Ibrutinib, a selective irreversible inhibitor of Bruton's tyrosine kinase (BTK), is an antineoplastic agent.1
Ibrutinib is used for the treatment of certain B-cell malignancies (chronic lymphocytic leukemia [CLL]/small lymphocytic leukemia [SLL] with or without 17p deletion, Waldenstrom macroglobulinemia) and for the treatment of chronic graft-versus-host disease (GVHD).1, 3, 16, 23, 25
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Ibrutinib is used for the treatment of CLL and SLL,1, 3, 16, 23, 25, 27 including those with CLL/SLL harboring the 17p13.1 deletion (17p deletion) chromosomal abnormality.1, 16, 17, 18 Ibrutinib has been designated an orphan drug by FDA for the treatment of these conditions.9
Safety and efficacy of ibrutinib in the treatment of CLL and SLL are based principally on favorable results of an uncontrolled, open-label, multicenter study (Study 1102)1 and 5 randomized, controlled phase 3 studies (RESONATE, RESONATE-2, HELIOS, ILLUMINATE, E1912); patients in Study 1102, RESONATE, and HELIOS had received at least one prior therapy for their disease and patients in the RESONATE-2, ILLUMINATE, and E1912 studies were treatment-naïve.1, 16, 23, 25, 27 Following initiation of single-agent ibrutinib therapy, lymphocytosis (i.e., absolute lymphocyte count exceeding 5000/mm3 and an increase of at least 50% from baseline) occurred in 66% of patients, generally during the initial month of therapy; lymphocytosis resolved in a median of 14 weeks.1 However, lymphocytosis occurred in 7% of patients receiving ibrutinib in combination with bendamustine and rituximab and also in those receiving the drug in combination with obinutuzumab.1
In Study 1102, the median age of patients was 67 years; all patients in the study had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1 Patients enrolled in the study had received a median of 4 prior therapies for their disease.1 In this study, 48 patients received ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity occurred.1 The overall response rate (as assessed by an independent review committee) was 58.3%; none of the patients achieved a complete response.1 At the time of data analysis, median duration of response had not been reached.1
In the RESONATE study, 391 patients with CLL or SLL who were at risk for a poor outcome were treated with ibrutinib or the anti-CD20 antibody ofatumumab.1, 16 Ibrutinib 420 mg was given orally once daily until disease progression or unacceptable toxicity occurred; ofatumumab was given by IV infusion at an initial dose of 300 mg (dose 1), followed by 2 g weekly for 7 doses (doses 2-8), then 2 g every 4 weeks for 4 doses (doses 9-12).1, 16 The primary efficacy end point was progression-free survival as assessed by an independent review committee.16 The median age of patients in the study was 67 years (range: 30-88 years); all patients had a baseline ECOG performance status of 0 or 1 and 32% of patients harbored the 17p deletion chromosomal abnormality.1, 16 Patients enrolled in the study had received a median of 2 (range: 1-13) prior therapies for their disease.1, 16 Progression-free survival and overall survival had not been reached at the time of the initial data analysis;16 however, patients receiving ibrutinib had a median reduction of 78% (range: 68-85%) in the risk of death or disease progression and a median reduction of 57% (range: 21-76%) in the risk of death compared with those receiving ofatumumab.1, 16 The overall response rates with ibrutinib and ofatumumab were 42.6 and 4.1%, respectively; there were no complete responses in either group.1, 16 In patients with CLL harboring the 17p deletion chromosomal abnormality, a similar reduction in the risk of death or progression (75%) and a higher overall response rate compared with those receiving ofatumumab (47.6 versus 4.7%) were observed.1, 16 In an updated analysis with a follow-up of 63 months, prolonged median investigator-assessed progression-free survival (44.1 versus 8.1 months) and a higher overall response rate (87.2 versus 22.4%) were observed in patients receiving ibrutinib compared with those receiving ofatumumab; prolonged median investigator-assessed progression-free survival (40.6 versus 6.2 months) and a higher overall response rate (88.9 versus 18.8%) also were observed in patients with CLL harboring the 17p deletion chromosomal abnormality receiving ibrutinib compared with those receiving ofatumumab.1
In the HELIOS study, 578 patients with previously treated CLL or SLL received ibrutinib or placebo until disease progression or unacceptable toxicity in addition to therapy with bendamustine and rituximab (bendamustine/rituximab) for a maximum of six 28-day cycles.1, 25 Ibrutinib 420 mg was given orally once daily; bendamustine 70 mg/m2 was given IV on days 2 and 3 of cycle 1 and on days 1 and 2 of cycles 2-6; and rituximab 375 mg/m2 was given IV on day 1 of cycle 1 followed by 500 mg/m2 on day 1 of cycles 2-6.1, 25 The primary efficacy end point was progression-free survival as assessed by an independent review committee.25 The median age of patients in the study was 64 years (range: 31-86 years); all patients had a baseline ECOG performance status of 0 or 1, 56% of patients had at least one tumor 5 cm or greater in size, and 26% of patients harbored the 11q22.3 deletion chromosomal abnormality.1 In this study, patients with CLL or SLL harboring the 17p deletion chromosomal abnormality were excluded because of known poor responses of such patients to bendamustine/rituximab.25 Patients enrolled in the study had received a median of 2 (range 1-11) prior therapies for their disease.1 At a median follow-up of 17 months, progression-free survival had not been reached in patients receiving ibrutinib in combination with bendamustine/rituximab; these patients had a median reduction of 80% (range: 72-85%) in the risk of death or disease progression.1, 25 The overall response rates with ibrutinib in combination with bendamustine/rituximab or placebo in combination with bendamustine/rituximab were 82.7 or 67.8%, respectively; 8.3% of patients receiving ibrutinib in combination with bendamustine/rituximab achieved a complete response.1 At the final analysis (median follow-up of 63.7 months), median progression-free survival with ibrutinib plus bendamustine/rituximab was 65.1 months compared to 14.3 months for placebo plus bendamustine/rituximab.32 At 60 months, the progression-free survival rate was 52.7 or 8.2% for ibrutinib or placebo, respectively.32 Median overall survival at 60 months was 75.7 or 61.2% for ibrutinib or placebo, respectively.32
