IMBRUVICA
Clinical safety rating
cautionComprehensive clinical and safety monograph for IMBRUVICA (IMBRUVICA).
Comprehensive clinical and safety monograph for IMBRUVICA (IMBRUVICA).
Mantle cell lymphoma (MCL) in patients who have received at least one prior therapyChronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL)Waldenström's macroglobulinemia (WM)Relapsed or refractory marginal zone lymphoma (MZL) in patients who have received at least one prior anti-CD20-based therapyChronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapyRelapsed or refractory follicular lymphoma (off-label)
Headache, Fever, Diarrhea, Stomatitis (Inflammation of the mouth), Nausea, Low blood platelets, Decreased white blood cell count (neutrophils), Fatigue, Musculoskeletal (bone, muscle or joint) pain, Rash, Anemia (low number of red blood cells), Bruising, Muscle spasm, Hemorrhage, Pneumonia, Cough, Dry eye, High blood pressure, Weight loss, Urinary tract infection, Peripheral edema, Subdural hematoma, Second primary malignancies
Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inhibition of BTK activity. BTK is a key signaling molecule in the B-cell antigen receptor (BCR) and cytokine receptor pathways, which are involved in the survival, proliferation, and migration of malignant B cells.
| Metabolism | Ibrutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, and to a minor extent by CYP2D6. The major active metabolite is PCI-45227, which has similar inhibitory activity against BTK. Avoid coadministration with strong or moderate CYP3A4 inhibitors or inducers. |
| Excretion | Primarily via feces (approximately 80% as metabolites and parent drug); renal excretion accounts for <10% of the dose. |
| Half-life | Terminal elimination half-life is approximately 4–6 hours. No clinically relevant accumulation is observed at steady state. |
| Protein binding | Approximately 97.3% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | Volume of distribution is approximately 10,000 L (extremely large, indicating extensive tissue distribution, but not typically expressed in L/kg). |
| Bioavailability | Oral bioavailability is approximately 2.9% (low due to extensive first-pass metabolism and poor absorption; food increases exposure by about 60%). |
| Onset of Action | Oral: Clinical effect (such as lymphocytosis) can be observed within 1–2 weeks. |
| Duration of Action | Continuous dosing required; duration of action persists as long as steady-state concentrations are maintained. Drug effect wanes over several days after discontinuation. |
| Molecular Weight | 440.3 |
| Action Class | Bruton's tyrosine kinase (BTK) inhibitors |
| Brand Substitutes | Bdbrut Capsule, IB-Tib Capsule, Ibronza 140mg Capsule, Ibrushil 140mg Capsule, Ibrukem Capsule |
560 mg orally once daily for mantle cell lymphoma; 420 mg orally once daily for chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström's macroglobulinemia, marginal zone lymphoma, and chronic graft versus host disease.
| Dosage form | SUSPENSION |
| Renal impairment | No dose adjustment required for GFR ≥ 30 mL/min. For GFR < 30 mL/min, use with caution and monitor closely; no specific dose recommendation available. |
| Liver impairment | Child-Pugh A: 280 mg orally once daily (starting dose for CLL/SLL, WM, MZL, cGVHD) or 420 mg orally once daily (starting dose for MCL). Child-Pugh B: 140 mg orally once daily (CLL/SLL, WM, MZL, cGVHD) or 280 mg orally once daily (MCL). Child-Pugh C: Not recommended. |
| Pediatric use | Not approved for pediatric use. Safety and efficacy not established. |
| Geriatric use | No specific dose adjustment required; patients ≥65 years experienced higher incidence of certain adverse events (e.g., atrial fibrillation, hypertension) in clinical trials; monitor closely. |
| 1st trimester | Avoid in pregnancy; BTK inhibitor associated with teratogenicity in animal studies. |
| 2nd trimester | Avoid in pregnancy; potential fetal harm based on mechanism. |
| 3rd trimester | Avoid in pregnancy; may cause fetal harm and adverse neonatal outcomes. |
Clinical note
Comprehensive clinical and safety monograph for IMBRUVICA (IMBRUVICA).
