Janssen Inc, in collaboration with Health Canada, has updated the Canadian Product Monograph for Imbruvica (ibrutinib) to include new warnings regarding serious and fatal cardiac arrhythmias (eg, atrial fibrillation, ventricular tachyarrhythmias) or cardiac failure, and the addition of new guidelines for dose modification or treatment discontinuation for patients with new onset or worsening cardiac arrhythmia or cardiac failure. Patients with significant cardiac comorbidities (eg, hypertension, history of arrhythmia) may be at greater risk for developing these events, including sudden fatal cardiac events.
Further information may be found at https://recalls-rappels.canada.ca/en/alert-recall/imbruvica-ibrutinib-risk-serious-and-fatal-cardiac-arrhythmias-or-cardiac-failure.
Note: Consider antimicrobial prophylaxis (according to standard of care) in patients at risk for opportunistic infection. Evaluate the risks and benefits of withholding ibrutinib for 3 to 7 days prior to and after surgery, depending on the procedure type and risk of bleeding.
Chronic graft-versus-host disease, refractory: Oral: 420 mg once daily; continue until chronic graft-versus-host disease (cGVHD) disease progression, recurrence of underlying malignancy, or unacceptable toxicity (Miklos 2017). When cGVHD treatment is no longer required, discontinue ibrutinib based on medical assessment of patient.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (including chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion): Oral: 420 mg once daily (either as monotherapy, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab); continue until disease progression or unacceptable toxicity (Byrd 2014; Chanan-Khan 2016; Moreno 2019; Shanafelt 2019).
Mantle cell lymphoma, previously treated: Oral: 560 mg once daily; continue until disease progression or unacceptable toxicity (Wang 2013; Wang 2015).
Ibrutinib in combination with venetoclax (off-label combination): Oral: 560 mg once daily (in combination with venetoclax) until disease progression or unacceptable toxicity; begin venetoclax (with ramp-up dosing) 4 weeks after ibrutinib initiation (Tam 2018).
Marginal zone lymphoma, relapsed/refractory: Oral: 560 mg once daily; continue until disease progression or unacceptable toxicity (Noy 2017).
Waldenström macroglobulinemia: Oral: 420 mg once daily (either as monotherapy or in combination with rituximab); continue until disease progression or unacceptable toxicity (Dimopoulos 2018; Treon 2015).
Missed doses: If a dose is not administered at the scheduled time, it may be administered as soon as possible on the same day; return to normal schedule the following day. Do not administer extra doses to make up for the missed dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥25 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, renal excretion is minimal and drug exposure is not altered in patients with mild to moderate impairment.
CrCl <25 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
End-stage renal disease requiring dialysis: There are no dosage adjustments provided in the manufacturer's labeling (no data available).
B-cell malignancies:
Mild impairment (Child-Pugh class A): Reduce dose to 140 mg once daily. Monitor closely for toxicities; may require treatment interruption.
Moderate impairment (Child-Pugh class B): Reduce dose to 70 mg once daily. Monitor closely for toxicities; may require treatment interruption.
Severe impairment (Child-Pugh class C): Avoid ibrutinib use.
Chronic graft-versus-host disease:
Total bilirubin >1.5 to 3 times ULN (unless of nonhepatic origin or due to Gilbert syndrome): Reduce dose to 140 mg once daily.
Total bilirubin >3 times ULN (unless of nonhepatic origin or due to Gilbert syndrome): Avoid ibrutinib use.
(For additional information see "Ibrutinib: Pediatric drug information")
Note: Pediatric dosing in both mg/m2 and mg (fixed dose); use caution during dose calculations. Consider antimicrobial prophylaxis (according to standard of care) in patients at risk for opportunistic infection. Evaluate the risks and benefits of withholding ibrutinib for 3 to 7 days prior to and after surgery, depending on the procedure type and risk of bleeding.
Chronic graft-versus-host disease (cGVHD), refractory: Note: Continue ibrutinib therapy until cGVHD disease progression, recurrence of underlying malignancy, or unacceptable toxicity. When cGVHD treatment is no longer required, discontinue ibrutinib based on medical assessment of patient.
Children <12 years:
BSA-directed dosing: Oral: 240 mg/m2 once daily; maximum dose: 420 mg/dose.
