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Ibrutinib

Pronunciation

(eye BROO ti nib)

Index Terms

  • BTK inhibitor PCI-32765
  • CRA-032765
  • PCI-32765

Dosage Forms

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

Capsule, Oral:

Imbruvica: 140 mg

Brand Names: U.S.

  • Imbruvica

Pharmacologic Category

  • Antineoplastic Agent
  • Antineoplastic Agent, Bruton Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Ibrutinib is a potent and irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an integral component of the B-cell receptor (BCR) and cytokine receptor pathways. Constitutive activation of B-cell receptor signaling is important for survival of malignant B-cells; BTK inhibition results in decreased malignant B-cell proliferation and survival.

Distribution

~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%

Special Populations: 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 patients with mild, moderate, or severe hepatic impairment as compared to patients with normal hepatic function in a single-dose hepatic impairment trial

Special Populations: Elderly

In patients between 67 to 81 years of age, exposure is predicted to increase by 14%.

Use: Labeled Indications

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

Waldenström macroglobulinemia: Treatment Waldenström macroglobulinemia

Contraindications

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

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

Dosing: Adult

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Oral: 420 mg once daily (either as monotherapy or in combination with bendamustine and rituximab); continue until disease progression or unacceptable toxicity (Byrd 2014; Chanan-Khan 2016).

CLL/SLL with 17p deletion: Oral: 420 mg once daily; continue until disease progression or unacceptable toxicity (Byrd 2014).

Mantle cell lymphoma (MCL), previously treated: Oral: 560 mg once daily; continue until disease progression or unacceptable toxicity (Wang 2013; Wang 2015).

Waldenström macroglobulinemia (WM): Oral: 420 mg once daily; continue until disease progression or unacceptable toxicity (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 capsules to make up for the missed dose.

Dosage adjustment for concomitant therapy:

Moderate or strong CYP3A inhibitors:

US labeling: Avoid concurrent use with moderate or strong CYP3A inhibitors which are taken chronically; consider an alternative agent with less CYP3A inhibition. If short term use (≤7 days) of a strong inhibitor is necessary, consider withholding ibrutinib therapy until the strong CYP3A inhibitor is discontinued. If concomitant use of a moderate inhibitor is necessary, reduce ibrutinib dose to 140 mg once daily. Monitor closely for toxicity during concomitant use.

Canadian labeling: Avoid concurrent use with moderate or strong CYP3A inhibitors; consider an alternative agent with less CYP3A inhibition. If use of a strong inhibitor is necessary, withhold ibrutinib temporarily until the strong CYP3A inhibitor is discontinued. If concomitant use of a moderate inhibitor is necessary, reduce ibrutinib dose to 140 mg once daily until the inhibitor is discontinued. Monitor closely for toxicity during concomitant use.

Strong CYP3A inducers: Avoid concurrent use with strong CYP3A inducers; consider alternative agents with less CYP3A induction.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥25 mL/minute (US labeling) or CrCl >30 mL/minute (Canadian labeling): 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 (US labeling) or CrCl ≤30 mL/minute (Canadian labeling): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

End-stage renal disease (ESRD) requiring dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

US labeling:

Mild impairment (Child-Pugh class A): Reduce dose to 140 mg once daily.

Moderate and severe impairment (Child-Pugh class B and C): Avoid use.

Canadian labeling:

Mild impairment (Child-Pugh class A): May consider dose reduction to 140 mg once daily (based on preliminary data) only if clinically indicated; monitor closely.

Moderate and severe impairment (Child-Pugh class B and C): Avoid use.

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 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

Mantle cell 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

Administration

Administer orally with water at approximately the same time every day. Swallow capsules whole; do not open, break, or chew the capsules. 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).

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of an intact capsule (NIOSH 2014).

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

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

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

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

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. 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

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

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

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

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. Monitor therapy

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. 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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

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

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

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

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. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Ibrutinib. Monitor therapy

Adverse Reactions

Incidences combined for mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), and Waldenström macroglobulinemia (WM), unless otherwise specified.

>10%:

Cardiovascular: Peripheral edema (MCL: 35%, CLL/SLL: 19% to 22%), hypertension (6% to 17%; CLL/SLL: 14% to 16%; grades 3/4: CLL/SLL: 4% to 8%)

Central nervous system: Fatigue (MCL: 41%, CLL/SLL, WM: 21% to 33%), dizziness (11% to 20%), headache (12% to 18%), chills (CLL/SLL: 12%)

Dermatologic: Skin rash (21% to 25%), skin infection (14% to 16%; grades 3/4: 2% to 6%), pruritus (WM: 11%)

Endocrine & metabolic: Increased uric acid (MCL: 40%; increased uric acid >10 mg/dL: MCL: 13%), hyperuricemia (MCL: 15%), dehydration (MCL: 12%)

Gastrointestinal: Diarrhea (CLL/SLL, MCL: 42% to 59%, WM: 37%), nausea (20% to 31%), constipation (CLL/SLL, MCL: 15% to 25%), abdominal pain (MCL: 24%, CLL/SLL: 14%), vomiting (CLL/SLL, MCL: 14% to 23%), decreased appetite (CLL/SLL, MCL: 16% to 21%), stomatitis (14% to 20%), gastroesophageal reflux disease (WM: 13%), dyspepsia (CLL/SLL, MCL: 11% to 12%)

Genitourinary: Urinary tract infection (CLL/SLL, MCL: 10% to 14%; grades 3/4: CLL/SLL, MCL: 1% to 4%)