In the RESONATE-2 study, 269 geriatric patients with treatment-naïve CLL or SLL were treated with ibrutinib or chlorambucil.1, 23 Ibrutinib 420 mg was given orally once daily until disease progression or unacceptable toxicity occurred; chlorambucil was given orally at an initial dosage of 0.5 mg/kg (dose escalation up to 0.8 mg/kg was permitted if tolerated) on days 1 and 15 of each 28-day cycle for a maximum of 12 cycles.1, 23 The primary efficacy end point was progression-free survival as assessed by an independent review committee.23 The median age of patients in the study was 73 years (range: 65-90 years); 91% patients had a baseline ECOG performance status of 0 or 1, 45% had Rai stage III or IV disease, and 20% of patients harbored the 11q22.3 deletion chromosomal abnormality.1, 23 At a median follow-up of 28.1 months,1 progression-free survival and overall survival had not been reached;1, 23 however, patients receiving ibrutinib had a median reduction of 84% (range: 72-91%) in the composite risk of death or disease progression and a median reduction of 84% (range: 44-95%) in the risk of death compared with those receiving chlorambucil.23 The overall response rates with ibrutinib and chlorambucil were 82.4 and 35.3%, respectively; complete responses were achieved in 3.7 and 1.5% of patients receiving ibrutinib and chlorambucil, respectively.1 Approximately one-half of the patients (41%) randomized to chlorambucil had therapy switched to ibrutinib; however, based on intent-to-treat analysis, patients receiving ibrutinib had a median reduction of 56% (range: 8-79%) in the risk of death compared with those receiving chlorambucil and a higher rate of 2-year overall survival (94.7 versus 84.3%).1 At a follow-up of 55 months, median progression-free survival had not been reached in patients receiving ibrutinib.1 At up to 8 years of follow-up (median 82.7 months), treatment with ibrutinib was associated with an 85% reduction in risk of progressive disease or death compared to chlorambucil.33 Median progression-free survival was not reached for ibrutinib and was 15 months for chlorambucil.33
In the ILLUMINATE study, 229 patients with treatment-naïve CLL or SLL were treated with obinutuzumab in combination with either ibrutinib or chlorambucil.1 Patients were randomized to receive ibrutinib 420 mg once daily continuously or chlorambucil 0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles; all patients received obinutuzumab 1 g by IV infusion once weekly for 3 doses during cycle 1, followed by 1 g by IV infusion every 4 weeks for an additional 5 cycles.1, 27 Patients enrolled in the study were 65 years of age or older or less than 65 years of age with coexisting medical conditions (i.e., creatinine clearance less than 70 mL/minute).1, 27 The primary efficacy end point was progression-free survival as assessed by an independent review committee (IRC).27 The median age of patients in the study was 71 years (range: 40-87 years); all patients had a baseline ECOG performance status of 0-2, 96% were white, and 65% of patients presented with CLL/SLL with high risk factors (presence of 17p or 11q22.3 deletion chromosomal abnormality or unmutated immunoglobulin heavy chain variable region).1 At a median follow-up of 31 months, progression-free survival had not been reached; however, the risk of death or disease progression was reduced by 77% in patients receiving ibrutinib and obinutuzumab compared with those receiving chlorambucil and obinutuzumab.1, 27 Higher overall response rates were observed in patients receiving ibrutinib in combination with obinutuzumab compared with those receiving chlorambucil in combination with obinutuzumab (88.5 versus 73.3%); complete responses were achieved in 19.5 or 7.8% of patients receiving the respective treatments.1 In the cohort of patients with high risk CLL or SLL, the risk of death or disease progression was reduced by 85%.1 At the final analysis of the ILLUMINATE study (median follow-up of 45 months), progression-free survival was longer with ibrutinib plus obinutuzumab compared to chlorambucil plus obinutuzumab (median not reached versus 22 months, respectively) for a 75% reduction in risk of disease progression or death.34
In the E1912 study, 529 adults with previously untreated CLL or SLL (without 17p deletion) were treated with ibrutinib in combination with rituximab, and compared with patients who received standard combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR).1, 30 Ibrutinib was administered at a dosage of 420 mg daily until disease progression or unacceptable toxicity occurred.1, 30 Fludarabine was administered at a dose of 25 mg/m2 and cyclophosphamide was administered at a dose of 250 mg/m2 on days 1, 2, and 3 of cycles 1-6.1, 30 When given with ibrutinib, rituximab was administered at 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and 500 mg/m2 on day 1 of cycles 3-7 for a total of six 28-day cycles.1, 30 When given with fludarabine and cyclophosphamide, rituximab was administered at 50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6 for a total of six 28-day cycles.1, 30 Patients enrolled in the study were 70 years of age or older and had a creatinine clearance less than 40 mL/minute at baseline.1, 30 The primary efficacy end point was progression-free survival.30 The median age of patients in the study was 58 years (range: 28-70 years); 98% had a baseline ECOG performance status of 0-1, 90% were white, and 59% presented with high risk factors (presence of TP53 mutation, 11q chromosome deletion [del11q], or unmutated immunoglobulin heavy change variable region).1 At a median follow-up of 37 months, progression-free survival had not been reached, but ibrutinib reduced the risk of disease progression or death by 66% compared to FCR.1 At a median follow-up of 49 months, median overall survival was not reached; 11 deaths (3%) occurred with ibrutinib plus rituximab and 12 deaths (7%) occurred with FCR.1 Long term outcomes for study E1912 have also been reported; at a median follow-up of 5.8 years, progression-free survival was greater with ibrutinib plus rituximab compared to FCR, with 5-year progression-free survival rates of 78 or 51%, respectively.35
Guidelines for CLL are available from the National Cancer Institute, with treatment individualized based on disease stage and behavior36 Observation may be an option for asymptomatic or minimally symptomatic patients.36 For symptomatic patients or patients with progressive CLL, first line agents include the BTK inhibitors acalabrutinib, ibrutinib, and zanubrutinib; venetoclax with initial use of obinutuzumab or rituximab; bendamustine and rituximab; fludarabine, cyclophosphamide, and rituximab; a BTK inhibitor (acalabruntinib or ibrutinib) plus venetoclax; or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).36
