Brand name: Imbruvica
Drug class: Antineoplastic Agents
- Bruton's Tyrosine Kinase Inhibitors
- Bruton Tyrosine Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one
Molecular formula: C₂₅H₂₄N₆O₂
CAS number: 936563-96-1

Medically reviewed by Drugs.com on Feb 15, 2024. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of Bruton's tyrosine kinase (BTK).

Uses for Ibrutinib

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least one prior therapy; designated an orphan drug by FDA for this use.

Current indication based on overall response rate; improvement in patient-reported outcomes and overall survival not established.

Continued FDA approval for this indication may be contingent on confirmation of clinical benefit in additional trials.

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Used alone, in combination with bendamustine and rituximab, or in combination with obinutuzumab or rituximab for the treatment of CLL and SLL, including CLL/SLL harboring the 17p13.1 deletion (17p deletion) chromosomal abnormality; designated an orphan drug by FDA for this use.

Marginal-zone Lymphoma

Treatment of marginal-zone lymphoma in patients who have received at least one prior anti-CD20-based therapy; designated an orphan drug by FDA for this use.

Current indication based on favorable overall response rate; clinical benefit not established. Continued FDA approval for this indication may be contingent on confirmation of clinical benefit in additional trials.

Waldenstrom Macroglobulinemia

Used alone or in combination with rituximab for the treatment of Waldenstrom macroglobulinemia; designated an orphan drug by FDA for this use.

Graft-versus-host Disease (GVHD)

Treatment of chronic GVHD following failure of at least one prior systemic therapy; designated an orphan drug by FDA for this use.

Ibrutinib Dosage and Administration

General

Pretreatment Screening

• Assess patient at baseline for cardiac arrhythmias and cardiac failure.

• Assess baseline risk for tumor lysis syndrome.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor complete blood counts (CBCs) monthly.

• Monitor for signs and symptoms of bleeding. Concomitant use of antiplatelet or anticoagulant therapy increases risk of major hemorrhage.

• Monitor for signs and symptoms of infection.

• Monitor patients clinically for cardiac arrhythmias and cardiac failure periodically during therapy.

• Monitor blood pressure.

• Monitor for tumor lysis syndrome.

Premedication and Prophylaxis

• Consider anti-infective prophylaxis in patients at increased risk of opportunistic infections.

Other General Considerations

• Consider the potential benefits and risks of withholding ibrutinib therapy for at least 3–7 days prior to and following surgery (based on the type of surgery and bleeding risk).

Administration

Oral Administration

Administer orally once daily at approximately the same time each day.

Swallow capsules whole with water; do not open, break, or chew.

Swallow tablets whole with water; do not cut, crush, or chew.

If a dose is missed, administer missed dose on the same day as soon as it is remembered and resume normal schedule the following day; do not take 2 doses on the same day to make up for a missed dose.

Dosage

Adults

Mantle Cell Lymphoma

Oral

560 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

CLL/SLL

Oral

420 mg once daily (as a single agent, in combination with bendamustine and rituximab, or in combination with rituximab or obinutuzumab). Continue therapy until disease progression or unacceptable toxicity occurs.

Consider administering ibrutinib prior to rituximab or obinutuzumab if administration occurs on the same day.

In the HELIOS study, patients received ibrutinib (420 mg once daily) continuously, bendamustine (70 mg/m² by IV infusion over 30 minutes) on days 2 and 3 of cycle 1 and on days 1 and 2 of cycles 2–6, and rituximab 375 mg/m² by IV infusion on day 1 of cycle 1 followed by 500 mg/m² on day 1 of cycles 2–6. Ibrutinib therapy was continued until disease progression or unacceptable toxicity occurred. Treatment cycles were repeated every 28 days.

In the ILLUMINATE study, patients received ibrutinib (420 mg once daily) continuously and obinutuzumab by IV infusion. During cycle 1, the dosage of obinutuzumab was 100 mg on day 1, followed by 900 mg on day 2, and then 1 g once weekly for 2 doses (days 8 and 15). During cycles 2–6, the dosage of obinutuzumab was 1 g every 4 weeks (day 1 of each cycle).

In the E1912 study, patients received ibrutinib (420 mg once daily) continuously and rituximab 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. Ibrutinib therapy was continued until disease progression or unacceptable toxicity occurred. Treatment cycles were repeated every 28 days.

Marginal-zone Lymphoma

Oral

560 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Waldenstrom Macroglobulinemia

Oral

420 mg once daily (as a single agent or in combination with rituximab). Continue therapy until disease progression or unacceptable toxicity occurs.

