ibrutinib (Rx)

Brand and Other Names:Imbruvica
  • Print

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 140mg

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) PO qDay until unacceptable toxicity or disease progression

In combination with bendamustine and rituximab

  • Ibrutinib 420 mg PO qDay plus bendamustine and rituximab administered q28d 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) PO qDay

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) PO qDay

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) PO qDay

Continue until disease progression or unacceptable toxicity

Graft vs Host Disease

Indicated for adults with chronic graft versus host disease (cGVHD) after failure of ≥1 lines of systemic treatment

420 mg (three 140-mg capsules) PO qDay until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity occurs

When a patient no longer requires therapy for the treatment of cGVHD, ibrutinib should be discontinued, taking under consideration the medical assessment of the individual patient

Dosage Modifications

Interrupt or discontinue therapy

  • Interrupt therapy for any nonhematological toxicity ≥Grade 3, neutropenia with infection or fever ≥Grade 3, or Grade 4 hematological toxicities
  • Reinitiate ibrutinib at the starting dose (indication specific) once toxicities have resolved to ≤Grade 1
  • If 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

  • B-cell malignancies
    • Moderate CYP3A inhibitor, posaconazole ≤200 mg BID, or voriconazole (any dose): Reduce dose to 140 mg qDay; interrupt dose as described (see Interrupt or discontinue therapy)
    • Posaconazole >200 mg BID or other strong CYP3A inhibitors: Avoid concomitant use; if inhibitor used short-term (eg, anti-infectives ≤7 days), interrupt ibrutinib dosing
  • cGVHD
    • Moderate CYP3A4 inhibitor: 420 mg qDay; modify dose as described (see Interrupt or discontinue therapy)
    • Posaconazole 200 mg BID or 300 mg qDay, or voriconazole at any dose: 280 mg qDay; modify dose as described (see Interrupt or discontinue therapy)
    • Posaconazole at other higher doses or other strong CYP3A inhibitors: Avoid concomitant use; if inhibitor used short-term (eg, anti-infectives ≤7 days), interrupt ibrutinib dosing

CYP3A inducers

  • Strong CYP3A inducers decrease ibrutinib plasma concentrations by approximately 10-fold
  • Avoid coadministration of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort, enzalutamide, mitotane)

Hepatic impairment

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

Dosing Considerations

Indications for mantle cell lymphoma and marginal zone lymphoma are based on overall response rate (both received accelerated approval from the FDA); continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial

Available via a limited distributed system from specialty pharmacies

Orphan Designations

Diffuse large B-cell lymphoma

Follicular lymphoma

Multiple myeloma

Sponsor

  • Pharmacyclics, Inc.; 995 E. Arques Avenue; Sunnyvale, CA 94085

Safety and efficacy not established

Next:

Interactions

Interaction Checker

and ibrutinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 
            Previous
            Next:

            Adverse Effects

            Percentages are for all grades of toxicity unless otherwise noted

            >10% (MCL)

            Increased serum creatinine, 1.5 x ULN (67%)

            Platelets decreased, all grades (57%)

            Diarrhea (51%)

            Hemorrhage (48%)

            Neutrophils decreased, all grades (47%)

            Hemoglobin decreased, all grades (41%)

            Fatigue (41%)

            Musculoskeletal pain (37%)

            Peripheral edema (35%)

            URI infection (34%)

            Nausea (31%)

            Bruising (30%)

            Neutropenia, grades 3 or 4 (29%)

            Dyspnea (27%)

            Constipation (25%)

            Rash (25%)

            Abdominal pain (24%)

            Vomiting (23%)

            Decreased appetite (221%)

            Cough (19%)

            Pyrexia (18%)

            Stomatitis (17%)

            Thrombocytopenia, grades 3 or 4 (17%)

            UTI infection (14%)

            Pneumonia (14%)

            Skin infections (14%)

            Asthenia (14%)

            Muscle spasms (14%)

            Dizziness (14%)

            Sinusitis (13%)

            Headache (13%)

            Dehydration (12%)

