Ibrutinib

Ibrutinib is a prescription medication used as an inhibitor of Bruton's tyrosine kinase (BTK) used to treat patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Ibrutinib is available under the following different brand names: Imbruvica.

Adult Dosages:

Capsule

• 140 mg

Dosage Considerations – Should be Given as Follows:

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Indicated for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) including patients who are treatment-naïve or have been previously treated; also indicated for patients who carry a deletion in chromosome 17 (del 17p CLL), which is associated with poor responses to standard treatment
• 420 mg (three 140-mg capsules) orally once daily until unacceptable toxicity or disease progression

• In combination with bendamustine and rituximab
  • Ibrutinib 420 mg orally each day plus bendamustine and rituximab administered every 28 days for up to 6 cycles until disease progression or unacceptable toxicity

Mantle Cell Lymphoma

• Indicated for mantle cell lymphoma in patients who have received at least 1 previous therapy
• 560 mg (four 140-mg capsules) orally once daily
• Continue until disease progression or unacceptable toxicity

Waldenström Macroglobulinemia

• Indicated for all lines of therapy for Waldenström macroglobulinemia (WM), a rare, indolent type of non-Hodgkin lymphoma (B-cell lymphoma)
• 420 mg (three 140-mg capsules) orally once daily

Marginal Zone Lymphoma

• Indicated for marginal zone lymphoma (MZL) in patients who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• 560 mg (four 140-mg capsules) orally once daily
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

Interrupt or discontinue therapy

• Interrupt therapy for any non-hematological toxicity Grade 3 or greater, neutropenia with infection or fever Grade 3 or greater, or Grade 4 hematological toxicities
• Reinitiate ibrutinib at the starting dose (indicated specific) once toxicities have resolved to Grade 1 or baseline (recovery)
• If the toxicity reoccurs, reduce dose by 1 capsule (140 mg/day)
• A second reduction of dose by 140 mg may be considered as needed
• Discontinue if these toxicities persist or recur following 2 dose reductions

CYP3A inhibitors

• Avoid coadministration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition
• Concomitant use of strong CYP3A inhibitors which would be taken chronically (ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended
• Short-term use (7 days or less) of strong CYP3A inhibitors: Consider interrupting ibrutinib until CYP3A inhibitor is no longer needed
• Coadministration with moderate CYP3A inhibitors (fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin): Reduce dose to 140 mg daily

CYP3A inducers

• Strong CYP3A inducers decrease ibrutinib plasma concentrations by approximately 10-fold
• Avoid concomitant use of strong CYP3A inducers (carbamazepine, rifampin, phenytoin, St. John's Wort)
• Consider alternative agents with less CYP3A induction

Hepatic impairment

• Mild (Child Pugh class A): 140 mg orally once daily
• Moderate-to-severe (Child Pugh Classes B and C): Avoid use

Pediatric Use

• Not indicated.

Dosage Considerations

• Indications for mantle cell lymphoma and marginal cell lymphoma is based on overall response rate (both received accelerated approval from the FDA); an improvement in survival or disease-related symptoms has not been established
• Available via a limited distributed system from specialty pharmacies

Common side effects of ibrutinib include:

• abdominal pain
• anemia
• anxiety
• bruising
• chills
• constipation
• cough
• decreased appetite
• dehydration
• diarrhea
• dizziness
• difficult breathing
• fatigue
• fever
• headache
• decreased hemoglobin levels
• bleeding
• high blood pressure (hypertension)
• increased serum creatinine, 1.5 times upper limit of normal (ULN)
• indigestion
• insomnia
• joint pain
• low platelet count
• muscle spasms
• musculoskeletal pain
• nausea
• decreased white blood cells
• nosebleed
• persistent sore throat
• numbness and tingling
• small, round spots on the skin
• platelets decreased
• pneumonia
• rash
• secondary primary malignancies
• shortness of breath
• sinus infection
• skin infections
• inflamed and sore mouth
• swelling of the extremities
• swelling of the mouth and lips
• upper respiratory tract infection
• urinary tract infection
• vomiting
• weakness

Postmarketing side effects of ibrutinib include:

• fatal bleeding events
• tumor lysis syndrome reported; use caution
• interstitial lung disease

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

• Ibrutinib has no known severe interactions with other drugs.
• Ibrutinib has serious interactions with 58 different drugs.
• Moderate interactions of ibrutinib include:
  • dabigatran
  • mitotane
  • naldemedine
• Ibrutinib has no known minor interactions with other drugs.

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns or for more information about this medicine.

Warnings

This medication contains ibrutinib. Do not take Imbruvica if you are allergic to ibrutinib or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• Documented hypersensitivity.

Effects of Drug Abuse

• None

Short-Term Effects

• See "What Are Side Effects Associated with Using Ibrutinib?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Ibrutinib?"

Cautions

• Fatal and non-fatal infection reported; 25-26% of patients had Grade 3 or higher.
• Myelosuppression reported (neutropenia 23-29%, thrombocytopenia 5-17%, anemia up to 9%); monitor complete blood count (CBC) monthly.
• Atrial fibrillation (AF) and flutter (6-9%) reported, particularly in patients with cardiac risk factors, acute infections, or a history of previous atrial fibrillation; periodically monitor; if AF occurs and persists, consider dose modifications or alternate treatment.
• Fatal and serious cases of renal failure have occurred; treatment-emergent increases in creatinine levels up to 1.5 times upper limit of normal (ULN) occurred in 67% (MCL) and 23% (CLL) and from 1.5-3 times upper limit of normal in 9% (MCL) and 4% (CLL); periodically monitor creatinine levels and maintain hydration.
• Other malignancies (5-14%) reported including carcinomas (1-3%); the most frequent second primary malignancy was nonmelanoma skin cancer (4-11%).
• Hypertension reported with a median time to onset of 4.5 months; monitor for new onset hypertension or hypertension that is not adequately controlled after initiating ibrutinib.
• Tumor lysis syndrome infrequently reported; assess the baseline risk (high tumor burden) and take appropriate precautions.
• Based on findings in animals, can cause fetal harm when administered to a pregnant woman.
• Metabolized in the liver; although no clinical trials have been completed in patients with impaired hepatic function, ibrutinib systemic exposure was approximately 6-fold higher in patients (N=3) with moderate hepatic impairment (Child-Pugh B) compared to healthy volunteers.
• Avoid grapefruit and Seville oranges during treatment, as these contain moderate inhibitors of CYP3A (also see Dosage Modifications).
• Hemorrhage
  • Grade 3 or higher, bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria) occur in up to 6%; bleeding events of any grade, including bruising and petechiae, occurred in about 50% of patients treated.
  • The mechanism for the bleeding events is not well understood.
  • Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.
  • Consider the benefit-risk of withholding ibrutinib for at least 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Pregnancy and Lactation

• Use ibrutinib during pregnancy only in LIFE-THREATENING emergencies when no safer drug is available.
• There is positive evidence of human fetal risk.
• Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant woman.
• If ibrutinib is used during pregnancy or if the patient becomes pregnant while taking ibrutinib, the patient should be apprised of the potential hazard to the fetus.
• Advise women to avoid becoming pregnant while taking ibrutinib and for 1 month after discontinuing treatment.
• In pregnant rats during the period of organogenesis, 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss; 80 mg/kg/day in animals is about 14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
• It is unknown if ibrutinib is distributed in human breast milk; consult your physician if breastfeeding.