Ibrutinib

Dosage Forms

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

Pharmacology

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/Pharmacodynamics

Distribution

~10,000 L (Marostica 2015)

Metabolism

Hepatic via CYP3A (major) and CYP2D6 (minor) to active metabolite PCI-45227

Excretion

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

Time to Peak

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

Half-Life Elimination

4 to 6 hours

Protein Binding

~97%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

AUC was increased 2.7-, 8.2-, and 9.8-fold, respectively, (C_max was increased 5.2-, 8.8-, and 7-fold, respectively) in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment compared with patients with normal hepatic function in a single-dose hepatic impairment trial.

Use: Labeled Indications

Chronic graft-versus-host disease (refractory): Treatment of chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

Chronic lymphocytic leukemia/small lymphocytic lymphoma: Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); treatment of CLL/SLL in patients with 17p deletion.

Mantle cell lymphoma, previously treated: Treatment of mantle cell lymphoma (MCL) in patients who have received at least 1 prior therapy

Marginal zone lymphoma, relapsed/refractory: Treatment of marginal zone lymphoma (MZL) in patients who require systemic therapy and have received at least one prior anti-CD20-based therapy.

Waldenström macroglobulinemia: Treatment of Waldenström macroglobulinemia

Contraindications

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

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

Dosage and Administration

Dosing: Adult

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: Oral: 420 mg once daily (either as monotherapy or in combination with bendamustine and rituximab or with obinutuzumab); continue until disease progression or unacceptable toxicity (Byrd 2014; Chanan-Khan 2016; Moreno 2019).

Chronic lymphocytic leukemia/small lymphocytic lymphoma (off-label combination): Adults <70 years of age; previously untreated (IGHV-unmutated and without 17p deletion): Oral: 420 mg once daily (in combination with rituximab [cycles 2 to 7]); continue ibrutinib until disease progression or unacceptable toxicity (Shanafelt 2019).

Chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion: Oral: 420 mg once daily; continue until disease progression or unacceptable toxicity (Byrd 2014).

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: 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:

Note: Resume previous ibrutinib dose after discontinuation of the CYP3A inhibitor.

B-cell malignancies:

Moderate CYP3A inhibitors: Reduce ibrutinib dose to 280 mg once daily.Monitor closely and modify ibrutinib treatment as recommended for toxicities.

Voriconazole 200 mg twice daily, posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily: Reduce ibrutinib dose to 140 mg once daily. Monitor closely and modify ibrutinib treatment as recommended for toxicities.

Posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole 300 mg IV once daily, or posaconazole delayed-release tablets 300 mg once daily: Reduce ibrutinib dose to 70 mg once daily. Monitor closely and interrupt ibrutinib treatment as recommended for toxicities.

Other strong CYP3A inhibitors: Avoid concurrent use. If these inhibitors will be used short-term (eg, anti-infectives for ≤7 days), interrupt ibrutinib treatment.

Chronic graft-versus-host disease:

Moderate CYP3A inhibitors: Administer ibrutinib at 420 mg once daily. Monitor closely and modify ibrutinib treatment as recommended for toxicities.

Voriconazole 200 mg twice daily, posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily: Reduce ibrutinib dose to 280 mg once daily. Monitor closely and modify ibrutinib treatment as recommended for toxicities.

Posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole 300 mg IV once daily, or posaconazole delayed-release tablets 300 mg once daily: Reduce ibrutinib dose to 140 mg once daily. Monitor closely and interrupt ibrutinib treatment as recommended for toxicities.

Other strong CYP3A inhibitors: Avoid concurrent use. If these inhibitors will be used short-term (eg, anti-infectives for ≤7 days), interrupt ibrutinib treatment.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic toxicity: ≥ Grade 3 neutropenia with infection or fever, or grade 4 toxicity: Interrupt therapy; upon improvement to grade 1 toxicity or baseline, resume dosing at the starting dose. If toxicity recurs, reduce daily dose by 140 mg. If toxicity recurs after first dose reduction, reduce daily dose by an additional 140 mg. If toxicity persists following 2 dose reductions, discontinue therapy.

