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Ibrutinib: Drug information

Ibrutinib: Drug information
(For additional information see "Ibrutinib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
Imbruvica Safety Alert August 2022

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.

Ibrutinib: Coronavirus disease 2019 (COVID-19) October 2020

Most recent update(s): The National Institute of Health’s COVID-19 guidelines recommend against the use of Bruton tyrosine kinase inhibitors, such as ibrutinib, for the treatment of COVID-19, except in a clinical trial.

As part of our response to the evolving COVID-19 pandemic, published literature and guidelines from major health organizations are continuously monitored for potential content updates. At this time, only investigational medications with data determined to be of relatively high quality and/or consistently showing positive clinical outcomes to support dosing recommendations will be included in the Lexicomp monograph, outside of this Special Alert field.

Further information may be found at:

IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/results?cond=COVID19&term=ibrutinib&cntry=&state=&city=&dist=&Search=Search

Brand Names: US
  • Imbruvica
Brand Names: Canada
  • Imbruvica
Pharmacologic Category
  • Antineoplastic Agent;
  • Antineoplastic Agent, Bruton Tyrosine Kinase Inhibitor;
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
Dosing: Adult

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

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

Chronic lymphocytic leukemia/small lymphocytic lymphoma: 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

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

Marginal zone lymphoma, relapsed/refractory: Oral: 560 mg once daily; continue until disease progression or unacceptable toxicity (Noy 2017).

Waldenström macroglobulinemia

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: 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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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).

Dosing: Hepatic Impairment: Adult

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.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Recommended ibrutinib dosage modifications for adverse reactions following improvement to grade 1 or baseline (recovery):

Ibrutinib Dose Modification for Adverse Reactions

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:

  • Other grade 3 or 4 nonhematological toxicitiesa

  • Grade 3 or 4 neutropenia with infection or fever

  • Grade 4 hematological 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.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Imbruvica: 70 mg, 140 mg

Tablet, Oral:

Imbruvica: 140 mg, 280 mg, 420 mg, 560 mg

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Imbruvica: 140 mg

Product Availability

Imbruvica 70 mg/mL oral suspension: FDA approved August 2022; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.

Administration: Adult

Oral: 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).

Use: Labeled Indications

Chronic graft-versus-host disease (refractory): Treatment of chronic graft-versus-host disease in adults 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.

Medication Safety Issues
Sound-alike/look-alike issues:

Ibrutinib may be confused with acalabrutinib, avapritinib, Ibrance, ibritumomab, idelalisib, imatinib, ivosidenib, zanubrutinib.

High alert medication:

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.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Hypertension (14% to 19%; cumulative rate increased over time), peripheral edema (12% to 35%)

Dermatologic: Pruritus (14%), skin infection (14% to 18%), skin rash (12% to 29%)

Endocrine & metabolic: Dehydration (12%), hyperuricemia (15% to 16%), hypoalbuminemia (14%), hypokalemia (12% to 13%)

Gastrointestinal: Abdominal pain (13% to 24%), constipation (12% to 25%), decreased appetite (16% to 21%), diarrhea (36% to 59%), dyspepsia (11% to 19%), gastroesophageal reflux disease (12%), nausea (20% to 31%), stomatitis (14% to 29%; grades ≥3: 1% to 2%), upper abdominal pain (13%), vomiting (11% to 23%)

Genitourinary: Urinary tract infection (10% to 14%)

Hematologic & oncologic: Anemia (≥30%; grades 3/4: 3%), bruise (≤51%; grades 3/4: 1% to 2%), hemorrhage (26% to 30%; grades ≥3: 2%), lymphocytosis (66%), neutropenia (≥30%; grades 3/4: 23%; grade 4: 2% to 13%), petechia (≤39%), thrombocytopenia (≥30%; grades 3/4: 8%; grade 4: 1% to 8%)

Infection: Infection (grade ≥3: 21%)

Nervous system: Anxiety (16%), chills (12%), dizziness (11% to 20%), falling (17%), fatigue (18% to 57%), headache (12% to 18%)

Neuromuscular & skeletal: Arthralgia (11% to 24%), asthenia (14%), muscle spasm (11% to 29%), musculoskeletal pain (14% to 40%)

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 21%), sinusitis (11% to 22%), upper respiratory tract infection (16% to 47%)

