eye- BROO-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• Mantle cell lymphoma in patients who have not responded to 1 previous therapy.
• Marginal zone lymphoma in patients who require systematic therapy and have received 1 anti-CD20–based therapy.
• Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (as monotherapy or in combination with rituximab or obinutuzumab or with bendamustine and rituximab).
• CLL/small lymphocytic leukemia in patients with the 17p deletion (as monotherapy or in combination with rituximab or obinutuzumab or with bendamustine and rituximab).
• Waldenström’s macroglobulinemia (as monotherapy or in combination with rituximab).
• Chronic graft-versus-host disease (cGVHD) after failure of 1 line of systemic therapy.

• Binds to and inactivates Bruton’s tyrosine kinase (BTK). Inhibits malignant B-cell proliferation. A deletion in chromosome 17 (17p deletion) is associated with poor responses to standard treatment for CLL.

• Decreased progression of mantle cell lymphoma.
• Decreased progression of and improved survival with CLL/small lymphocytic leukemia.
• Decreased progression of Waldenström’s macroglobulinemia.
• Decreased progression of marginal zone lymphoma.
• Reduced severity of cGVHD,

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 97.3%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A isoenzymes. One minor metabolite has antineoplastic activity. Metabolites are mostly eliminated in feces (80%), <10% excreted in urine.

Half-life: 4–6 hr.

(response)

†Median time to response.

Contraindicated in:

• Severe hepatic impairment
• Concurrent use of strong CYP3A4 inducers/inhibitors (other than posaconazole or voriconazole)
• Total bilirubin level >3× upper limit of normal (ULN) (unless due to non-hepatic cause or Gilbert's syndrome) (for cGVHD)
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Mild or moderate hepatic impairment (↓ dose)
• Concurrent use of moderate CYP3A4 inhibitors, posaconazole, or voriconazole (↓ ibrutinib dose)
• Concurrent use of antiplatelet agents/anticoagulants (↑ risk of bleeding)
• Surgical procedures (if possible withhold for 3–7 days pre- and postoperatively
• Cardiac risk factors, acute infections, history of cardiac arrhythmias (↑ risk of cardiac arrhythmias)
• Rep: Women and men of reproductive potential
• Pedi: Safety and effectiveness not established in children.

CV: hypertension, peripheral edema, atrial fibrillation/flutter, HF, SUDDEN CARDIAC DEATH, VENTRICULAR ARRHYTHMIAS.

EENT: rash.

GI: abdominal pain, constipation, ↓appetite, diarrhea, vomiting.

GU: RENAL FAILURE.

Hemat: thrombocytopenia, anemia, BLEEDING, NEUTROPENIA.

MS: musculoskeletal pain.

Neuro: fatigue, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), STROKE, transient ischemic attack.

Resp: dyspnea.

Misc: infection, MALIGNANCY, tumor lysis syndrome.

Drug-Drug:

• Chronic concurrent use of strong CYP3A inhibitors including clarithromycin, cobicistat, conivaptan, diltiazem, idelalisib, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, and ritonavir significantly ↑ levels and should be avoided. If short term use of strong CYP3A inhibitors is necessary, ibrutinib may be temporarily interrupted.
• Moderate CYP3A inhibitors, including aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib or verapamil↑ levels and the risk of toxicity; if concurrent therapy is necessary, ↓ ibrutinib dose in patients with mantle cell lymphoma, marginal zone lymphoma, CLL/small lymphocytic leukemia, or Waldenström’s Macroglobulinemia; in patients with cGVHD, ibrutinib dose may be modified if adverse reactions develop.
• Posaconazole and voriconazole↑ levels and the risk of toxicity; if voriconazole is necessary, ↓ ibrutinib dose; if concurrent therapy with posaconazole is necessary, concurrent therapy may need to be avoided or dose of ibrutinib may need to be ↓ based on dose of posaconazole used.
• Concurrent therapy with strong CYP3A inducers, including carbamazepine, enzalutamide, phenytoin, and rifampin significantly ↓ blood levels and effectiveness and should be avoided.
• Concurrent use of antiplatelet agents or anticoagulants↑ risk of bleeding.

Natural-Natural Products:

• Concurrent use of St. John's wort↓ blood levels and effectiveness and should be avoided.

Natural-Food Products:

• Grapefruit juice or Seville oranges↑ blood levels and the risk of toxicity, avoid concurrent ingestion.

Mantle Cell Lymphoma or Marginal Zone Lymphoma

• PO (Adults): 560 mg once daily until disease progression or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors — 280 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily — 140 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily — 70 mg once daily until disease progression or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors — Avoid concurrent use.

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia or Waldenström’s Macroglobulinemia

• PO (Adults): 420 mg once daily until disease progression or unacceptable toxicity; if given with rituximab or obinutuzumab, administer ibrutinib before the rituximab or obinutuzumab when given on the same day; Concurrent use of moderate CYP3A inhibitors — 280 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily — 140 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily — 70 mg once daily until disease progression or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors — Avoid concurrent use.

Chronic Graft-Versus-Host Disease

• PO (Adults and Children 12 yr): 420 mg once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors — 420 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily — 280 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily — 140 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors — Avoid concurrent use.
• PO (Children 1–11 yr): 240 mg/m² (max = 420 mg) once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m²; capsule, tablets, or oral suspension can be used if BSA >0.7 m²); Concurrent use of moderate CYP3A inhibitors — 240 mg/m² (max = 420 mg) once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m²; capsule, tablets, or oral suspension can be used if BSA >0.7 m²); Concurrent use of voriconazole suspension 9 mg/kg twice daily — 160 mg/m² once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m²; capsule, tablets, or oral suspension can be used if BSA >0.7 m²); Concurrent use of posaconazole — 80 mg/m² once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m²; capsule, tablets, or oral suspension can be used if BSA >0.7 m²);Concurrent use of other strong CYP3A inhibitors — Avoid concurrent use.