Consider administering ibrutinib prior to rituximab if administration occurs on the same day.

In the INNOVATE study, patients received ibrutinib (420 mg once daily) continuously and rituximab 375 mg/m² by IV infusion once weekly for 4 consecutive weeks during weeks 1–4 and weeks 17–20.

Dosage adjustment not necessary in patients undergoing plasmapheresis.

Chronic GVHD

Oral

420 mg once daily. Continue therapy until progression of chronic GVHD, recurrence of underlying malignancy, or unacceptable toxicity occurs. Discontinue therapy when treatment for chronic GVHD is no longer necessary.

Dosage Modification for Toxicity

If grade 3 or 4 nonhematologic toxicity, grade 3 or 4 neutropenia with infection or fever, or grade 4 hematologic toxicity occurs, interrupt therapy. Following recovery from toxicity (i.e., return to baseline or resolution to grade 1), resume (or discontinue) therapy as described in Table 1.

Dosage Modification for Concomitant Use with CYP3A Inhibitors

Avoid concomitant use with potent CYP3A inhibitors; if short-term (≤7 days) therapy with a potent CYP3A inhibitor is necessary, withhold ibrutinib during such therapy. If concomitant use with posaconazole or voriconazole cannot be avoided, reduce ibrutinib dosage. Ibrutinib dosage reduction also required if used concomitantly with a moderate CYP3A inhibitor.

Special Populations

Hepatic Impairment

Mild (Child-Pugh class A) hepatic impairment: Reduce dosage to 140 mg once daily. Closely monitor for signs of toxicity.

Moderate (Child-Pugh class B) hepatic impairment: Reduce dosage to 70 mg once daily. Closely monitor for signs of toxicity.

Severe (Child-Pugh class C) hepatic impairment: Avoid use.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time; however, certain ibrutinib toxicities may be more frequent in geriatric patients.

Cautions for Ibrutinib

Contraindications

• None.

Warnings/Precautions

Hemorrhage

Hemorrhagic events, sometimes fatal, observed. Serious (grade 3 or higher) bleeding events, including intracranial hemorrhage, subdural hematoma, GI bleeding, hematuria, and postprocedural hemorrhage, observed.

Increased risk of hemorrhagic events with concomitant use of ibrutinib and antiplatelet or anticoagulant therapies; consider potential benefits and risks of concomitant anticoagulant or antiplatelet therapy. Monitor for manifestations of bleeding.

Consider potential benefits and risks of withholding ibrutinib therapy for at least 3–7 days prior to and following surgery.

Infectious Complications

Serious infections (bacterial, viral, or fungal), sometimes fatal, observed.

Progressive leukoencephalopathy (PML) and Pneumocystis jirovecii (formerly P. carinii) pneumonia also observed.

Monitor for signs and symptoms of infection and initiate appropriate anti-infective treatment as clinically indicated. Consider prophylaxis according to current standard of care in patients at high risk for opportunistic infections.

Myelosuppression

Cytopenias, including thrombocytopenia, anemia, and neutropenia, observed. Serious (grade 3 or 4) cytopenias observed in patients with B-cell malignancies receiving single-agent ibrutinib.

Monitor CBC counts monthly. If myelosuppression occurs, reduce dosage or interrupt therapy.

Cardiac Effects

Serious arrhythmias and cardiac failure, sometimes fatal, observed, including (grade 3 or higher) ventricular tachyarrhythmias, atrial fibrillation, and atrial flutter.

Increased risk in patients with cardiac risk factors, hypertension, acute infections, or history of arrhythmias.

Hypertension also reported.

Monitor for development of arrhythmia, new-onset hypertension, or hypertension not adequately controlled with medical management.

If symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, angina) or new-onset dyspnea occur, monitor ECG and manage as clinically indicated. If arrhythmia persists, consider reducing dosage and carefully weigh potential benefit of drug against risks of continued therapy.

If hypertension occurs, initiate or adjust antihypertensive therapy as clinically indicated.

Development of Second Primary Malignancy

Development of other malignancies, including non-skin carcinomas, reported in 10% of ibrutinib-treated patients. Non-melanoma skin cancer occurred in 6% of ibrutinib-treated patients.

Tumor Lysis Syndrome

Tumor lysis syndrome reported infrequently.

Assess risk of developing tumor lysis syndrome at baseline and take appropriate precautions. Closely monitor patients and treat as clinically indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy and for 1 month after discontinuance of drug. (See Females and Males of Reproductive Potential under Cautions.)