            Dyspepsia (11%)

            Petechiae (11%)

            Arthralgia (11%)

            Epistaxis (11%)

            >10% (CLL)

            Platelets decreased, all grades (71%)

            Diarrhea (63%)

            Bruising (54%)

            Neutrophils decreased, all grades (54%)

            URT infection (48%)

            Hemoglobin decreased, all grades (44%)

            Fatigue (31%)

            Rash (27%)

            Musculoskeletal pain (27%)

            Neutropenia, grades 3 or 4 (27%)

            Pyrexia (25%)

            Peripheral edema (23%)

            Constipation (23%)

            Arthralgia (23%)

            Nausea (21%)

            Stomatitis (21%)

            Sinusitis (21%)

            Dizziness (21%)

            Vomiting (19%)

            Cough (19%)

            Muscle spasms (19%)

            Headache (19%)

            Skin infection (17%)

            Petechiae (17%)

            Decreased appetite (17%)

            Hypertension (17%

            Abdominal pain (15%)

            Oropharyngeal pain (15%)

            Dyspepsia (13%)

            Asthenia (13%)

            Chills (13%)

            1-10% (MCL)

            Anemia, grades 3 or 4 (9%)

            Increased serum creatinine, 1.5-3 x ULN (9%)

            Hemorrhage, grades 3 or 4 (5%)

            Secondary primary malignancies (5%)

            1-10% (CLL)

            Pneumonia (10%)

            UTI (10%)

            Dyspnea (10%)

            Peripheral neuropathy (10%)

            Second malignancies (10%)

            Anxiety (10%)

            Insomnia (10%)

            Thrombocytopenia, grades 3 or 4 (10%)

            Postmarketing reports

            Fatal bleeding events have occurred

            Tumor lysis syndrome reported; use caution

            Interstitial lung disease

            Previous
            Next:

            Warnings

            Contraindications

            None

            Cautions

            Fatal and non-fatal infection reported; 25-26% of patients had ≥Grade 3

            Myelosuppression reported (neutropenia 23-29%, thrombocytopenia 5-17%, anemia up to 9%); monitor CBC monthly

            Atrial fibrillation 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 x ULN occurred in 67% (MCL) and 23% (CLL) and from 1.5-3 x ULN 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 (eg, 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 ~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 bleeding events (subdural hematoma, GI bleeding, hematuria) occur in up to 6%; bleeding events of any grade, including bruising and petechiae, occurred in ~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
            Previous
            Next:

            Pregnancy & Lactation

            Pregnancy Category: D

            Based on findings in animals, can cause fetal harm when administered to a pregnant woman; if ibrutinib 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 ~14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily

            Lactation: Unknown if distributed in human breast milk

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

            more...
            Previous
            Next:

            Pharmacology

            Mechanism of Action

            Bruton’s tyrosine kinase (BTK) inhibitor; forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity; BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways

            BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion

            Absorption

            Peak plasma concentration: 1-2 hr

            AUC: 953 ± 705 ng•h/mL

            Administration with food increases ibrutinib exposure ~2-fold compared with administration after overnight fasting

            Distribution

            Protein bound: 97.3%

            Vd: 10,000 L

            Metabolism

            Metabolized to several metabolites primarily by cytochrome P450 CYP3A, and to a minor extent by CYP2D6

            Active metabolite: PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK ~15 times lower than that of ibrutinib

            Mean metabolite to parent ratio: 1:2.8

            Elimination

            Half-life: 4-6 hr

            Clearance: 1000 L/hr

            Excretion: 80% feces (as metabolites); 10% urine

            Previous
            Next:

            Administration

            Oral Administration

            Administer once daily at approximately the same time each day

            Swallow capsule whole, do not chew, break, open, or crush capsules

            Missed dose

            • Take missed dose as soon as possible on the same day and return to normal schedule the following day
            • Do not take extra capsules to make up for the missed dose
            Previous
            Next:

            Images

            Previous
            Next:

            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
            Email to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Email Forms to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Previous