(Generic available)

• Capsules: 70 mg; 140 mg;
• Tablets: 140 mg; 280 mg; 420 mg; 560 mg;
• Oral suspension: 70 mg/mL;

• Assess for signs and symptoms of infection (fever, chills) during therapy. Consider prophylaxis.
• Monitor for signs and symptoms of bleeding (blood in stools or urine, prolonged or uncontrolled bleeding) during therapy.
• Assess cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (ECG, echocardiogram) for patients who develop symptoms of arrhythmia (palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns.
• Monitor BP frequently during therapy. Begin or adjust antihypertensive medication as indicated.
• Interrupt therapy for any non-hematological toxicities Grade 3 until resolution to Grade 1 or baseline.
• Monitor for symptoms of cardiac arrhythmias (palpitations, lightheadedness, syncope, chest pain, new onset dyspnea) at baseline and periodically during therapy. If symptoms occur, obtain ECG and manage with antiarrhythmic therapy.
• Monitor blood pressure periodically during therapy. May cause hypertension requiring antihypertensive therapy.
• Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and/or dehydration). Prevent by maintain adequate hydration and correcting uric acid levels prior to starting ibrutinib.

• Verify negative pregnancy test before starting therapy.
  • Monitor CBC monthly; may cause neutropenia, thrombocytopenia, and anemia. Interrupt therapy for Grade 3 neutropenia with infection or fever, or Grade 4 hematological toxicities. When toxicity recovers to Grade 1, return to starting dose. If toxicity recurs, decrease dose by 140 mg/day to 420 mg/day. If toxicity recurs a 3rd time, reduce dose by 140 mg/day to 280 mg/day. If toxicity returns a 4th time, permanently discontinue ibrutinib.
  • Monitor serum creatinine levels periodically during therapy; may cause renal failure.

• Recommended Dose Reductions: Grade 2 cardiac failure:1st occurrence — If starting dose was 420 mg, restart at 280 mg daily. If starting dose was 240 mg/m², restart at 160 mg/m² daily. 2nd occurrence — If starting dose was 420 mg, restart at 140 mg daily. If starting dose was 240 mg/m², restart at 80 mg/m² daily. 3rd occurrence — discontinue ibrutinib. Grade 3 cardiac arrhythmias:If starting dose was 420 mg, restart at 280 mg daily. If starting dose was 140 mg/m², restart at 80 mg/m² daily. 3rd occurrence — discontinue ibrutinib. Grade 3 cardiac arrhythmias:1st occurrence — If starting dose was 420 mg, restart at 280 mg daily. If starting dose was 240 mg/m², restart at 160 mg/m² daily. 2nd occurrence — discontinue ibrutinib. Grade 3 or 4 cardiac failure or Grade 4 cardiac arrhythmias: Discontinue ibrutinib. Other Grade 3 or 4 nonhematological toxicities, Grade 3 or 4 neutropenia with infection or fever, or Grade 4 hematological toxicities: 1st occurrence — If starting dose was 420 mg, restart at 280 mg daily. If starting dose was 240 mg/m², restart at 160 mg/m² daily. 2nd occurrence — If starting dose was 420 mg, restart at 140 mg daily. If starting dose was 240 mg/m², restart at 80 mg/m² daily. 3rd occurrence — discontinue ibrutinib.
• PO: Administer once daily with a whole glass of water at the same time each day. DNC: Swallow capsule or tablet whole; do not open, break, crush, or chew.
  • Oral suspension is white to off-white. Do not remove the bottle adapter. Only use reusable 3-mL oral dosing syringes that come with suspension. Do not use the syringes for other patients or with other medicines.
  • Consider holding doses for 3–7 days before and after surgery.

• Instruct patient to take ibrutinib as directed, at the same time each day. Take missed doses as soon as remembered on same day and return to normal schedule; do not take extra capsules to make up for missed dose. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
• Caution patient to avoid grapefruit, grapefruit juice, and Seville oranges during therapy; may increase amount of ibrutinib in blood.
• Advise patient to maintain adequate hydration during therapy to prevent renal failure.
• Instruct patient to notify health care professional if signs and symptoms of infection, tumor lysis syndrome, or bleeding (blood in stools or black stools, pink or brown urine, unexpected bleeding or uncontrollable severe bleeding, vomiting blood or vomit that looks like coffee grounds, coughing up blood or blood clots, increased bruising, dizziness or weakness, confusion, change in speech, headache that last a long time) occur.
• Inform patient of risk of other types of cancer including skin cancer.
• Advise patient of common side effects: low blood platelet count, diarrhea, low white blood cell count, low red blood cell count, fatigue, muscle and bone pain, swelling legs and feet, upper respiratory tract infection, nausea, bruising, shortness of breath, constipation, rash, stomach pain, vomiting, decreased appetite. Instruct patient to notify health care professional if diarrhea is persistent.
• Advise patient to notify health care professional of medication regimen before treatment or surgery.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products, especially St. John's wort, being taken and to consult with health care professional before taking other medications.
• Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 1 mo following end of therapy and to avoid breastfeeding during and for 1 wk after last dose. Advise patient to notify health care professional if pregnancy is suspected or if breastfeeding.

• Decreased progression of mantle cell lymphoma.
• Decreased progression of CLL/small lymphocytic leukemia.
• Decreased progression of Waldenström’s macroglobulinemia.
• Decreased progression of marginal zone lymphoma.
• Reduced severity of cGVHD,

Imbruvica

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