Hematologic & oncologic: Thrombocytopenia (CLL/SLL, MCL: 52% to 69%, WM: 43%; grades 3/4: 5% to 17%), neutropenia (44% to 53%; grades 3/4: 19% to 29%), bruise (12% to 51%; grades 3/4: CLL/SLL: ≤2%), anemia (CLL/SLL, MCL: 36% to 43%, WM: 13%; grades 3/4: ≤9%), petechia (CLL/SLL, MCL: 11% to 16%), malignant neoplasm (secondary; 5% to 16%; non-melanoma skin cancer was most frequently reported; also includes carcinoma and one case of histiocytic sarcoma)

Infection: Infection (≥grade 3: 14% to 29%)

Neuromuscular & skeletal: Musculoskeletal pain (CLL/SLL, MCL: 25% to 37%), arthralgia (CLL/SLL: 16% to 24%, MCL: 11%), muscle spasm (11% to 21%), weakness (CLL/SLL, MCL: 14%), arthropathy (WM: 13%)

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

Respiratory: Upper respiratory tract infection (16% to 47%; grades 3/4: CLL/SLL: 1% to 2%), dyspnea (MCL: 27%, CLL/SLL: 12%), sinusitis (11% to 22%; grades 3/4: CLL/SLL, MCL: 1% to 6%), cough (13% to 22%), epistaxis (MCL, WM: 11% to 19%), pneumonia (12% to 15%; grades 3/4: 6% to 10%), oropharyngeal pain (CLL/SLL: 14%)

Miscellaneous: Fever (CLL/SLL, MCL: 17% to 25%; grades 3/4: CLL/SLL, MCL: ≤2%)

1% to 10%:

Cardiovascular: Atrial fibrillation (≤6% to 9%), atrial flutter (≤6% to 9%)

Hematologic & oncologic: Hemorrhage (≤6%; grade 3 or higher bleeding events including gastrointestinal bleeding, hematuria, postprocedural bleeding, intracranial hemorrhage, subdural hematoma)

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

<1% (Limited to important or life threatening): Hepatic failure, hypersensitivity (includes anaphylactic shock, angioedema, urticaria), pneumonitis (Mato 2016), progressive multifocal leukoencephalopathy, renal failure, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Atrial fibrillation and atrial flutter have occurred, particularly in patients with cardiac risk factors, hypertension, infections (acute), or with a history of atrial fibrillation. Monitor periodically for clinical symptoms of atrial fibrillation (eg, palpitations, light-headedness); an ECG should be performed if symptoms or new-onset dyspnea develop. Manage atrial fibrillation appropriately; for persistent atrial fibrillation, evaluate the risk-benefit 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 or driving).

• Gastrointestinal toxicity: Diarrhea has been commonly observed; maintain adequate hydration.

• Hematologic effects: Grade 3 and 4 neutropenia, thrombocytopenia, and anemia occurred commonly during clinical studies. 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: Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and postprocedural bleeding) have occurred; some events were fatal. Bleeding events of any grade, including bruising and petechiae have occurred in approximately half of patients receiving ibrutinib. Monitor for signs of bleeding. Patients receiving concurrent antiplatelet or anticoagulant treatment may have an increased risk for bleeding. Evaluate the risk-benefit of withholding ibrutinib for 3 to 7 days prior to and after surgery, depending on the procedure type and risk of bleeding. Due to the increased risk of bleeding, the Canadian label recommends avoiding concomitant warfarin or other vitamin K antagonists with ibrutinib.

• Hypertension: Hypertension has been reported with ibrutinib therapy. The median onset of hypertension was 4.6 months (range: 0.03 to 22 months). Monitor for new onset hypertension or hypertension that is not adequately controlled after treatment initiation. May require antihypertensive therapy or adjustment of existing antihypertensive regimen.

• Infections: Serious infections (some fatal) have been observed; evaluate for fever and other signs/symptoms of infection and manage appropriately.

• Progressive multifocal encephalopathy: Progressive multifocal encephalopathy (PML) 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 times 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. Evaluate for sign/symptoms of 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 (Child-Pugh class A) impairment; avoid use in patients with moderate or severe (Child-Pugh class B or 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 pre-existing 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:

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

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 women of childbearing potential); sign/symptoms of bleeding, infections, progressive multifocal encephalopathy, tumor lysis syndrome, and second primary malignancies; signs/symptoms of atrial fibrillation; ECG prior to initiation (patients with cardiac risk factors or history of atrial fibrillation) and during therapy if clinically indicated.

Pregnancy Considerations

Based on animal reproduction studies, may cause fetal harm if administered during pregnancy. For women of childbearing potential, verify pregnancy status prior to treatment initiation. The US labeling recommends women of reproductive potential avoid pregnancy during therapy and for 1 month after treatment cessation; males should avoid fathering a child during treatment and for 1 month after the last dose. The Canadian labeling recommends women of reproductive potential use highly effective contraception during and for 3 months after completion of treatment. If using a hormonal method of contraception, add a barrier method; male patients should use a condom (during and for 3 months after completion of treatment) when engaging in sexual activity with a pregnant woman.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, nausea, vomiting, abdominal pain, constipation, muscle pain, joint pain, or muscle spasms. Have patient report immediately to prescriber signs of infection, signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), shortness of breath, excessive weight gain, swelling of arms or legs, burning or numbness feeling, angina, tachycardia, passing out, abnormal heartbeat, severe diarrhea, severe loss of strength and energy, dry mouth, dry skin, severe headache, dizziness, vision changes, skin growths, or mole changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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