Weight-banded dosing: Oral:
|
BSA (m2 ) |
Oral Suspension (70 mg/mL) Daily Dose (mg) |
Capsule/Tablet Daily Dose (mg) |
|---|---|---|
|
>0.3 to 0.4 m2 |
84 mg |
|
|
>0.4 to 0.5 m2 |
105 mg |
|
|
>0.5 to 0.6 m2 |
133 mg |
|
|
>0.6 to 0.7 m2 |
154 mg |
|
|
>0.7 to 0.8 m2 |
182 mg |
210 mg |
|
>0.8 to 0.9 m2 |
203 mg |
210 mg |
|
>0.9 to 1 m2 |
231 mg |
210 mg |
|
>1 to 1.1 m2 |
252 mg |
280 mg |
|
>1.1 to 1.2 m2 |
280 mg |
280 mg |
|
>1.2 to 1.3 m2 |
301 mg |
280 mg |
|
>1.3 to 1.4 m2 |
322 mg |
350 mg |
|
>1.4 to 1.5 m2 |
350 mg |
350 mg |
|
>1.5 to 1.6 m2 |
371 mg |
350 mg |
|
>1.6 m2 |
420 mg |
420 mg |
Children ≥12 years and Adolescents: Oral: 420 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Note: Pediatric dosing is in both mg/m2and mg; please review dosing units closely in table.
Children and Adolescents: Oral:
|
Adverse Reaction |
Occurrence |
Ages 1 to <12 Years (Based on Starting Dose ~240 mg/m2) |
Age ≥12 Years (Starting Dose: 420 mg) |
|---|---|---|---|
|
a For other grade 4 nonhematologic toxicities, evaluate risks versus benefits prior to resuming ibrutinib. | |||
|
Cardiac arrhythmias: Grade 3 |
First |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 160 mg/m2 once daily (after assessment of risks vs benefits). |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 280 mg once daily (after assessment of risks vs benefits). |
|
Second |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
|
Cardiac arrhythmias: Grade 4 |
First |
Discontinue ibrutinib. |
Discontinue ibrutinib. |
|
Heart failure: Grade 2 |
First |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 160 mg/m2 once daily (after assessment of risks vs benefits). |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 280 mg once daily (after assessment of risks vs benefits). |
|
Second |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 80 mg/m2 once daily (after assessment of risks vs benefits). |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 140 mg once daily (after assessment of risks vs benefits). | |
|
Third |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
|
Heart failure: Grade 3 or 4 |
First |
Discontinue ibrutinib. |
Discontinue ibrutinib. |
|
Hypertension |
Any |
Initiate or adjust antihypertensive therapy as appropriate. If ≥ grade 3 hypertension occurs, follow dosage modifications below for other grade 3 or 4 nonhematologic toxicities. | |
|
Other toxicities: • Other grade 3 or 4 nonhematological toxicitiesa • Grade 3 or 4 neutropenia with infection or fever • Grade 4 hematological toxicities |
First |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 160 mg/m2 once daily (after assessment of risks vs benefits). |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 280 mg once daily. |
|
Second |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 80 mg/m2 once daily (after assessment of risks vs benefits). |
Hold dose until improved to Grade 1 or baseline (recovery). Restart at 140 mg once daily. | |
|
Third |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
Children and Adolescents: Oral:
CrCl ≥25 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, renal excretion is minimal and drug exposure is not altered in patients with mild to moderate impairment.
CrCl <25 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
End-stage renal disease requiring dialysis: There are no dosage adjustments provided in the manufacturer's labeling (no data available).
Total bilirubin >1.5 to 3 times ULN (unless nonhepatic origin or Gilbert syndrome):
Children <12 years: Oral: 80 mg/m2once daily.
Children ≥12 years and Adolescents: Oral: 140 mg once daily.
Total bilirubin >3 times ULN (unless nonhepatic origin or Gilbert syndrome): Children and Adolescents: Avoid use.
Refer to adult dosing.