Miscellaneous: Fever (12% to 24%)

1% to 10%:

Cardiovascular: Atrial fibrillation (≤8%), atrial flutter (≤8%), cardiac failure (2%), cardiac flutter (ventricular: ≤1%), cerebral ischemia (≤1%), cerebrovascular accident (≤1%), ischemic stroke (≤1%), subdural hematoma (grades ≥3: ≤4%), transient ischemic attacks (≤1%), ventricular arrythmia (≤1%), ventricular fibrillation (≤1%), ventricular premature contractions (≤1%), ventricular tachycardia (≤1%)

Endocrine & metabolic: Weight loss (10%)

Gastrointestinal: Gastrointestinal hemorrhage (grades ≥3: ≤4%)

Genitourinary: Hematuria (grades ≥3: ≤4%)

Hematologic & oncologic: Carcinoma (non-skin: 4%), major hemorrhage (grade ≥3: ≤4%), postprocedural hemorrhage (grades ≥3: ≤4%), second primary malignant neoplasm (10%; grades ≥3: 2%), skin carcinoma (nonmelanoma: 6%)

Infection: Sepsis (10%)

Nervous system: Intracranial hemorrhage (grades ≥3: ≤4%)

Renal: Increased serum creatinine (1.5 to 3 x ULN: 9%)

Postmarketing:

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: Acute hepatic failure, hepatic cirrhosis, hepatic failure

Hypersensitivity: Anaphylactic shock, angioedema

Infection: Reactivation of HBV

Nervous system: Peripheral neuropathy, progressive multifocal leukoencephalopathy

Neuromuscular & skeletal: Panniculitis

Renal: Renal failure syndrome

Respiratory: Interstitial pulmonary disease, pneumonia due to Pneumocystis jirovecii, pneumonitis (Mato 2016)

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Known hypersensitivity to ibrutinib or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: 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. These events occurred particularly in patients with cardiac risk factors, including hypertension, diabetes mellitus, acute infections, or with a history of arrhythmias. Ibrutinib has also been associated with a higher incidence of cardiovascular adverse events, including ventricular arrhythmia, supraventricular arrhythmia, heart failure, hypertension, conduction disorders, and CNS hemorrhagic or ischemic events as compared to all adverse reactions in an analysis utilizing the international pharmacovigilance database (Salem 2019). Cardiac events have occurred in patients with or without preexisting hypertension or cardiac risk factors; patients with cardiac comorbidities may be at increased risk.

• 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.

• Hematologic effects: Grade 3 and 4 neutropenia, thrombocytopenia, and anemia occurred during clinical studies in patients who received single-agent ibrutinib for B-cell malignancies. Lymphocytosis (≥50% increase from baseline) may occur upon therapy initiation, generally within the first few weeks of therapy. The increase in lymphocytes is temporary and resolves by a median of 8 weeks (mantle cell lymphoma) or 14 weeks (chronic lymphocytic leukemia). Some patients who developed lymphocytosis (lymphocytes >400,000/mcL) have developed intracranial hemorrhage, lethargy, headache, and gait instability (some cases may have been associated with disease progression).

• Hemorrhage: Major hemorrhage (≥ grade 3, serious, or any CNS events; eg, intracranial hemorrhage [including subdural hematoma], GI bleeding, hematuria, postprocedural bleeding) has occurred. Some events were fatal. Bleeding events of any grade, including bruising and petechiae, have occurred in almost 40% of patients receiving ibrutinib. Patients receiving concurrent antiplatelet or anticoagulant treatment have an increased risk for bleeding; consider the risks and benefits of concurrent antiplatelet or anticoagulant therapy.

• Hypertension: Hypertension has been reported with ibrutinib therapy. The median onset of grade 3 or greater hypertension was ~6 months (range: 0.03 to 24 months). 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 (MACE); while no single class of antihypertensives has been shown to control ibrutinib-associated hypertension, initiation of antihypertensive therapy has been associated with a lower risk of MACE (Dickerson 2019).

• Infections: Serious infections (some fatal) have been observed, including bacterial, viral, and fungal infections. Cases of Pneumocystis jirovecii pneumonia have also been reported (Ahn 2016). Evaluate for fever and other signs/symptoms of infection and manage appropriately.