Waldenstrom's Macroglobulinemia (WM)
Ibrutinib is used for the treatment of Waldenstrom's macroglobulinemia (WM);1, 19, 28 the drug has been designated an orphan drug by FDA for the treatment of this condition.9
Evidence of safety and efficacy of ibrutinib in the treatment of WM is based principally on the results of an open-label, multicenter study (Study 1118) in patients who had received prior therapy for this disease and a randomized, double-blind, placebo-controlled study (INNOVATE) in patients with treatment-naïve or previously treated WM.1, 19
In Study 1118, 63 patients received single-agent ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity occurred.1 The median age of patients enrolled in the study was 63 years (range: 44-86 years);1, 19 all patients had a baseline ECOG performance status of 0 or 1.1 Patients in the study received a median of 2 (range: 1-11) prior therapies for their disease.1 Response to ibrutinib treatment was assessed by investigators and an independent review committee (IRC) based on criteria from the International Workshop on WM.1 The IRC-assessed response rate, consisting of complete plus very good partial plus partial responses, was 61.9%; there were no complete responses.1 At the time of data analysis, responses were ongoing.1, 19 The median time to response was 1.2 (range: 0.7-13.4) months.1 Substantial reductions from baseline in serum IgM concentration and bone marrow involvement and increases in hemoglobin concentration occurred with ibrutinib treatment, and overall toxicity (e.g., neutropenia, thrombocytopenia, bleeding, infection) was reported to be moderate.19 In addition, 31 patients with previously treated WM who failed prior rituximab-containing therapy in the INNOVATE study received single-agent ibrutinib (420 mg once daily).1, 29 At a median follow-up of 34 months, the response rate was 71% in patients receiving single-agent ibrutinib; there were no complete responses.1 At the time of analysis, the median duration of response had not been reached.1
In the INNOVATE study, 150 patients were randomized to receive ibrutinib 420 mg orally once daily or placebo in combination with rituximab; rituximab 375 mg/m2 was given IV once weekly for 4 consecutive weeks during weeks 1-4 and weeks 17-20.1, 28 The median age of patients enrolled in the study was 69 years (range: 36-89 years); 93% had a baseline ECOG performance status of 0 or 1, 79% were white, 77% of patients had disease harboring MYD88 L265P mutation, 55% of patients had previously treated disease, 45% were treatment-naïve, and median baseline serum IgM concentration was 3.2 g/dL.1 Patients who had received prior therapy for their disease received a median of 2 (range: 1-6) prior therapies.1 At a follow-up of 30 months, progression-free survival had not been reached in patients receiving ibrutinib and rituximab; however, the risk of death or disease progression was reduced by 80% in patients receiving ibrutinib and rituximab compared with those receiving placebo and rituximab.1, 28 Response to ibrutinib treatment was assessed by an IRC.1, 28 The IRC-assessed response rate, consisting of complete plus very good partial plus partial responses, was 72% in patients receiving combination therapy with ibrutinib and rituximab and 32% in those receiving placebo and rituximab; complete responses were achieved in 3 or 1% of patients receiving combination therapy with ibrutinib and rituximab or placebo and rituximab, respectively.1, 28 At the time of data analysis, responses were ongoing in patients receiving combination therapy with ibrutinib and rituximab.1 Increases in hemoglobin concentration (increase of 2 g/dL or more from baseline) for at least 8 weeks without RBC transfusions or hematopoietic growth factor support occurred in 65% of patients receiving ibrutinib in combination with rituximab and in 39% of those receiving placebo and rituximab.1 At final data analysis (median 50 months follow-up), progression-free survival was longer with ibrutinib plus rituximab compared to placebo plus rituximab, for a 75% reduction in risk of disease progression or death (median progression-free survival not reached for ibrutinib and 20.3 months for placebo).37 Overall response rate was also substantially higher with ibrutinib (92%) compared to placebo (44%).37
A recent consensus statement outlined treatment options for WM.38 For treatment-naïve patients with symptomatic WM, first-line therapy options include chemoimmunotherapy (e.g., dexamethasone, cyclophosphamide plus rituximab; bendamustine plus rituximab), ibrutinib alone or plus rituximab, or zanubrutinib, with selection based on patient factors such as comorbidities, tumor burden, and risks of toxicity.38 For patients with relapsed or refractory disease, selection of therapy depends on initial treatment used and can include chemoimmunotherapy and/or a covalent BTK inhibitor (e.g., acalabrutinib, ibrutinib, or zarubrutinib).39 Additional factors to consider when selecting treatment for relapsed or refractory disease include patient age, comorbidities, hematopoietic reserve, and type of relapse.39
Graft-versus-host Disease (GVHD)
Ibrutinib is used for the treatment of chronic GVHD following failure of at least 1 prior systemic therapy in adults and pediatric patients 1 year of age or greater;1 the drug has been designated an orphan drug by FDA for the treatment of this condition.9
The current indication for ibrutinib in the treatment of chronic GVHD in adults is based principally on the results of an open-label, multicenter study (Study 1129) in patients who required additional therapy following failure of first-line corticosteroid therapy.1, 40 The median age of patients enrolled in the study was 56 (range: 19-74) years; 88% of patients had at least 2 organs involved at baseline, and 60% of patients had a baseline Karnofsky performance status of 80 or less.1 The most common underlying malignancies resulting in stem cell transplantation were acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and CLL.1 Patients in the study received a median of 2 (range: 1-3) prior therapies for chronic GVHD.1 Approximately 50% of patients were receiving immunosuppressants and systemic corticosteroids (median daily prednisone [or equivalent] dosage was 0.3 mg/kg) at baseline.1 In this study, 42 patients received ibrutinib 420 mg orally once daily.1 Response to ibrutinib treatment was assessed by investigators based on criteria from the National Institutes of Health (NIH) Consensus Panel.1