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status prior to initiating ibrutinib therapy in females of reproductive potential. If used during pregnancy or if patient becomes pregnant while receiving drug, apprise patient of potential fetal hazard.

Females and Males of Reproductive Potential

Females of reproductive potential should avoid becoming pregnant during therapy and for 1 month after discontinuance of therapy; males should also avoid conceiving a child during therapy and for 1 month after discontinuance of therapy.

Lactation

Not known whether ibrutinib or its metabolites are distributed into human milk or if drug has any effect on milk production or breast-fed infant.

Breast-feeding is not recommended during treatment with ibrutinib and for 1 week after discontinuing use due to the potential for severe adverse events in the breast-fed child.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical trials, no difference in efficacy in geriatric patients (≥65 years of age) compared with younger adults, but some adverse effects (e.g., anemia, grade 3 or higher pneumonia, thrombocytopenia, hypertension, atrial fibrillation) occurred more frequently in geriatric patients.

Hepatic Impairment

Safety not established.

Increased systemic exposure and peak plasma concentrations in patients with mild to severe hepatic impairment.

Adjust dosage as appropriate and monitor for toxicity if used in patients with mild or moderate hepatic impairment.

Avoid use in patients with severe hepatic impairment.

Renal Impairment

Systemic exposure apparently not affected in patients with Cl_cr >25 mL/minute.

No experience in patients with severe renal impairment (Cl_cr <25 mL/minute) or in those undergoing dialysis.

Common Adverse Effects

Mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, or Waldenstrom macroglobulinemia (≥30%): Thrombocytopenia, diarrhea, anemia, neutropenia, musculoskeletal pain, rash, bruising, nausea, fatigue.

Chronic GVHD (≥20%): Fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia, pneumonia.

Drug Interactions

Principally metabolized by CYP3A and, to a lesser extent, by CYP2D6 to an active dihydrodiol metabolite (PCI-45227).

Ibrutinib and PCI-45227 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 in vitro.

Ibrutinib not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro; may inhibit P-gp and BCRP transport at clinically relevant concentrations.

CYP3A Inhibitors

Possible pharmacokinetic interaction (increased serum ibrutinib concentrations) and increased incidence of drug toxicity. Moderate CYP3A inhibitors may increase AUC and peak plasma concentrations of ibrutinib by approximately threefold. Larger increases in AUC and peak plasma concentrations (e.g., by 24- and 29-fold, respectively) possible with potent CYP3A inhibitors; however, less substantial increases in AUC expected with voriconazole (e.g., by approximately 5.7-fold) and posaconazole (e.g., by threefold to tenfold). (See Specific Drugs and Foods under Interactions.)

Avoid concomitant use with potent CYP3A inhibitors. If short-term (≤7 days) administration of a potent CYP3A inhibitor is required, withhold ibrutinib during such administration. If concomitant use with posaconazole or voriconazole cannot be avoided, reduce ibrutinib dosage. (See Specific Drugs and Foods under Interactions.)

If concomitant use with a moderate CYP3A inhibitor is necessary, reduce ibrutinib dosage to 280 mg once daily in patients with mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, or Waldenstrom macroglobulinemia, and to 420 mg once daily in patients with chronic GVHD. If the moderate CYP3A inhibitor is discontinued, resume ibrutinib therapy at the dosage used prior to initiation of the moderate CYP3A inhibitor.

Closely monitor patient for adverse effects if concomitant use of a CYP3A inhibitor cannot be avoided, and adjust dosage accordingly.

CYP3A Inducers

Possible pharmacokinetic interaction (decreased serum ibrutinib concentrations). Potent inducers of CYP3A may reduce peak plasma concentration and AUC of ibrutinib by >10-fold. Moderate CYP3A inducers may reduce ibrutinib AUC by up to threefold.

Avoid concomitant use with potent CYP3A inducers. (See Specific Drugs and Foods under Interactions.)

Substrates of Efflux Transport Systems

Concomitant use of ibrutinib with oral drugs that are substrates of P-gp or BCRP and have a narrow therapeutic index (e.g., digoxin, methotrexate) may result in increased concentrations of the substrate drug.

Specific Drugs and Foods

Ibrutinib Pharmacokinetics

Absorption

Food

Following oral administration in healthy individuals in a fasted condition, absolute bioavailability is 2.9%.

Systemic exposure increases with doses up to 840 mg in patients with B-cell malignancies.