| Placental transfer | Expected to cross placenta; low molecular weight and high plasma protein binding suggest limited transfer, but animal studies show fetal exposure and teratogenicity. |
| Breastfeeding | Not recommended during breastfeeding; likely present in milk based on molecular weight and lipid solubility; risk of infant toxicity. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Embryo-fetal toxicity risk. Based on mechanism of action (Bruton's tyrosine kinase inhibitor) and animal studies, there is potential for teratogenicity. Avoid use during pregnancy unless benefit outweighs risk. For first trimester: high risk due to critical organogenesis; second and third trimesters: may cause fetal harm, including low birth weight and developmental abnormalities. |
| Fetal Monitoring | Monitor pregnancy status prior to initiation; verify pregnancy in females of reproductive potential. Perform pregnancy testing before, during, and after treatment. Monitor for fetal heartbeat and growth if exposure occurs. Ensure effective contraception during treatment and for 1 month after last dose. |
| Fertility Effects | May impair male and female fertility based on animal studies. Reversible effects on spermatogenesis and ovarian function noted. In female rats, decreased ovulation and corpora lutea; in male dogs, testicular degeneration. Clinical significance in humans unknown. |
■ FDA Black Box Warning
Hemorrhage: Fatal and serious hemorrhagic events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3) has occurred in up to 6% of patients. Bleeding events include intracranial hemorrhage, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage. Monitor for signs of bleeding. Consider benefit-risk of surgery and the need for temporary interruption.
| Serious Effects |
Hypersensitivity to ibrutinib or any excipientConcurrent use with St. John's wortSevere hepatic impairment (Child-Pugh class C)
| Precautions | Hemorrhage: risk of bleeding, including fatal events; consider withholding for at least 3-7 days pre- and post-surgery, Infections: fatal and serious infections have occurred (e.g., pneumonia, sepsis); monitor for infections, Cytopenias: Grade 3/4 neutropenia, thrombocytopenia, and anemia may occur; monitor blood counts, Cardiac arrhythmias: atrial fibrillation and ventricular tachyarrhythmias; monitor electrocardiogram and manage as appropriate, Tumor lysis syndrome: risk in patients with high tumor burden; ensure adequate hydration and monitoring, Hypertension: monitor blood pressure and initiate antihypertensive therapy as needed, Second primary malignancies: including skin cancers and other carcinomas, Hepatotoxicity: elevations in liver enzymes; monitor hepatic function, Embryo-fetal toxicity: can cause fetal harm; advise women of reproductive potential to avoid pregnancy |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and pomelos. These fruits inhibit CYP3A4 and increase ibrutinib levels, raising toxicity risk (bleeding, arrhythmias). No other significant food interactions. |
| Clinical Pearls | Monitor for atrial fibrillation (ECG if palpitations), bleeding risk due to antiplatelet effect (hold 3-7 days before surgery), and tumor lysis syndrome (especially CLL with high lymphocytosis). CYP3A4 substrate: avoid strong inhibitors (ketoconazole, clarithromycin) and reduce dose with moderate inhibitors (fluconazole, diltiazem). Check for HBV reactivation before starting. |
| Patient Advice | Take with a full glass of water at the same time each day. Swallow capsules whole, do not open, break, or chew. · Do not drink grapefruit juice, Seville oranges, or pomelos while taking this medication. · Report any new or worsening bruising, bleeding, black/tarry stools, or pink/dark urine immediately. · Seek medical attention for symptoms of atrial fibrillation like palpitations, chest discomfort, or shortness of breath. · Avoid activities that increase bleeding risk (e.g., contact sports) until you know how the drug affects you. · Inform all healthcare providers (including dentists) that you are taking ibrutinib before any procedures. |
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