Recommended ibrutinib dosage modifications for adverse reactions following improvement to grade 1 or baseline (recovery):
|
Adverse reaction |
Occurrence |
Mantle cell lymphoma and marginal zone lymphoma (Initial dose: 560 mg once daily) |
Chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic graft-versus-host disease, and Waldenström macroglobulinemia (Initial dose: 420 mg once daily) |
|---|---|---|---|
|
a For other grade 4 nonhematologic toxicities, evaluate risks versus benefits prior to resuming ibrutinib. | |||
|
Cardiac arrhythmias: Grade 3 |
First occurrence |
Restart at 420 mg once daily (after assessment of risks vs benefits). |
Restart at 280 mg once daily (after assessment of risks vs benefits). |
|
Second occurrence |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
|
Cardiac arrhythmias: Grade 4 |
First occurrence |
Discontinue ibrutinib. |
Discontinue ibrutinib. |
|
Heart failure: Grade 2 |
First occurrence |
Restart at 420 mg once daily (after assessment of risks vs benefits). |
Restart at 280 mg once daily (after assessment of risks vs benefits). |
|
Second occurrence |
Restart at 280 mg once daily (after assessment of risks vs benefits). |
Restart at 140 mg once daily (after assessment of risks vs benefits). | |
|
Third occurrence |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
|
Heart failure: Grade 3 or 4 |
First occurrence |
Discontinue ibrutinib. |
Discontinue ibrutinib. |
|
Hypertension |
Any |
Initiate or adjust antihypertensive therapy as appropriate. If ≥ grade 3 hypertension occurs, follow dosage modifications below for other grade 3 or 4 nonhematologic toxicities. | |
|
Other toxicities:
|
First occurrence |
Restart at 420 mg once daily. |
Restart at 280 mg once daily. |
|
Second occurrence |
Restart at 280 mg once daily. |
Restart at 140 mg once daily. | |
|
Third occurrence |
Discontinue ibrutinib. |
Discontinue ibrutinib. | |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Imbruvica: 70 mg, 140 mg
Suspension, Oral:
Imbruvica: 70 mg/mL (108 mL)
Tablet, Oral:
Imbruvica: 140 mg, 280 mg, 420 mg, 560 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Imbruvica: 140 mg
Oral:
Capsules and tablets: Administer with a glass of water at approximately the same time each day. Swallow capsules or tablets whole. Do not open, break, or chew capsules; do not cut, crush, or chew tablets. Maintain adequate hydration during treatment.
Based on an analysis of 3 pharmacokinetic studies, it is suggested that ibrutinib may be administered without regard to food (de Jong 2015).
Ibrutinib was administered via NG and percutaneous endoscopic gastrostomy tube (single case report) by opening the capsule contents and flushing the contents down the tube(s) with water (Maddox 2016).
When administering ibrutinib in combination with rituximab or obinutuzumab, consider administering ibrutinib prior to rituximab or obinutuzumab when given on the same day.
Suspension: Bottle is supplied with 2 reusable oral dosing syringes. Use only the oral dosing syringes that are supplied with ibrutinib suspension, do not use syringes for other patients or from other medications; do not use a household teaspoon (overdosage may occur). Shake well before use. Do not remove the bottle adapter. When measuring dose, remove air bubbles to ensure correct dose. Administer as soon as possible after withdrawing dose from bottle. Administer water after the ibrutinib suspension dose. Following administration, rinse oral syringe with water and let air-dry (do not use soap to clean; do not put in dishwasher). Refer to manufacturer’s instructions for more details.
Oral:Administer with a glass of water at approximately the same time each day. Maintain adequate hydration during treatment.
Capsules/tablets: Swallow capsules or tablets whole. Do not open, break, or chew capsules; do not cut, crush, or chew tablets.
Oral suspension: With first use, document 60 days from opening as the discard date on the container. Shake well before use; attached bottle adapter should not be removed and may be wiped with a disposable tissue; use provided oral syringes to measure dose (if air bubble[s], pull plunger back a bit and tap side of syringe to remove air bubbles); squirt dose along inside of mouth along cheek; follow dose with a glass of water. After use, rinse oral syringe with water only and let air dry; do not clean with soap or in the dishwasher.
Missed dose: Administer as soon as the missed dose is remembered on the same day; return to normal scheduling the following day. Do not take extra doses to make up for the missed dose.
Chronic graft-versus-host disease, refractory: Treatment of chronic graft-versus-host disease in adults and pediatric patients ≥1 year of age after failure of ≥1 lines of systemic therapy.
Chronic lymphocytic leukemia/small lymphocytic lymphoma:
Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in adults.
Treatment of CLL/SLL in adults with 17p deletion.
Mantle cell lymphoma, previously treated: Treatment of mantle cell lymphoma in adults who have received at least 1 prior therapy.