Following repeated doses of 420 or 560 mg daily, steady-state concentrations achieved in 1 week with accumulation ratio of 1–1.6.

Oral administration with high-fat, high-calorie meal (800–1000 calories with approximately 50% of calories from fat) increases peak plasma concentration by twofold to fourfold and systemic exposure by twofold, compared with administration following overnight fasting.

Special Populations

Patients with mild hepatic impairment (Child-Pugh class A): Peak plasma concentration or systemic exposure increased by 5.2- or 2.7-fold, respectively.

Patients with moderate hepatic impairment (Child-Pugh class B): Peak plasma concentration or systemic exposure increased by 8.8- or 8.2-fold, respectively.

Patients with severe hepatic impairment (Child-Pugh class C): Peak plasma concentration or systemic exposure increased by 7- or 9.8-fold, respectively.

Systemic exposure apparently not affected in patients with Cl_cr >25 mL/minute.

Distribution

Extent

Extensive tissue distribution; not known whether distributed into milk.

Plasma Protein Binding

97.3%.

Elimination

Metabolism

Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6 to the active dihydrodiol metabolite PCI-45227.

Elimination Route

Eliminated in feces (80%) and urine (<10%).

Half-life

4–6 hours.

Special Populations

Age and gender do not substantially affect pharmacokinetics of ibrutinib.

Stability

Storage

Oral

Capsules and Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Selectively and irreversibly inhibits BTK, resulting in inhibition of downstream effector activity within the B-cell antigen receptor (BCR) signaling pathway.

• Inhibits other receptor kinases (e.g., Bmx/Etk, EGFR, Hck, Yes) in vitro.

• Inhibits proliferation and survival of malignant B-cells in vivo.

• Demonstrates cell migration and substrate adhesion of CLL cells and mantle cell lymphoma cells in vitro; mobilization of cells from tissues to peripheral blood results in a transient increase in absolute lymphocyte count in peripheral blood.

• Demonstrates substantial activity in activated B-cell-like diffuse B-cell non-Hodgkin's lymphoma (ABC-DLBCL) cells expressing wild-type caspase recruitment domain-containing protein-11 (wild-type CARD-11) in vitro and in vivo.

Advice to Patients

• Advise patients to take ibrutinib as directed by their clinician and at approximately the same time each day. If a dose is missed, administer missed dose on the same day as soon as it is remembered. Advise patients not to take 2 doses on the same day to make up for a missed dose.

• Advise patients to take ibrutinib capsules or tablets orally with a glass of water; do not open, break, or chew capsules or cut, crush, or chew tablets.

• Risk of bleeding. Inform clinician of any episodes of unusual bleeding (e.g., severe headache, blood in stool or urine, prolonged or uncontrolled bleeding). Notify clinician of any planned surgeries, including dental procedures.

• Risk of serious infection. Report signs or symptoms of possible infection (e.g., chills, fever, weakness, confusion).

• Risk of arrhythmias and cardiac failure. Inform clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, edema, or chest discomfort occurs.

• Risk of hypertension; may require antihypertensive therapy.

• Possible risk of developing a second primary malignancy (e.g., skin cancer).

• Risk of tumor lysis syndrome. Report signs or symptoms of tumor lysis syndrome (e.g., arrhythmia, seizure).

• Risk of fetal harm. Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential hazard to the fetus if used during pregnancy. Females of reproductive potential should avoid becoming pregnant during therapy and for 1 month after discontinuance of therapy; males should also avoid conceiving a child during therapy and for 1 month after discontinuance of therapy.

• Due to potential adverse events to the breast-fed child, do not breast-feed during treatment and for at least 1 week after discontinuation of therapy.

• Risk of diarrhea. Advise patients to maintain adequate hydration during ibrutinib therapy. Inform clinician if diarrhea persists.

• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses. Advise patients not to consume grapefruit or Seville oranges.

• Inform patients of other important precautionary information. (See Cautions.)

Preparations

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. Contact the manufacturer or consult the Imbruvica website ([Web]) for specific availability information.

Reload page with references included

Frequently asked questions

• How long can you stay on Imbruvica (ibrutinib)?
• How much does Imbruvica cost?
• Can ibrutinib be stopped safely?
• Acalabrutinib vs. ibrutinib: How do they compare?
• How quickly does Imbruvica (ibrutinib) work?
• Does ibrutinib cause hair loss?
• Is Imbruvica a chemotherapy drug?
• What are the names of the BTK inhibitors?
• Who makes Imbruvica?

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