In this study, the overall response rate was 67%; 21% of patients receiving the drug achieved a complete response.1 At the time of data analysis, 48% of patients had sustained responses of 20 weeks or more.1 Responses in all organs affected by chronic GVHD (i.e., skin, mouth, GI tract, liver) were observed.1 The median time to response was 12.3 (range: 4.1-42.1) weeks.1 Exploratory analysis of patient-reported symptoms based on the Lee Symptom Scale showed at least a 7-point decrease in overall summary score in 24% of patients on at least 2 consecutive assessments (visits).1 After a median follow-up of 26 months, the best overall response rate in patients treated with ibrutinib was 69%, with 31% of patients achieving a complete response and 38% achieving a partial response.41
Efficacy of ibrutinib in pediatric (1 year of age and greater) and young adult ( less than 22 years) patients with moderate to severe chronic GVHD was evaluated in the IMAGINE study, an open-label, phase 1/2, single arm trial.1, 42 A total of 47 patients (median 13 years of age) who failed 1 or more prior lines of therapy were treated with ibrutinib 420 mg once daily (12 years of age and greater) or 240 mg/m2 once daily (1 year of age and greater to less than 12 years of age).1 Supportive therapies for chronic GVHD were allowed.1 At week 25, the overall response rate (primary outcome) was 60%, with a complete response seen in 4% of patients and a partial response in 55% of patients.1 The median time to first response was 0.9 months, with a median duration of response of 5.3 months.1 The median time to death or new systemic therapies for chronic GVHD after first response was 14.8 months.1
Ibrutinib is available as immediate-release capsules containing 70 mg or 140 mg; immediate-release tablets containing 140 mg, 280 mg, or 420 mg; and as an immediate-release oral suspension containing 70 mg of ibrutinib per mL.1 The oral suspension bottle is provided in a carton with two 3 mL reusable oral dosing syringes.1
Administer ibrutinib orally once daily at approximately the same time each day.1 Swallow tablets or capsules whole with a glass of water; do not open, break, or chew capsules, and do not cut, crush, or chew tablets.1 For administration of ibrutinib oral suspension, refer to the full instructions for use in the prescribing information for details.1
Store ibrutinib capsules and tablets in the original packaging at 20-25°C; brief exposures to 15-30°C are permitted.1
Store ibrutinib oral suspension at 2-25°C; do not freeze.1 Dispense in original sealed container, and do not use if the carton seal is missing or broken.1 Discard any unused oral suspension remaining 60 days after first opening the bottle.1
If a dose is missed, administer the missed dose on the same day as soon as it is remembered and resume the normal schedule the following day; do not take extra doses to make up for a missed dose.1
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the recommended dosage of ibrutinib is 420 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
For CLL or SLL, ibrutinib can be administered as a single agent, in combination with bendamustine and rituximab, or in combination with obinutuzumab or rituximab.1 When ibrutinib is administered on the same day as rituximab or obinutuzumab, consider administering ibrutinib prior to rituximab or obinutuzumab.1
Waldenstrom's Macroglobulinemia (WM)
For the treatment of Waldenstrom's macroglobulinemia (WM), the recommended dosage of ibrutinib is 420 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
For WM, ibrutinib can be administered as a single agent or in combination with rituximab.1 When ibrutinib is administered on the same day as rituximab, consider administering ibrutinib prior to rituximab.1
Dosage adjustment is not necessary in patients undergoing plasmapheresis.1
Chronic Graft-versus-host Disease (GVHD)
For the treatment of chronic graft-versus-host disease (GVHD) following failure of 1 or more prior systemic therapy, the recommended dosage of ibrutinib is 420 mg once daily.1 Continue therapy until progression of chronic GVHD, recurrence of the underlying malignancy, or unacceptable toxicity occurs.1 When treatment for chronic GVHD is no longer necessary, discontinue ibrutinib considering the medical assessment of the individual patient.1
Chronic Graft-versus-host Disease (GVHD)
For the treatment of chronic GVHD following failure of 1 or more prior systemic therapy for patients 12 years of age and greater, the recommended dosage of ibrutinib is 420 mg once daily.1
For the treatment of chronic GVHD following failure of 1 or more prior systemic therapy for patients 1 to less than 12 years of age, the recommended dosage of ibrutinib is 240 mg/m2 once daily (up to a dose of 420 mg).1 Refer to Table 1 for the recommended dosage to achieve 240 mg/m2 based on body surface area (BSA) for patients 1 to less than 12 years of age.1
Continue therapy until progression of chronic GVHD, recurrence of the underlying malignancy, or unacceptable toxicity occurs.1 When treatment for chronic GVHD is no longer necessary, discontinue ibrutinib considering the medical assessment of the individual patient.1
BSA (m2) range | Dose (mg) of ibrutinib capsules or tablets to administer | Volume (mL) of ibrutinib oral suspension to administer |
|---|---|---|
>0.3-0.4 | 1.2 mL | |
>0.4-0.5 | 1.5 mL | |
>0.5-0.6 | 1.9 mL | |
>0.6-0.7 | 2.2 mL | |
>0.7-0.8 | 210 mg | 2.6 mL |
>0.8-0.9 | 210 mg | 2.9 mL |
>0.9-1 | 210 mg | 3.3 mL |
>1-1.1 | 280 mg | 3.6 mL |
>1.1-1.2 | 280 mg | 4 mL |
>1.2-1.3 | 280 mg | 4.3 mL |
>1.3-1.4 | 350 mg | 4.6 mL |
>1.4-1.5 | 350 mg | 5 mL |
>1.5-1.6 | 350 mg | 5.3 mL |
>1.6 | 420 mg | 6 mL |
Dosage Modification for Toxicity
Withhold ibrutinib therapy for adverse reactions listed in Table 2.1 Upon improvement to grade 1 or baseline (recovery), follow the recommended dosage modifications described in Table 2.1
Adverse Reaction | Occurrence | Dosage Modification for CLL/SLL, WM, and Patients 12 Years of Age and Greater with Chronic GVHD after Recovery Starting Dose = 420 mg | Dosage Modification for Patients 1 to Less than 12 Years of Age with Chronic GVHD after Recovery Starting Dose =240 mg/m2 a |
|---|---|---|---|
Grade 2 cardiac failure | First | Restart at 280 mg dailyb | Restart at 160 mg/m2 dailyb |
Grade 2 cardiac failure | Second | Restart at 140 mg dailyb | Restart at 80 mg/m2 dailyb |
Grade 2 cardiac failure | Third | Discontinue ibrutinib | Discontinue ibrutinib |
Grade 3 cardiac arrhythmias | First | Restart at 280 mg dailyb | Restart at 160 mg/m2 dailyb |
Grade 3 cardiac arrhythmias | Second | Discontinue ibrutinib | Discontinue ibrutinib |
Grade 3 or 4 cardiac failure, OR Grade 4 cardiac arrhythmias | First | Discontinue ibrutinib | Discontinue ibrutinib |
