ibrutinib

General

Genetic Implications: Genetic Implications

Pronunciation:
eye- broo-ti-nib


Trade Name(s)

  • Imbruvica

Ther. Class.
antineoplastics

Pharm. Class.
kinase inhibitors

Indications

  • Mantle cell lymphoma (MCL) in patients who have not responded to at least one previous therapy.
  • Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL).
  • Genetic implication CLL/SLL in patients with the 17p deletion.
  • Waldenström's macroglobulinemia.
  • Marginal zone lymphoma (MZL) in patients who require systematic therapy and have received ≥1 anti-CD20–based therapy.
  • Chronic graft-versus-host disease (cGVHD) after failure of ≥1 line of systemic therapy.

Action

Genetic implication 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.

Therapeutic Effect(s):

  • Decreased progression of MCL.
  • Decreased progression of and improved survival with CLL/SLL.
  • Decreased progression of Waldenström's macroglobulinemia.
  • Decreased progression of MZL.
  • Reduced severity of cGVHD,

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 97.3%

Metabolism and Excretion: Mostly metabolized, primarily by the CYP3A enzyme system. One minor metabolite has antineoplastic activity. Metabolites are mostly eliminated in feces (80%), <10% excreted in urine.

Half-life: 4–6 hr.

TIME/ACTION PROFILE (response)

ROUTEONSETPEAKDURATION
PO1.9 mo†unknownunknown
†Median time to response.

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment;
  • Concurrent use of strong CYP3A4 inducers/inhibitors (other than posaconazole or voriconazole);
  • OB: May cause fetal harm; avoid pregnancy;
  • Lactation: Breastfeeding should be avoided.

Use Cautiously in:

  • Mild or moderate hepatic impairment (↓ dose of ibrutinib)
  • Concurrent use of moderate inhibitors of CYP3A4, posaconazole, or voriconazole (↓ dose of ibrutinib may be necessary);
  • Concurrent use of antiplatelet agents/anticoagulants (↑ risk of bleeding);
  • Surgical procedures (if possible withhold for 3–7 days pre- and post-operatively;
  • Cardiac risk factors, hypertension, acute infections, history of cardiac arrhythmias (↑ risk of cardiac arrhythmias)
  • Rep: Women and men of reproductive potential.

Adverse Reactions/Side Effects

CNS: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), fatigue

CV: VENTRICULAR ARRHYTHMIAS, hypertension, peripheral edema, atrial fibrillation/flutter

Resp: dyspnea

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

GU: RENAL FAILURE

EENT: rash

Hemat: BLEEDING, neutropenia, thrombocytopenia, anemia

MS: musculoskeletal pain

Misc: INFECTIONS, SECOND MALIGNANCIES, tumor lysis syndrome

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Natural-Natural:

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

natural food interaction

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

Route/Dosage

MCL or MZL

PO (Adults) 560 mg once daily until disease progression or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors, 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.

CLL/SLL or Waldenström's Macroglobulinemia

PO (Adults) 420 mg once daily until disease progression or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors, 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.

cGVHD

PO (Adults) 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 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 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 or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors–Avoid concurrent use.

Hepatic Impairment
PO (Adults) Mild hepatic impairment (Child–Pugh A)–140 mg once daily. Moderate hepatic impairment (Child–Pugh B)–70 mg once daily.

Availability

Capsules: 70 mg, 140 mg

Tablets: 140 mg, 280 mg, 420 mg, 560 mg

Assessment

  • Assess for signs and symptoms of infection (fever, chills) during therapy.
  • Monitor for signs and symptoms of bleeding (blood in stools or urine, prolonged or uncontrolled bleeding) during therapy.
  • 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) periodically during therapy. If symptoms occur, obtain ECG and manage with antiarrhythmic 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.

Lab Test Considerations: 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.

Potential Diagnoses

Implementation

  • PO Administer once daily with a whole glass of water at the same time each day. Swallow capsule whole; do not open, crush, or chew.
    • If therapy is interrupted for any adverse reactions, once symptoms have resolved to Grade 1 or baseline, reinitiate therapy at starting dose. If toxicity reoccurs, reduce dose by 1 capsule (140 mg/day); restart dose after first toxicity occurrence 560 mg/day; second occurrence at 420 mg/day, third occurrence at 280 mg/day, and if fourth toxicity occurs discontinue therapy.
    • Consider holding doses for 3–7 days before and after surgery.

Patient/Family Teaching

  • 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.
  • 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 being taken and to consult with health care professional before taking other medications.
  • Rep: Advise female patient to use effective contraception and avoid pregnancy and breastfeeding during and for at least 1 mo following end of therapy; may be harmful to fetus.

Evaluation/Desired Outcomes

  • Decreased progression of mantle cell lymphoma.
  • Decreased progression of CLL/SLL.
  • Decreased progression of Waldenström's macroglobulinemia.
  • Decreased progression of MZL.
  • Reduced severity of cGVHD,
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