Nonhematologic toxicity: ≥ Grade 3 toxicity: Interrupt therapy; upon improvement to grade 1 toxicity or baseline, resume dosing at the starting dose. If toxicity recurs, reduce daily dose by 140 mg. If toxicity recurs after first dose reduction, reduce daily dose by an additional 140 mg. If toxicity persists following 2 dose reductions, discontinue therapy.

Recommend dose reductions for toxicity (following recovery):

Chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic graft-versus-host disease,and Waldenström macroglobulinemia:

First occurrence: Restart at 420 mg once daily

Second occurrence: Restart at 280 mg once daily

Third occurrence: Restart at 140 mg once daily

Fourth occurrence: Discontinue ibrutinib

Mantle cell lymphoma and marginal zone lymphoma:

First occurrence: Restart at 560 mg once daily

Second occurrence: Restart at 420 mg once daily

Third occurrence: Restart at 280 mg once daily

Fourth occurrence: Discontinue ibrutinib

Administration

Administer orally with a glass of water at approximately the same time every day. Swallow capsules and tablets whole. Do not open, break, or chew the capsules; do not cut, crush, or chew the tablets. Maintain adequate hydration during treatment. When administering ibrutinib in combination with rituximab or obinutuzumab, consider administering ibrutinib prior to rituximab or obinutuzumab when given on the same day.

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 (PEG) tube (single case report) by opening the capsule contents and flushing the contents down the tube(s) with water (Maddox 2016).

Dietary Considerations

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

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Keep in original container until dispensing.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Ibrutinib may enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Ibrutinib may enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bitter Orange: May increase the serum concentration of Ibrutinib. Avoid combination

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ibrutinib. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ibrutinib. 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. 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. Avoid combination

Dabigatran Etexilate: Ibrutinib may enhance the anticoagulant effect of Dabigatran Etexilate. Ibrutinib may increase the serum concentration of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Digoxin: Ibrutinib may increase the serum concentration of Digoxin. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

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

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

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flaxseed Oil: May enhance the antiplatelet effect of Ibrutinib. Monitor therapy

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

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Ibrutinib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

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

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Methotrexate: Ibrutinib may increase the serum concentration of Methotrexate. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Ibrutinib. Monitor therapy

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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 monograph for details. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

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

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

St John's Wort: May decrease the serum concentration of Ibrutinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Ibrutinib. 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 and the voriconazole dose. See full monograph for details. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (12% to 35%), hypertension (12% to 16%)

Dermatologic: Skin rash (12% to 29%), skin infection (14% to 18%), pruritus (11% to 14%)

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

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

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

Hematologic & oncologic: Thrombocytopenia (33% to 69%; grades 3/4: 5% to 17%; grade 4: 3% to 8%), neutropenia (22% to 53%; grades 3/4: 13% to 29%; grade 4: 2% to 13%), bruise (12% to 51%; grades 3/4: ≤2%), hemorrhage (≤44%; grades ≥3: ≤6%), decreased hemoglobin (13% to 43%; grades 3/4: ≤13%), petechia (11% to 16%), second primary malignant neoplasm (10% to 12%; grades ≥3: 2%)

Infection: Infection (grade ≥3: 24%)

Nervous system: Fatigue (18% to 57%), dizziness (11% to 20%), headache (12% to 18%), anxiety (16%), chills (12%)

Neuromuscular & skeletal: Musculoskeletal pain (14% to 40%), muscle spasm (11% to 29%), arthralgia (11% to 24%), asthenia (14%), arthropathy (13%)

Ophthalmic: Dry eye syndrome (17%), increased lacrimation (13%), blurred vision (10% to 13%), decreased visual acuity (11%)

Respiratory: Upper respiratory tract infection (16% to 47%), dyspnea (10% to 27%), cough (13% to 22%), sinusitis (11% to 22%), pneumonia (11% to 21%), epistaxis (11% to 19%), oropharyngeal pain (14%), bronchitis (11%)

Miscellaneous: Fever (12% to 25%), falling (17%)

1% to 10%:

Cardiovascular: Atrial fibrillation (≤9%), atrial flutter (≤9%), subdural hematoma (grades ≥3: ≤3%), ventricular tachycardia (1%)

Endocrine & metabolic: Weight loss (10%)

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

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

Hematologic & oncologic: Skin carcinoma (non-melanoma; 6%), anemia (grades 3/4: 3%), postprocedural hemorrhage (grades ≥3: ≤3%)