Other grade 3 or 4 nonhematological toxicitiesc, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities | First | Restart at 280 mg daily | Restart at 160 mg/m2 dailyb |
Other grade 3 or 4 nonhematological toxicitiesc, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities | Second | Restart at 140 mg daily | Restart at 80 mg/m2 dailyb |
Other grade 3 or 4 nonhematological toxicitiesc, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities | Third | Discontinue ibrutinib | Discontinue ibrutinib |
a See Table 3 for dosage modifications based on BSA.1
bAssess the benefit-risk before resuming treatment.1
cFor grade 4 non-hematologic toxicities, assess the benefit-risk before resuming treatment.1
BSA (m2) range | Dose (mg) of capsules or tablets to administer to achieve 160 mg/m2 | Volume (mL) of ibrutinib oral suspension to administer to achieve 160 mg/m2 | Dose (mg) of capsules or tablets to administer to achieve 80 mg/m2 | Volume (mL) of ibrutinib oral suspension to administer to achieve 80 mg/m2 |
|---|---|---|---|---|
>0.3-0.4 | 0.8 mL | 0.4 mL | ||
>0.4-0.5 | 1 mL | 0.5 mL | ||
>0.5-0.6 | 1.3 mL | 0.6 mL | ||
>0.6-0.7 | 1.5 mL | 0.7 mL | ||
>0.7-0.8 | 140 mg | 1.7 mL | 70 mg | 0.9 mL |
>0.8-0.9 | 140 mg | 1.9 mL | 70 mg | 1 mL |
>0.9-1 | 140 mg | 2.2 mL | 70 mg | 1.1 mL |
>1-1.1 | 140 mg | 2.4 mL | 70 mg | 1.2 mL |
>1.1-1.2 | 210 mg | 2.6 mL | 1.3 mL | |
>1.2-1.3 | 210 mg | 2.9 mL | 1.4 mL | |
>1.3-1.4 | 210 mg | 3.1 mL | 1.5 mL | |
>1.4-1.5 | 210 mg | 3.3 mL | 140 mg | 1.7 mL |
>1.5-1.6 | 280 mg | 3.5 mL | 140 mg | 1.8 mL |
>1.6 | 280 mg | 4 mL | 140 mg | 2 mL |
Dosage Modification with Concomitant Use of CYP3A Inhibitors
Refer to Table 4 for recommended dosage modifications for use of ibrutinib with cytochrome P-450 (CYP) 3A inhibitors.1 After discontinuation of a CYP3A inhibitor, resume previous dosage of ibrutinib.1
Patient Population | Coadministered Drug | Recommended Ibrutinib Dosage |
|---|---|---|
B-cell malignancies (CLL/SLL or WM) | Moderate CYP3A inhibitor | 280 mg once daily Modify dosage as recommended for adverse reactions |
B-cell malignancies (CLL/SLL or WM) | Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 140 mg once daily Modify dosage as recommended for adverse reactions |
B-cell malignancies (CLL/SLL or WM) | Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole IV 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 70 mg once daily Interrupt dosage as recommended for adverse reactions |
B-cell malignancies (CLL/SLL or WM) | Other strong CYP3A inhibitors | Avoid concomitant use If these inhibitors will be used short-term (e.g., anti-infectives for 7 days or less), interrupt ibrutinib |
Patients 12 years of age and greater with chronic GVHD | Moderate CYP3A inhibitor | 420 mg once daily Modify dosage as recommended for adverse reactions |
Patients 12 years of age and greater with chronic GVHD | Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 280 mg once daily Modify dosage as recommended for adverse reactions |
Patients 12 years of age and greater with chronic GVHD | Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole IV 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 140 mg once daily Interrupt dosage as recommended for adverse reactions |
Patients 12 years of age and greater with chronic GVHD | Other strong CYP3A inhibitors | Avoid concomitant use If these inhibitors will be used short-term (e.g., anti-infectives for 7 days or less), interrupt ibrutinib |
Patients 1 to less than 12 years of age with chronic GVHD | Moderate CYP3A inhibitor | 240 mg/m2 once daily Modify dosage as recommended for adverse reactions |
Patients 1 to less than 12 years of age with chronic GVHD | Voriconazole for suspension 9 mg/kg (maximum dose: 350 mg) twice daily | 160 mg/m2 a |
Patients 1 to less than 12 years of age with chronic GVHD | Posaconazole at any dosage | 80 mg/m2 a |
Patients 1 to less than 12 years of age with chronic GVHD | Other strong CYP3A inhibitors | Avoid concomitant use If these inhibitors will be used short-term (e.g., anti-infectives for 7 days or less), interrupt ibrutinib |
a See Table 3 for dosage modifications based on BSA.1
Adults with B-cell Malignancies (CLL/SLL or WM)
For adults with mild hepatic impairment (Child-Pugh class A), the manufacturer recommends an ibrutinib dosage of 140 mg once daily.1
For adults with moderate hepatic impairment (Child-Pugh class B), the manufacturer recommends an ibrutinib dosage of 70 mg once daily.1
Avoid use of ibrutinib in adults with severe hepatic impairment (Child-Pugh class C).1
For patients 12 years of age and greater with total bilirubin level greater than 1.5-3 times upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert's syndrome), the manufacturer recommends an ibrutinib dosage of 140 mg once daily.1
For patients 1 to less than 12 years of age with total bilirubin level greater than 1.5-3 times ULN (unless of non-hepatic origin or due to Gilbert's syndrome), the manufacturer recommends an ibrutinib dosage of 80 mg/m2 daily.1
Avoid use of ibrutinib in patients with total bilirubin level greater than 3 times ULN (unless of non-hepatic origin or due to Gilbert's syndrome).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1 Certain ibrutinib toxicities may be more frequent in geriatric patients.1
Hemorrhage, sometimes fatal, has been reported in patients receiving ibrutinib.1 Grade 3 or higher bleeding events (i.e., intracranial hemorrhage, subdural hematoma, GI bleeding, hematuria, postprocedural hemorrhage) occurred in 4.2% of patients treated with ibrutinib in clinical trials; fatal cases were reported in 0.4% of patients.1 Overall, hemorrhagic events of any grade or severity, including bruising and petechiae, occurred in 39% of patients receiving ibrutinib, and events excluding bruising and petechiae occurred in 23% of patients in clinical trials.1 The mechanism of bleeding with ibrutinib therapy is unclear.1
Concomitant use of ibrutinib with antiplatelet or anticoagulant therapies may increase the risk of hemorrhagic events.1 In clinical trials, major hemorrhagic events were reported in 3.1, 4.4, or 6.1% of patients receiving ibrutinib without antiplatelet or anticoagulant therapy, with concomitant antiplatelet therapy with or without anticoagulant therapy, or with concomitant anticoagulant therapy with or without antiplatelet therapy, respectively.1
Consider the potential benefits and risks of concomitant anticoagulant or antiplatelet therapy.1 Monitor patients for manifestations of bleeding.1
Because of the risk of bleeding, consider the potential benefits and risks of withholding ibrutinib therapy for ≥3-7 days prior to and following surgery (based on the type of surgery and bleeding risk).1
