Active Ingredient: Ibrutinib
Ibrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (ibrutinib + R-CHOP) alternating with R-DHAP (or R-DHAOx) without ibrutinib, followed by ibrutinib monotherapy, is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplantation (ASCT).
Ibrutinib as a single agent is indicated for the treatment of adult patients with relapsed or refractory MCL.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 560 milligrams ibrutinib, once daily.
The recommended dose for the treatment of previously untreated MCL is ibrutinib 560 mg once daily (see table).
Ibrutinib dosing schedule for previously untreated MCL:
| Treatment | Cycle number | Treatment | Ibrutinib |
|---|---|---|---|
| Part I* | 1, 3, 5 | Ibrutinib in combination with R-CHOP§ | On days 1-19 |
| 2, 4, 6 | R-DHAP#§ | Without ibrutinib | |
| Part II± | Ibrutinib | Daily for 24 Months |
R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-DHAP = rituximab, dexamethasone, cytarabine, cisplatin
* 6 cycles; each cycle is 21 days.
§ See the Summary of Product Characteristics (SmPC) for dosing information for each medicinal product.
# Interchangeable with R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin)§.
± Treatment should start after recovery of peripheral blood counts. Rituximab may be added as per national treatment guidelines.
The recommended dose for the treatment of previously treated MCL is ibrutinib 560 mg once daily as a single agent. Treatment with ibrutinib as a single agent should continue until disease progression or no longer tolerated by the patient.
Moderate and strong CYP3A4 inhibitors increase the exposure of ibrutinib.
The dose of ibrutinib should be reduced to 280 mg once daily when used concomitantly with moderate CYP3A4 inhibitors.
The dose of ibrutinib should be reduced to 140 mg once daily or withheld for up to 7 days when it is used concomitantly with strong CYP3A4 inhibitors.
Ibrutinib therapy should be withheld for any new onset or worsening grade 2 cardiac failure, grade 3 cardiac arrhythmias, grade ≥3 non-haematological toxicity, grade 3 or greater neutropenia with infection or fever, or grade 4 haematological toxicities. Once the symptoms of the toxicity have resolved to grade 1 or baseline (recovery), resume ibrutinib therapy at the recommended dose as per the tables below.
Recommended dose modifications for non-cardiac events are described below:
| Events† | Toxicity occurrence | MCL dose modification after recovery |
|---|---|---|
| Grade 3 or 4 non-haematological toxicities Grade 3 or 4 neutropenia with infection or fever Grade 4 haematological toxicities | First* | restart at 560 mg daily |
| Second | restart at 420 mg daily | |
| Third | restart at 280 mg daily | |
| Fourth | discontinue ibrutinib |
† Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria.
* When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the toxicity reoccurs, reduce daily dose by 140 mg.
Recommended dose modifications for events of cardiac failure or cardiac arrhythmias are described below:
| Events | Toxicity occurrence | MCL dose modification after recovery |
|---|---|---|
| Grade 2 cardiac failure | First | restart at 420 mg daily |
| Second | restart at 280 mg daily | |
| Third | discontinue ibrutinib | |
| Grade 3 cardiac arrhythmias | First | restart at 420 mg daily† |
| Second | discontinue ibrutinib | |
| Grade 3 or 4 cardiac failure Grade 4 cardiac arrhythmias | First | discontinue ibrutinib |
† Evaluate the benefit-risk before resuming treatment.
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The patient should not take extra capsules to make up the missed dose.
Ibrutinib must not be taken with grapefruit juice or Seville oranges.
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