Marginal zone lymphoma, relapsed/refractory: Treatment of marginal zone lymphoma in adults who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.
Waldenström macroglobulinemia: Treatment of Waldenström macroglobulinemia in adults.
Ibrutinib may be confused with acalabrutinib, avapritinib, Ibrance, ibritumomab, idelalisib, imatinib, ivosidenib, zanubrutinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) included among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
Serious (and some fatal) cardiac arrhythmias and heart failure have occurred with ibrutinib, including ≥ grade 3 atrial fibrillation, atrial flutter, heart failure, and ventricular tachyarrhythmias. In an analysis utilizing the international pharmacovigilance database, ibrutinib was associated with higher reporting of cardiovascular adverse events, including heart failure, supraventricular cardiac arrhythmia, ventricular arrhythmia, cardiac conduction disorder, hypertension, and CNS hemorrhagic or ischemic events (Ref). Events have occurred in patients with and without preexisting cardiac risk factors.
Mechanism: Heart failure: May be caused by off-target blockade of HER2 and/or phosphoinositide 3-kinase-protein kinase B (PI3K–AKT) pathways. Supraventricular arrhythmias: May occur due to blockade of PI3K-AKT pathway, leading to activation of the late sodium current (INa-L) in atrial cells. Ventricular arrhythmias: Not clearly established; does not appear to be caused by QTc prolongation (Ref).
Onset: Varied; Heart failure: Median ~2 months (interquartile range: ~3 weeks to 5 months). Supraventricular arrhythmias: Median ~2.5 months (interquartile range: ~1 to 6.5 months). Ventricular arrhythmias: Median ~2 months (interquartile range: ~1 to 5 months) (Ref).
Risk factors:
• Older age (>70 years) (Ref)
• Males (Ref)
• History of cardiac arrhythmia (Ref)
• Hypertension (Ref)
• Preexisting cardiac disease (Ref)
• Diabetes mellitus
• Acute infections
• Concurrent cardiotoxic agents
Grade 3 and 4 neutropenia, thrombocytopenia, and anemia occurred during clinical studies in patients who received single-agent ibrutinib for B-cell malignancies. An increased risk of opportunistic infection, including pneumonia due to Pneumocystis jirovecii (PJP), have occurred in patients treated with ibrutinib. Lymphocytosis (≥50% increase from baseline) and leukostasis may occur upon therapy initiation. Some patients who developed lymphocytosis (lymphocytes >400,000/mcL) developed intracranial hemorrhage, lethargy, headache, and abnormal gait; however, some cases may have been associated with disease progression. Lymphocytosis resolves within 8 weeks (mantle cell lymphoma) or 14 weeks (chronic lymphocytic leukemia) (Ref).
Mechanism: Related to mechanism of action; inhibits B-cell function, increasing the risk for opportunistic infections, such as PJP (Ref). Lymphocytosis is caused by disruption of integrin-mediated adhesion and homing of malignant B-cells, leading to release from the lymphoid microenvironment into systemic circulation (Ref).
Onset: Pancytopenia: Varied; within the initial months after initiation. Lymphocytosis: Intermediate; within the first few weeks/first month of therapy (Ref).
Major hemorrhage (and some fatal) has occurred with therapy, including ≥ grade 3, serious, or any CNS events (eg, intracranial hemorrhage [including subdural hematoma]), gastrointestinal hemorrhage, hematuria, and postprocedural hemorrhage (Ref). Bleeding events of any grade, including mucocutaneous bleeding (eg, bruise, petechia), have also occurred (Ref).
Mechanism: Related to mechanism of action; ibrutinib has anti-platelet effects, likely mediated by targeting von Willebrand factor (vWF)-glycoprotein Ib and collagen-glycoprotein VI signal transduction (Ref).
Onset: Varied; often corresponding to thrombocytopenia. Median onset of CNS hemorrhagic events ~2 months (interquartile range: ~3 weeks to 6 months) (Ref).
Risk factors:
• Concurrent anticoagulant and/or antiplatelet therapy
• Lower baseline Factor VIII & vWF activity levels (Ref)
Hypertension has commonly been reported in patients treated with ibrutinib. Hypertension may require initiation of antihypertensive therapy or adjustment of existing antihypertensive regimen. New or worsening hypertension has been associated with a higher risk of subsequent major adverse cardiovascular events (Ref).