Serious infections (bacterial, viral, or fungal), sometimes fatal, have been reported in patients receiving ibrutinib.1 Grade 3 or higher infections occurred in 21% of patients with B-cell malignancies receiving ibrutinib in clinical trials.1 Progressive multifocal leukoencephalopathy and Pneumocystis jirovecii (formerly P. carinii ) pneumonia also have been reported.1
Monitor patients for signs and symptoms of infection and initiate appropriate anti-infective treatment as clinically indicated.1 Consider prophylaxis according to current standards of care in patients who are at increased risk for opportunistic infections.1
Cytopenias, including thrombocytopenia, anemia, and neutropenia, have been reported in patients receiving ibrutinib.1 Grade 3 or 4 neutropenia, thrombocytopenia, or anemia was reported in 23, 8, or 2.8%, respectively, of patients with B-cell malignancies receiving single-agent ibrutinib in clinical trials.1
Monitor CBC counts monthly.1 Temporary interruption of ibrutinib therapy or dosage reduction may be necessary if myelosuppression occurs.1
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death
Serious arrhythmias, sometimes fatal, and cardiac failure have been reported in patients receiving ibrutinib.1 Sudden deaths or deaths due to cardiac causes occurred in 1% of patients who received ibrutinib in clinical trials, including in patients who received ibrutinib in unapproved monotherapy or combination regimens.1 These events occurred in patients with and without preexisting hypertension or cardiac comorbidities; however, patients with cardiac comorbidities may be at greater risk.1
Grade 3 or higher ventricular tachyarrhythmias occurred in 0.2%, grade 3 or higher atrial fibrillation and atrial flutter occurred in 3.7%, and grade 3 or higher cardiac failure occurred in 1.3% of patients receiving ibrutinib in clinical trials, including in patients who received ibrutinib in unapproved monotherapy or combination regimens.1 These events have occurred particularly in patients with cardiac risk factors (e.g., hypertension, diabetes), acute infections, and a previous history of cardiac arrhythmias.1
Assess cardiac history and function at baseline.1 Monitor patients for cardiac arrhythmias and cardiac function.1 Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, angina), new-onset dyspnea, or other cardiovascular issues.1 Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification recommendations (refer to "Dosage Modification for Toxicity" section), and consider the risks and benefits of continued ibrutinib therapy.1
Hypertension has been reported in 19% of patients with B-cell malignancies receiving ibrutinib in clinical trials.1 Grade 3 or higher hypertension occurred in 8% of patients.1 The median time to occurrence of grade 3 or higher hypertension was 5.9 months (range: 0-24 months).1 In a long-term (5-year) safety study evaluating ibrutinib in patients with B-cell malignancies, the incidence of hypertension increased over time with prolonged ibrutinib therapy; the overall incidence for the 5-year period was 11%.1
Monitor blood pressure in patients treated with ibrutinib, and initiate or adjust anti-hypertensive therapy throughout treatment with ibrutinib as appropriate.1 Follow dosage modification recommendations for grade 3 or higher hypertension (refer to "Dosage Modification for Toxicity" section).1
Other malignancies (10%), including non-skin carcinomas (3.9%), have been reported in ibrutinib-treated patients with B-cell malignancies in clinical trials.1 Non-melanoma skin cancer was the most frequent second primary malignancy, occurring in 6% of ibrutinib-treated patients.1
Hepatotoxicity, Including Drug-induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including ibrutinib.1
Evaluate bilirubin and transaminases at baseline and throughout treatment.1 For patients who develop abnormal liver tests after ibrutinib therapy, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.1 If DILI is suspected, withhold ibrutinib.1 Upon confirmation of DILI, discontinue therapy.1
Tumor lysis syndrome has been reported infrequently in patients receiving ibrutinib.1
Assess the potential for developing tumor lysis syndrome (e.g., large tumor burden) at baseline and take appropriate precautions.1 Monitor patients closely and treat as clinically indicated.1
Fetal/Neonatal Morbidity and Mortality
Based on findings in animals, ibrutinib may cause fetal harm if administered to pregnant females.1 There are no available data in pregnant females to inform a drug-associated risk.1 Embryofetal toxicity (i.e., increased fetal resorption, postimplantation loss) and teratogenicity (i.e., visceral and skeletal anomalies) have been demonstrated in animals receiving ibrutinib at exposure levels 3-20 times the human exposure at the maximum recommended dosage (i.e., 420 mg daily).1
Avoid pregnancy during ibrutinib therapy.1 Verify pregnancy status in in females of reproductive potential prior to initiating ibrutinib therapy .1 If ibrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential fetal hazard.1 Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with ibrutinib and for 1 month after the last dose.1
Although there are no available data in pregnant females, ibrutinib may cause fetal harm based on animal findings.1 Verify pregnancy status prior to initiating ibrutinib therapy in females of reproductive potential.1 If ibrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential fetal hazard.1
It is not known whether ibrutinib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Advise females not to breast-feed during treatment with ibrutinib and for 1 week after discontinuing the drug due to the potential for serious adverse reactions in the breast-fed child.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ibrutinib therapy.1 Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraceptive methods during and for 1 month after discontinuance of ibrutinib.1
Safety and efficacy of ibrutinib have been established for treatment of chronic graft-versus-host-disease (GVHD) after failure of ≥1 lines of systemic therapy in pediatric patients ≥1 year of age.1 For this indication, the recommended dosage of ibrutinib in children ≥12 years of age is the same as that in adults, and the recommended dosage in children 1 to <12 years of age is based on body surface area.1 Safety and efficacy of ibrutinib have not been established for treatment of chronic GVHD in pediatric patients <1 year of age.1
Safety and efficacy of ibrutinib have not been established in pediatric patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), CLL/SLL with 17p deletion, or Waldenstrom's macroglobulinemia.1
