibitors
See Drug Interactions section for specific dose modifications
PML Hold and investigate. Discontinue if confirmed.
New or worsening respiratory symptoms Hold, manage appropriately and investigate for ILD. Discontinue if confirmed.

 

 



Hepatic Impairment

Ibrutinib is metabolized in the liver and increased exposure has been demonstrated in patients with hepatic impairment. The risk of bleeding increases in moderate to severe hepatic impairment. Patients with AST/ALT ≥ 3 x ULN were excluded from clinical trials


Suggested dose modifications:  

Hepatic impairment
Ibrutinib dose
Child-Pugh Class A
140 mg daily (if benefits of treatment outweigh risks)
Child-Pugh Class B or C
Do not start ibrutinib

Renal Impairment

 Ibrutinib has minimal renal clearance.

Creatinine clearance (mL/min)
Ibrutinib dose
> 30                        
No change; monitor creatinine
≤ 30 or dialysis
No data

Dosage in the Elderly

No difference in effectiveness of ibrutinib was observed for patients over 65 years of age compared to younger patients. Steady state drug levels are higher in the elderly, but no starting dosage adjustment is required. Grade 3 or higher adverse events (including fatal events) occurred more frequently, including anemia, pneumonia, atrial fibrillation, hypertension, cellulitis and dehydration.


 
F - Adverse Effects

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


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Lymphocytosis (including leucostasis) 
  • Diarrhea (may be severe)
  • Fatigue
  • Musculoskeletal pain
  • Nausea, vomiting
  • Edema
  • Cough, dyspnea
  • Rash
  • Fever
  • Myelosuppression +/- infection (includes opportunistic, hepatitis B and other viral reactivation), bleeding (may be severe)
  • Mucositis
  • Constipation
  • Headache
  • Dizziness
  • Blurred vision
  • Hypertension (may be severe)
  • Anorexia
  • GERD

 

  • Atrial fibrillation
  • Increased LFTs
  • Hypersensitivity
  • Tumour lysis syndrome
  • Secondary malignancy (non-melanoma skin cancer)
  • Leukoencephalopathy (PML)
  • Interstitial lung disease

 

 
G - Interactions

Refer to ibrutinib drug monograph(s) for additional details


  • Ibrutinib is primarily metabolized by CYP3A. 
  • For strong CYP3A inhibitors: 
    • Avoid concomitant use, where possible. If not possible to avoid, hold ibrutinib for duration of inhibitor use ≤ 7 days.
  • For moderate CYP3A inhibitors:
    • Reduce ibrutinib dose to 140 mg daily for duration of inhibitor use. 
  • For strong CYP3A inducers, avoid concomitant use, where possible. May co-administer with mild inducers. 
  • Avoid anticoagulants and antiplatelet medications if possible. Do not use concomitant warfarin.
  • PGP substrates (i.e. verapamil, digoxin) and BRCP substrates (i.e. methotrexate) with narrow therapeutic range must be taken ≥ 6 hours before or after the ibrutinib dose

 

 
H - Drug Administration and Special Precautions

Refer to ibrutinib drug monograph(s) for additional details


Administration:

  • Administer ibrutinib orally, with or without food, with a glass of water once daily, at approximately the same time each day. Do not open, break or chew the capsules.
  • Avoid grapefruit and Seville orange juice during treatment.
  • If a dose of ibrutinib is missed, it can be taken as soon as possible on the same day. Return to the regular dosing schedule the following day. Do not take extra capsules to make up for a missed dose.
  • Store at room temperature (15-30oC)
     

Contraindications:

  • Patients who have a hypersensitivity to this drug or to any of its components
  • Patients with moderate or severe hepatic impairment
  • Do not use concomitantly with strong CYP3A inhibitors (refer to Interactions section)
  • Do not use warfarin or other vitamin K antagonists concomitantly with ibrutinib
     

Special Precautions:

  • Should not be used in patients with moderate or severe hepatic impairment
  • Do not use concomitantly with strong CYP3A inhibitors or warfarin like anticoagulants  (refer to Interactions section)
  • Major bleeding events have been reported. Exercise caution in patients at risk of bleeding, including those receiving concomitant antiplatelet therapy or anticoagulants.
  • Exercise caution in patients with cardiac risk factors, history of atrial fibrillation or acute infection
  • Use with caution in patients with high tumour burden due to risk of TLS
  • Hold for 3 to 7 days pre and post surgery
     

Pregnancy and Lactation:

  • Ibrutinib should not be used 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 not donate sperm.
  • Breastfeeding is not recommended.
 
I - Recommended Clinical Monitoring

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

Recommended Clinical Monitoring

  • CBC; baseline and each visit
  • Liver function tests; baseline and at each visit
  • Renal function tests; baseline and at each visit
  • Blood pressure; baseline and at each visit
  • Coagulation parameters; baseline and as clinically indicated, more frequent in patients at risk of bleeding
  • Clinical toxicity assessment for infection, hepatitis B reactivation, leucostasis, TLS,  bleeding, GI, cardiac and respiratory effects; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

     

Suggested Clinical Monitoring

ECG in patients with cardiac risk factors, history of atrial fibrillation or acute infection; Baseline and as clinically indicated


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Ibrutinib drug monograph, Cancer Care Ontario.

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

June 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.