Mechanism: Not clearly established; may occur due to downregulation of nitric oxide formation and endothelial dysfunction. Another postulated mechanism is inhibition of phosphoinositide-3-protein kinase B (PI3K)-AKT pathway, including indirect downregulation of PI3K-p110α, leading to vascular tissue fibrosis and cellular remodeling (Ref).
Onset: Varied; median ~5.5 months (interquartile range ~3 weeks to 9 months) (Ref).
Risk factors:
• Preexisting hypertension (Ref)
• Older age (Ref)
• Increased BMI (Ref)
• History of diabetes mellitus (Ref)
• Chronic lymphocytic leukemia (Ref)
• Concurrent anthracycline use (Ref)
• Concurrent CYP3A4 inhibitors (Ref)
Progressive multifocal leukoencephalopathy is a rare and often fatal infection of the cerebrum caused by the John Cunningham (JC) virus. Patients present with rapidly progressive neurological symptoms including, but not limited to confusion, speech or gait disorders, and urinary incontinence (Ref). Diagnosis may be delayed due to lack of awareness (Ref).
Mechanism: Not clearly established; may be related to inhibition of B-cell function, allowing JC virus reactivation (Ref).
Onset: Varied; ranges from ~1 month to 2 years after initiation in case reports (Ref).
Risk factors:
• Concurrent use of other B-cell–depleting agents (eg, rituximab, brentuximab, fludarabine) (Ref)
• Chronic lymphocytic leukemia (Ref)
Patients treated with Bruton's tyrosine kinase inhibitors (BTKi), including ibrutinib, have developed second primary malignant neoplasm, such as nonmelanoma skin carcinoma and other non-skin carcinoma (Ref).
Mechanism: Not clearly established; may be related to immune dysfunction due to BTK inhibition (Ref).
Onset: Varied; median time to diagnosis 26 months (range: ~12 days to ≥7 years) after initiation (Ref).
Risk factors:
• Chronic lymphocytic leukemia (Ref)
• Smoking (Ref)
• Higher baseline platelet count (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for ibrutinib monotherapy.
>10%:
Cardiovascular: Hypertension (11% to 16%; cumulative rate increased over time) (table 1), peripheral edema (12% to 35%), sinus tachycardia (11%)
|
Drug (Ibrutinib) |
Comparator (Chlorambucil) |
Population |
Dose |
Indication |
Number of Patients (Ibrutinib) |
Number of Patients (Chlorambucil) |
Comments |
|---|---|---|---|---|---|---|---|
|
11% |
N/A |
Children, adolescents, and adults |
≥12 years: 420 mg orally once daily, 1 to 12 years: 240 mg/m2 orally once daily |
Chronic graft-versus-host disease |
47 |
N/A |
iMAGINE |
|
16% |
N/A |
Adults |
420 mg once daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
51 |
N/A |
Study 1102 |
|
14% |
1% |
Adults |
420 mg daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
135 |
132 |
RESONATE-2 |
|
14% |
N/A |
Adults |
560 mg once daily |
Marginal zone lymphoma |
63 |
N/A |
Study 1121 |
|
14% |
N/A |
Adults |
420 mg once daily |
Waldenström macroglobulinemia and marginal zone lymphoma |
94 |
N/A |
Study 1118 and INNOVATE |
Dermatologic: Pruritus (13% to 14%), skin infection (14% to 18%), skin rash (12% to 29%)
Endocrine & metabolic: Dehydration (12%), hyperuricemia (15% to 16%), hypoalbuminemia (14%), hypokalemia (12% to 15%)
Gastrointestinal: Abdominal pain (13% to 24%), constipation (12% to 25%), decreased appetite (16% to 21%), diarrhea (28% to 59%; grades ≥3: 2% to 10%), dyspepsia (11% to 19%), gastroesophageal reflux disease (12%), nausea (19% to 31%; grades ≥3: 1% to 4%), stomatitis (14% to 29%; grades ≥3: 1% to 9%), upper abdominal pain (13%), vomiting (11% to 23%; grades 3/4: 2%)
Genitourinary: Urinary tract infection (10% to 14%)