In clinical trials of ibrutinib for B-cell malignancies or chronic GVHD, 62% of patients were ≥65 years of age and 22% were ≥75 years of age.1 No overall differences in efficacy were observed between geriatric and younger patients, but some adverse effects (e.g., anemia, grade 3 or higher pneumonia, thrombocytopenia, hypertension, atrial fibrillation) occurred more frequently in geriatric patients.1
Adults with B-cell malignancies: Avoid use of ibrutinib in patients with severe hepatic impairment (Child-Pugh class C).1 The safety of ibrutinib has not been evaluated in mild to severe hepatic impairment by Child-Pugh criteria.1 Reduce the recommended dosage of ibrutinib in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), and monitor patients more frequently for adverse reactions of ibrutinib.1
Patients with chronic GVHD: Avoid use of ibrutinib in patients with total bilirubin level >3 times upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert's syndrome).1 Reduce the recommended dosage of ibrutinib in patients with total bilirubin level >1.5-3 times ULN (unless of non-hepatic origin or due to Gilbert's syndrome).1
In a single-dose study, systemic exposure of ibrutinib was increased 2.7-, 8.2-, or 9.8-fold in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, respectively, compared with that in individuals with normal hepatic function.1 In addition, peak plasma concentration of ibrutinib was increased 5.2-, 8.8-, or 7-fold in patients with mild, moderate, or severe hepatic impairment, respectively, compared with that in individuals with normal hepatic function.1
Systemic exposure of ibrutinib does not appear to be altered in patients with mild or moderate renal impairment (creatinine clearance >25 mL/minute).1 The manufacturer states that there is no experience with ibrutinib in patients with severe renal impairment (creatinine clearance <25 mL/minute) or in patients undergoing dialysis.1
Adverse effects reported in ≥30% of patients with B-cell malignancies include thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.1
Adverse effects reported in ≥20% of adult or pediatric patients with chronic graft versus host disease include fatigue, anemia, bruising, diarrhea, thrombocytopenia, musculoskeletal pain, pyrexia, muscle spasms, stomatitis, nausea, hemorrhage, abdominal pain, headache, and pneumonia.1
Metabolism of ibrutinib to several metabolites is mediated principally by cytochrome P-450 (CYP) isoenzyme 3A and, to a lesser extent, by CYP2D6.1
In vitro studies indicate that ibrutinib and PCI-45227 (active metabolite) are not expected to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP isoenzymes 1A2, 2B6, or 3A at clinically relevant concentrations.1
In vitro studies indicate that ibrutinib may inhibit P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transport at clinically relevant concentrations.1 In vitro studies suggest that ibrutinib is not a substrate of P-gp or BCRP.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of ibrutinib with strong or moderate inhibitors of CYP3A may result in increased plasma concentrations of ibrutinib and an increased risk of drug-related toxicity.1
When the strong CYP3A inhibitor ketoconazole was administered concomitantly with ibrutinib, the peak plasma concentration and AUC of ibrutinib were increased by 29- and 24-fold, respectively.1
With multiple dosing of the strong CYP3A inhibitor voriconazole concomitantly with ibrutinib, the peak plasma concentration and AUC of ibrutinib were increased by 6.7- and 5.7-fold, respectively.1
Simulations suggest that the strong CYP3A inhibitor posaconazole may increase the AUC of ibrutinib by threefold to tenfold under fed conditions.1
With repeated dosing of the moderate CYP3A inhibitor erythromycin concomitantly with ibrutinib, the peak plasma concentration and AUC of ibrutinib were increased by 3.4- and 3-fold, respectively.1
If concomitant use of the strong CYP3A inhibitor posaconazole or voriconazole or a moderate CYP3A inhibitor is required, reduce the daily dosage of ibrutinib as recommended in Table 4 in the "Dosage" section.1 Avoid concomitant use of other strong CYP3A inhibitors; interrupt ibrutinib therapy if these inhibitors will be used short-term (e.g., anti-infectives for ≤7 days).1
Avoid grapefruit products and Seville oranges during ibrutinib therapy since they are known to contain strong or moderate inhibitors of CYP3A.1
Concomitant use of ibrutinib with strong inducers of CYP3A may result in decreased plasma concentrations of ibrutinib.1
Administration of the strong CYP3A inducer rifampin concomitantly with ibrutinib reduced the peak plasma concentration and AUC of ibrutinib by more than 13- and 10-fold, respectively.1 Other simulations suggest that the moderate CYP3A inducer efavirenz may decrease the AUC of ibrutinib by threefold.1
Avoid concomitant use of ibrutinib with strong CYP3A inducers.1
Substrates of Efflux Transport Systems
Concomitant use of ibrutinib with oral drugs that are substrates of P-gp or BCRP (e.g., digoxin, methotrexate) may result in increased concentrations of the substrate drug.1
Anticoagulants and Antiplatelet Agents
Use of anticoagulant or antiplatelet agents concomitantly with ibrutinib increases risk of hemorrhagic events.1 Monitor patients for bleeding manifestations.1
Ibrutinib is a selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK); the drug is an antineoplastic agent.1, 4, 5, 6, 7 BTK, a member of the tyrosine protein kinase (Tec) family of kinases, is positioned early within the B-cell antigen receptor (BCR) signaling pathway.4, 5, 10 BCR is involved in the initiation of various cascades of intracellular signaling events, including activation of BTK, which leads to cell proliferation, differentiation, apoptosis, and cell migration essential for the development and survival of normal and malignant B-cells.1, 4, 5, 6, 7 Ibrutinib binds covalently to the active site of the tyrosine kinase BTK and irreversibly inhibits phosphorylation of tyrosine kinase, resulting in inhibition of downstream effector activity within the BCR signaling pathway.1, 4, 5, 6, 7
In vitro kinase assays also have shown that ibrutinib inhibits (with up to tenfold less activity) the activity of several other receptor tyrosine kinases, including Bmx/Etk, epidermal growth factor receptor (EGFR), and members of the Src family of tyrosine kinases (e.g., Hck, Yes).8 In vivo, ibrutinib inhibits the proliferation and survival of malignant B-cells.1 The drug also has demonstrated cell migration and substrate adhesion in vitro;1 the mobilization of cells from tissues to peripheral blood results in a transient increase in absolute lymphocyte count (lymphocytosis) in the peripheral blood.12, 13
