Dosing and uses of Imbruvica (ibrutinib)
Adult dosage forms and 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
Waldenström Macroglobulinemia
Indicated for all lines of therapy for Waldenström macroglobulinemia (WM), a rare, indolent type of of non-Hodgkin lymphoma (B-cell lymphoma)
420 mg (three 140-mg capsules) PO qDay
Dosage modifications
Interrupt or discontinue therapy
- Interrupt therapy for any non-hematological toxicity ≥Grade 3, neutropenia with infection or fever ≥Grade 3, 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 (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended
- Short-term use (≤7 days) of strong CYP3A inhibitors: Consider interrupting ibrutinib until CYP3A inhibitor is no longer needed
- Coadministration with moderate CYP3A inhibitors (eg, 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 (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort)
- Consider alternative agents with less CYP3A induction
Hepatic impairment
- Mild (Child Pugh class A): 140 mg PO qDay
- Moderate-to-severe (Child Pugh Classes B and C): Avoid use
Dosing Considerations
Indication for mantle cell lymphoma is based on overall response rate; an improvement in survival or disease-related symptoms has not been established
Available via a limited distributed system from specialty pharmacies
Orphan Designations
Diffuse large B-cell lymphoma
Extranodal marginal zone lymphoma (mucosa associated lymphoid tissue [MALT type] lymphoma)
Follicular lymphoma
Multiple myeloma
Nodal marginal zone lymphoma
Splenic marginal zone lymphoma
Chronic graft vs host disease
Sponsor
- Pharmacyclics, Inc.; 995 E. Arques Avenue; Sunnyvale, CA 94085
Pediatric dosage forms and strengths
Safety and efficacy not established
Imbruvica (ibrutinib) adverse (side) 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
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
Pregnancy and 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.
Pharmacology of Imbruvica (ibrutinib)
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
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