Hematologic & oncologic: Anemia (≥30%; grades 3/4: 3%), bruise (11% to 51%; grades 3/4: 1% to 2%), hemorrhage (17% to 30%; grades ≥3: 2%; including major hemorrhage, gastrointestinal hemorrhage, hematuria, and postprocedural hemorrhage), hypogammaglobulinemia (11%), lymphocytosis (66%), neutropenia (≥30%; grades ≥3: 2% to 23%) (table 2), petechia (11% to 16%), thrombocytopenia (≥30%; grades ≥3: 1% to 8%) (table 3)
|
Drug (Ibrutinib) |
Comparator |
Population |
Dose |
Indication |
Number of Patients (Ibrutinib) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|
|
Grade 4: 3% |
N/A |
Children, adolescents, and adults |
≥12 years: 420 mg orally once daily, 1 to 12 years: 240 mg/m2 orally once daily |
Chronic graft-versus-host disease |
47 |
N/A |
|
Grade 4: 2% |
N/A |
Adults |
420 mg once daily |
Chronic graft-versus-host disease |
42 |
N/A |
|
Grade 4: 12% |
N/A |
Adults |
420 mg once daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
51 |
N/A |
|
Grade 4: 11% |
Chlorambucil: 12% |
Adults |
420 mg daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
135 |
132 |
|
Grade 4: 8% |
Ofatumumab: 8% |
Adults |
420 mg daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
195 |
191 |
|
Grade 4: 13% |
N/A |
Adults |
560 mg daily |
Mantle cell lymphoma |
111 |
N/A |
|
Grade 4: 6% |
N/A |
Adults |
560 mg once daily |
Marginal zone lymphoma |
63 |
N/A |
|
Grade 4: 7% |
N/A |
Adults |
420 mg once daily |
Waldenström macroglobulinemia and marginal zone lymphoma |
94 |
N/A |
|
Grades 3/4: 23% |
N/A |
N/A |
N/A |
B-cell malignancies |
645 |
N/A |
|
Drug (Ibrutinib) |
Comparator |
Population |
Dose |
Indication |
Number of Patients (Ibrutinib) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|---|
|
Grade 4: 8% |
N/A |
Adults |
420 mg once daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
51 |
N/A |
|
Grade 4: 6% |
N/A |
Adults |
560 mg daily |
Mantle cell lymphoma |
111 |
N/A |
|
Grade 4: 4% |
N/A |
Adults |
420 mg once daily |
Waldenström macroglobulinemia and marginal zone lymphoma |
94 |
N/A |
|
Grade 4: 3% |
N/A |
Adults |
560 mg once daily |
Marginal zone lymphoma |
63 |
N/A |
|
Grade 4: 2% |
Ofatumumab: 3% |
Adults |
420 mg daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
195 |
191 |
|
Grade 4: 1% |
Chlorambucil: 3% |
Adults |
420 mg daily |
Chronic lymphocytic leukemia/small lymphocytic lymphoma |
135 |
132 |
|
Grades 3/4: 8% |
N/A |
N/A |
N/A |
B-cell malignancies |
645 |
N/A |
Hepatic: Increased serum alanine aminotransferase (11%)
Infection: Infection (including bacterial infection, fungal infection, and viral infection [reactivation of HBV]), sepsis (10% to 11%)
Nervous system: Anxiety (16%), asthenia (14%), chills (12%), dizziness (11% to 20%), falling (17%), fatigue (18% to 57%), headache (12% to 21%)
Neuromuscular & skeletal: Arthralgia (11% to 24%), muscle spasm (11% to 29%), musculoskeletal pain (14% to 40%), osteonecrosis (11%)
Ophthalmic: Blurred vision (≤13%), decreased visual acuity (≤11%), dry eye syndrome (17%), increased lacrimation (13%)
Respiratory: Bronchitis (11%), cough (13% to 22%), dyspnea (10% to 27%), epistaxis (11%), oropharyngeal pain (14%), pneumonia (11% to 23%), sinusitis (11% to 22%), upper respiratory tract infection (16% to 47%)
Miscellaneous: Fever (12% to 30%)
1% to 10%:
Cardiovascular: Atrial fibrillation (≤8%) (table 4), atrial flutter (≤8%) (table 5), heart failure (2%) (table 6), ventricular tachyarrhythmia (1%; including ventricular arrythmia, ventricular fibrillation, cardiac [ventricular] flutter, ventricular premature contractions, ventricular tachycardia) (table 7)
|
Drug (Ibrutinib) |