When given in a single dose of 1680 mg (3 times the maximum recommended daily dosage), ibrutinib did not prolong the QT interval to any clinically relevant extent.1 In vitro, the 50% inhibitory concentration of ibrutinib for collagen-induced platelet aggregation is 2026 ng/mL in blood samples from healthy donors, 1321 ng/mL in those with severe renal dysfunction, and 352 ng/mL in those taking warfarin.1 Clinically meaningful inhibition of adenosine diphosphate (ADP), arachidonic acid, ristocetin, and thrombin receptor agonist peptide-6 (TRAP-6) by ibrutinib have not been demonstrated.1
Following oral administration of ibrutinib in healthy, fasting individuals, the absolute bioavailability of the drug was 2.9%.1 Ibrutinib is absorbed after oral administration with a median time to peak plasma concentration of 1-2 hours.1 Systemic exposure of ibrutinib increases with doses up to 840 mg in patients with B-cell malignancies.1 Following repeated doses of ibrutinib 420 mg daily, steady-state concentrations of the drug were achieved in 1 week and the accumulation ratio for the drug was 1-1.6.1 Administration of ibrutinib with a high-fat, high-calorie meal (800-1000 calories with fat accounting for approximately 50% of caloric content) resulted in an approximately twofold to fourfold increase in peak plasma concentrations and an approximately twofold increase in systemic exposure, compared with administration following overnight fasting.1
Ibrutinib is metabolized to several metabolites by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A and to a minor extent by isoenzyme 2D6.1 The active metabolite, PCI-45227 (a dihydrodiol metabolite), has demonstrated BTK inhibition approximately 15 times less than that of ibrutinib.1 In vitro, ibrutinib is 97.3% bound to plasma proteins.1 Following administration of a single radiolabeled dose of ibrutinib, 80% of the dose was recovered in feces and <10% was recovered in urine; unchanged drug accounted for 1% of the dose recovered in feces.1 The elimination half-life of ibrutinib is 4-6 hours.1 The pharmacokinetics of ibrutinib do not appear to be affected by age or sex.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Ibrutinib can only be obtained through designated specialty pharmacies.31 Contact the manufacturer or consult the Imbruvica website ([Web]) for specific availability information.31
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 70 mg | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) |
140 mg | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) | ||
Tablets | 140 mg | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) | |
280 mg | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) | ||
420 mg | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) | ||
Oral Suspension | 70 mg/mL | Imbruvica® | Pharmacyclics (comarketed by Janssen Biotech) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pharmacyclics, Inc. and Janssen Biotech, Inc. Imbruvica® (ibrutinib) capsules, tablets, and oral suspension, for oral use prescribing information. South San Francisco, CA; 2024 May. [Web]
3. Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med . 2013; 369:32-42. [PubMed 23782158]
4. Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol . 2013; 31:88-94. [PubMed 23045577]
5. Dasmahapatra G, Patel H, Dent P et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol . 2013; 161:43-56. [PubMed 23360303]
6. Chavez JC, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid . 2013; 8:37-45. [PubMed 23717217]
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13. Herman SE, Niemann CU, Farooqui M et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia . 2014; :. [PubMed 24699307]
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17. Farooqui MZ, Valdez J, Martyr S et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol . 2015 Feb; 16:169-76.
18. Byrd JC, Furman RR, Coutre S et al. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naive (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: New and updated results of 116 patients in a phase Ib/II study. Blood . 2012; 120:189. Abstract.
19. Treon SP, Tripsas CK, Meid K et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med . 2015; 372:1430-40. [PubMed 25853747]
23. Burger JA, Tedeschi A, Barr PM et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med . 2015; 373:2425-37. [PubMed 26639149]
25. 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; 17:200-211. [PubMed 26655421]
26. de Zwart L, Snoeys J, De Jong J et al. Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling. Clin Pharmacol Ther . 2016; 100:548-557. [PubMed 27367453]
27. Moreno C, Greil R, Demirkan F et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol . 2019; 20:43-56. [PubMed 30522969]
28. Dimopoulos MA, Tedeschi A, Trotman J et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. N Engl J Med . 2018; 378:2399-2410. [PubMed 29856685]
29. US National Library of Medicine. Clinicaltrials.gov. Ibrutinib with rituximab in adults with Waldenström's macroglobulinemia. NCT02165397.
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32. Fraser G, Chanan-Khan A, Demirkan F, et al. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma . 2020;61(13):3188-3197.
33. Barr P, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv . 2022;6(11):3440-3450.
34. Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica . 2022;107: 2108-2120.
35. Shanafelt T, Wang X, Hanson C, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood . 2022;140(2):112-120.
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37. Buske C, Tedeschi A, Trotman J, et al.Ibrutinib plus rituximab versus placebo plus rituximab for Waldenstrom's macroglobulinemia: final analysis from the randomized phase III iNNOVATE study. J Clin Oncol . 2021;40:52-62.
38. Buske C, Castillo J, Abeykoon J, et al. Report of consensus panel 1 from the 11th workshop on Waldenstrom's macroglobulinema on management of symptomatic, treatment-naïve patients. Semin Hematol . 2023;60:73-79.
39. D'Sa S, Matous J, Advani R, et al. Report of consensus panel 2 from the 11th international workshop on Waldenstrom's macroglobulinemia on the management of relapsed or refractory WM patients. Semin Hematol . 2023;60:80-89.
40. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood . 2017;130(21):2243-2250.
41. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant . 2019;25(10):2002-2007.
42. Carpenter P, Kang H, Yoo K,, et al. Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from the phase 1/2 iMAGINE study. Transplant Cell Ther . 2022;28(11):771.e1-771.e10.