• Progressive multifocal encephalopathy: Progressive multifocal encephalopathy has been observed; evaluate for symptoms and manage appropriately.

• Renal toxicity: Renal failure has been reported with ibrutinib; some cases were fatal. Clinical trials report serum creatinine increases of up to 3 × ULN; maintain hydration.

• Second primary malignancies: Patients treated with ibrutinib have developed second primary malignancies, including nonmelanoma skin cancers and other non-skin carcinomas. The most frequent second primary malignancy was nonmelanoma skin cancer. Evaluate for sign/symptoms of secondary malignancy during treatment.

• Tumor lysis syndrome: Tumor lysis syndrome has been reported (rare); increased uric acid levels have been observed, including grade 4 elevations. Assess risk for tumor lysis syndrome (eg, high tumor burden); monitor closely in patients at risk and manage appropriately.

Disease-related concerns:

• Hepatic impairment: Ibrutinib is hepatically metabolized, and exposure is increased in patients with hepatic dysfunction.

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.

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).

Metabolism/Transport Effects

Substrate of CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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 vaccine at least 28 days after the primary vaccine dose. Patients should also receive 2 booster doses of mRNA vaccine - one 2 months after the 2nd (additional) dose and another 4 months after the first booster dose. 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 based on the brand of mRNA vaccine received. 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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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 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 post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. 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: For use with voriconazole 200 mg twice daily - reduce ibrutinib to 140 mg daily (for B-cell malignancies) and reduce ibrutinib to 280 mg daily (for GVHD). Avoid concomitant use of ibrutinib with higher voriconazole doses. 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

Food Interactions

Grapefruit and Seville oranges inhibit CYP3A (moderately or strongly) and may increase ibrutinib exposure. Management: Avoid grapefruit and Seville oranges during therapy.

Reproductive Considerations

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.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, ibrutinib may cause fetal harm if administered during pregnancy.

Breastfeeding Considerations

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.

Dietary Considerations

Avoid grapefruit, grapefruit juice, and Seville oranges during therapy.

Monitoring Parameters

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.

Mechanism of Action

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.

Pharmacokinetics

Distribution: ~10,000 L (Marostica 2015)

Bioavailability: Absolute bioavailability in fasted condition was 2.9% and doubled when combined with a meal. Administration with food 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: 4 to 6 hours

Time to peak: 1 to 2 hours (4 hours under fed conditions [de Jong 2015])

Excretion: Feces (80%; 1% as unchanged drug); urine (<10%, as metabolites)

Pharmacokinetics: Additional Considerations

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.

Pricing: US

Capsules (Imbruvica Oral)

70 mg (per each): $640.98

140 mg (per each): $213.66

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

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Imbruvica (AU, BB, BE, BH, BR, CH, CN, CR, CZ, DE, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, JP, KR, LB, LT, LU, LV, MT, MY, NI, NL, NO, NZ, PA, PH, PL, PT, RO, RU, SA, SE, SG, SI, SK, SV, TW, VN)


For country abbreviations used in Lexicomp (show table)
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  2. Ahn IE, Jerussi T, Farooqui M, Tian X, Wiestner A, Gea-Banacloche J. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128(15):1940-1943. [PubMed 27503501]
  3. Barr PM, Brown JR, Hillmen O, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-2615. [PubMed 28373262]
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  5. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. [PubMed 24881631]
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  7. 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(2):200-211. [PubMed 26655421]
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  9. de Jong J, Sukbuntherng J, Skee D, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother Pharmacol. 2015;75(5):907-916. [PubMed 25724156]
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  12. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770-778. [PubMed 26673811]
  13. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
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  15. Imbruvica (ibrutinib) [product monograph]. Toronto, Ontario, Canada: Janssen Inc; June 2022.
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  17. Lampson BL, Yu L, Glynn RJ, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017;129(18):2581-2584. [PubMed 28223277]
  18. Maddox JM, Majid M. Use of ibrutinib via nasogastric (NG) tube & percutaneous endoscopic gastrostomy (PEG) tube. Blood. 2016;128(22):5371 [abstract from 2016 American Society of Hematology annual meeting].
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  21. 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. doi: 10.1182/blood-2017-07-793786. [PubMed 28924018]
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