Control |
Number of Patients (Ibrutinib) |
Number of Patients (Control) |
Comments |
|---|---|---|---|---|
|
8% |
2% |
1,157 |
958 |
Combined term with atrial flutter |
|
Drug (Ibrutinib) |
Control |
Number of Patients (Ibrutinib) |
Number of Patients (Control) |
Comments |
|---|---|---|---|---|
|
8% |
2% |
1,157 |
958 |
Combined term with atrial fibrillation |
|
Drug (Ibrutinib) |
Control |
Number of Patients (Ibrutinib) |
Number of Patients (Control) |
|---|---|---|---|
|
2% |
0.5% |
1,157 |
958 |
|
Drug (Ibrutinib) |
Control |
Number of Patients (Ibrutinib) |
Number of Patients (Control) |
|---|---|---|---|
|
1% |
0.4% |
1,157 |
958 |
Endocrine & metabolic: Weight loss (10%)
Hematologic & oncologic: Second primary malignant neoplasm (10%; grades ≥3: 2%; including carcinoma [non-skin] and skin carcinoma [nonmelanoma])
Nervous system: Cerebrovascular disease (1%; including cerebral ischemia, cerebrovascular accident, intracranial hemorrhage, ischemic stroke, subdural hematoma, transient ischemic attacks) (table 8)
|
Drug (Ibrutinib) |
Control |
Number of Patients (Ibrutinib) |
Number of Patients (Control) |
|---|---|---|---|
|
1% |
0.4% |
1,157 |
958 |
Renal: Increased serum creatinine (1.5 to 3 × ULN: 9%)
Frequency not defined: Nervous system: Abnormal gait, lethargy
Postmarketing:
Cardiovascular: Cardiac conduction disorder (Salem 2019), supraventricular cardiac arrhythmia (Salem 2019)
Dermatologic: Dermatologic disorder (neutrophilic dermatoses), onychoclasis, Stevens-Johnson syndrome, urticaria
Endocrine & metabolic: Hyponatremia (Burger 2015)
Hematologic & oncologic: Abnormal platelet aggregation (Kamel 2015), tumor lysis syndrome
Hepatic: Hepatic cirrhosis, hepatic failure
Hypersensitivity: Anaphylactic shock, angioedema
Nervous system: Peripheral neuropathy (Shaikh 2019), progressive multifocal leukoencephalopathy (Hsiehchen 2018)
Neuromuscular & skeletal: Panniculitis
Renal: Acute kidney injury (including acute interstitial nephritis) (Markoth 2021), renal failure syndrome
Respiratory: Interstitial pulmonary disease, pneumonia due to Pneumocystis jirovecii (de Weerdt 2017), pneumonitis (Mato 2016)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known hypersensitivity to ibrutinib or any component of the formulation.
Concerns related to adverse effects:
• CNS effects: May cause dizziness, fatigue, and/or weakness, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• GI toxicity: Diarrhea has been commonly observed; maintain adequate hydration.
Disease-related concerns:
• Hepatic impairment: Use with caution in hepatic impairment; see "Dosing: Hepatic Impairment: Adult" for additional information.
Special populations:
• Older adults: Anemia (all grades), thrombocytopenia, pneumonia (≥ grade 3), hypertension, and atrial fibrillation occurred more frequently in patients ≥65 years of age.
• Waldenström macroglobulinemia: Hyperviscosity may require plasmapheresis prior to or during ibrutinib treatment in patients with Waldenström macroglobulinemia; adjustment of ibrutinib dose due to plasmapheresis is not necessary.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
Other warnings/precautions:
• Adherence: A retrospective analysis of a phase 3 efficacy trial in previously treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma evaluated the effect of dose intensity on progression-free survival (PFS) and overall response rate (ORR). A higher dose intensity was associated with longer median PFS and a higher ORR; optimal outcomes were achieved in patients with sustained adherence to a 420 mg/day dosing schedule (Barr 2017).