Infection: Sepsis (10%)

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

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

<1%, postmarketing, and/or case reports: Abnormal platelet aggregation (Kamel 2015), acute anaphylactic shock, angioedema, hepatic cirrhosis, hepatic failure, hyponatremia (Burger 2015), interstitial pulmonary disease, onychoclasis, panniculitis, peripheral neuropathy, pneumonia due to Pneumocystis jirovecii, pneumonitis (Mato 2016), progressive multifocal leukoencephalopathy, reactivation of HBV, renal failure syndrome, Stevens-Johnson syndrome, tumor lysis syndrome, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Serious (and some fatal) cardiac arrhythmias have occurred with therapy, including ≥ grade 3 atrial fibrillation, atrial flutter, and ventricular tachyarrhythmias. 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 particularly in patients with cardiac risk factors, hypertension, infections (acute), or with a history of arrhythmias. Monitor periodically for clinical symptoms of cardiac arrhythmias (eg, palpitations, light-headedness, syncope, chest pain); an ECG should be performed if symptoms or new-onset dyspnea develop. Manage arrhythmias appropriately; for persistent events, evaluate the risks and benefits of ibrutinib treatment and dose modification.
• 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. Monitor blood counts monthly or as clinically necessary. 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). Monitor for leukostasis, particularly in patients experiencing a rapid increase in lymphocytes to >400,000/mcL.
• 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. Monitor for signs and symptoms of bleeding. Patients receiving concurrent antiplatelet or anticoagulant treatment have an increased risk for bleeding; consider the risks and benefits of concurrent antiplatelet or anticoagulant therapy. 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.
• Hypertension: Hypertension has been reported with ibrutinib therapy. The median onset of grade 3 hypertension was 5 months (range: 0.03 to 24 months). Monitor blood pressure for new onset hypertension or hypertension that is not adequately controlled after treatment initiation. May require 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). Monitor and evaluate for fever and other signs/symptoms of infection and manage appropriately. Consider prophylaxis (according to standard of care) for patients at increased risk for opportunistic infections.
• Progressive multifocal encephalopathy: Progressive multifocal encephalopathy has been observed; evaluate for symptoms and manage appropriately.
• Renal toxicity: Renal failure has been reported with use; some cases were fatal. Clinical trials report serum creatinine increases of up to 3 × ULN; monitor renal function periodically and maintain hydration.
• Second primary malignancies: Patients treated with ibrutinib have developed second primary malignancies, including skin cancers and other 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. Dosage adjustment is recommended in patients with mild or moderate (Child-Pugh class A or B) impairment; avoid use in patients with severe (Child-Pugh class C) impairment. Monitor closely for toxicity.
• Renal impairment: While ibrutinib is minimally excreted by the kidney and exposure is not affected in patients with mild to moderate impairment, renal failure has been observed in studies. Use with caution in patients with preexisting renal impairment; has not been studied in those with severe impairment or in patients on dialysis.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: 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).

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 females of reproductive potential); monitor blood pressure; monitor for sign/symptoms of bleeding, infections, progressive multifocal encephalopathy, tumor lysis syndrome, second primary malignancies; signs/symptoms of cardiac arrhythmias; ECG prior to initiation (patients with cardiac risk factors or history of cardiac arrhythmias) and during therapy if clinically indicated. Monitor adherence.

Pregnancy

Pregnancy Considerations

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

Verify pregnancy status in females of reproductive potential prior to treatment initiation. Females of reproductive potential should avoid pregnancy during therapy and for up to 1 month after treatment cessation; males should avoid fathering a child during treatment and for 1 month after the last dose.

Patient Education

What is this drug used for?

• It is used to treat a type of lymphoma.
• It is used to treat a type of leukemia.
• It is used to treat Waldenstrom' macroglobulinemia (WM).
• It is used to treat graft versus host effects after a bone marrow transplant.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Lack of appetite
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Muscle pain
• Joint pain
• Anxiety
• Common cold symptoms
• Trouble sleeping
• Dry eyes
• Tearing
• Muscle spasms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Skin infection
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Chest pain
• Fast heartbeat
• Passing out
• Abnormal heartbeat
• Severe loss of strength and energy
• Severe headache
• Severe dizziness
• Vision changes
• Skin growths
• Mole changes
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.