Substrate of CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Ibrutinib may enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Anticoagulants: Ibrutinib may enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bitter Orange: May increase the serum concentration of Ibrutinib. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ibrutinib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ibrutinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued. Risk X: Avoid combination
Dabigatran Etexilate: Ibrutinib may enhance the anticoagulant effect of Dabigatran Etexilate. Ibrutinib may increase the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Digoxin: Ibrutinib may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Flaxseed Oil: May enhance the antiplatelet effect of Ibrutinib. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Ibrutinib. Risk X: Avoid combination
Icosapent Ethyl: May enhance the antiplatelet effect of Ibrutinib. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Methotrexate: Ibrutinib may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Ibrutinib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Posaconazole: May increase the serum concentration of Ibrutinib. Management: Ibrutinib dose reductions are required when combined with posaconazole. Dose recommendations depend on the indication for ibrutinib, age of the patient, and the posaconazole dose. See full Lexi Interact monograph for details. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Ibrutinib. Risk X: Avoid combination
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Vitamin E (Systemic): May enhance the antiplatelet effect of Ibrutinib. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Ibrutinib. Management: Ibrutinib dose reductions are required when combined with voriconazole. Dose recommendations depend on the indication for ibrutinib, age of the patient, and the voriconazole dose. See full Lexi Interact monograph for details. Risk D: Consider therapy modification
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Grapefruit and Seville oranges inhibit CYP3A (moderately or strongly) and may increase ibrutinib exposure. Management: Avoid grapefruit and Seville oranges during therapy.
Verify pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use effective contraception during treatment and for 1 month after the last ibrutinib dose; patients with partners who could become pregnant should use effective contraception during treatment and for 1 month after the last ibrutinib dose.
Based on the mechanism of action and data from animal reproduction studies, ibrutinib may cause fetal harm if administered during pregnancy.
It is not known if ibrutinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 1 week after the last ibrutinib dose.
Avoid grapefruit, grapefruit juice, and Seville oranges during therapy.
Monitor blood counts monthly or as clinically necessary; renal and hepatic function; uric acid levels as clinically necessary. Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor BP. Evaluate cardiac history/function at baseline; monitor cardiac function and for cardiac arrhythmias as clinically indicated, and monitor for signs/symptoms of cardiac arrhythmias and/or heart failure; obtain further evaluation (ECG or echocardiogram) as clinically indicated in patients who develop signs/symptoms of arrhythmias. Monitor for sign/symptoms of bleeding, infections, progressive multifocal encephalopathy, tumor lysis syndrome, and/or second primary malignancies. Monitor for signs of leukostasis, particularly in patients experiencing a rapid increase in lymphocytes to >400,000/mcL. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Ibrutinib is a potent and irreversible inhibitor of Bruton's tyrosine kinase (BTK), an integral component of the B-cell receptor (BCR) and cytokine receptor pathways. Constitutive activation of B-cell receptor signaling is important for survival of malignant B-cells; BTK inhibition results in decreased malignant B-cell proliferation and survival.
Distribution: Adults: Vd: 683 L; Vdss/F: ~10,000 L (Marostica 2015).
Bioavailability: Absolute bioavailability in fasted condition was 2.9% and doubled when combined with a meal. Administration with a high-fat, high-calorie meal (800 to 1,000 calories with ~50% of caloric content from fat) increased the Cmax by ~2- to 4-fold and the AUC 2-fold (compared with overnight fasting). Administration under fasting conditions resulted in exposure of ~60% compared to when administered either 30 minutes before or after a meal, or 2 hours after a high-fat meal (de Jong 2015).
Protein binding: ~97%.
Metabolism: Hepatic via CYP3A (major) and CYP2D6 (minor) to active metabolite PCI-45227.
Half-life elimination: Adults: 4 to 6 hours.
Time to peak: Adults: 1 to 2 hours (4 hours under fed conditions [de Jong 2015]).
Excretion: Feces (80%; 1% as unchanged drug); urine (<10%, as metabolites).
Clearance (apparent): Oral: Adults: 2,000 L/hour (fasted); 1,000 L/hour (fed).
Hepatic function impairment: AUC was increased 2.7-, 8.2-, and 9.8-fold, respectively, (Cmax was increased 5.2-, 8.8-, and 7-fold, respectively) in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment compared with subjects with normal hepatic function in a single-dose hepatic impairment trial.
Capsules (Imbruvica Oral)
70 mg (per each): $640.98
140 mg (per each): $213.66
Suspension (Imbruvica Oral)
70 mg/mL (per mL): $106.83
Tablets (Imbruvica Oral)
140 mg (per each): $640.98
280 mg (per each): $640.98
420 mg (per each): $640.98
560 mg (per each): $640.98
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