IBRUTINIB
Clinical safety rating
avoidContraindicated (not allowed)
Contraindicated (not allowed)
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)Marginal zone lymphoma (MZL) in patients who require systemic therapy and 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)
mantle cell lymphoma
Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in BTK's active site, leading to irreversible inhibition. BTK is essential for B-cell receptor signaling and survival of malignant B cells. Inhibition of BTK blocks pathways that promote B-cell proliferation, migration, and adhesion.
| Metabolism | Primarily metabolized by cytochrome P450 3A4 (CYP3A4). Minor metabolism by CYP2D6. The active metabolite is PCI-45227. |
| Excretion | Primarily fecal (80%) as metabolites, with renal excretion accounting for <10% (mostly as metabolites). |
| Half-life | Terminal half-life is approximately 4-6 hours, supporting twice-daily dosing for sustained BTK inhibition. |
| Protein binding | 97.3% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent Vd is approximately 10,000 L (large), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is 62% (range 52-74%) under fasted conditions; food increases AUC by 1.7-fold. |
| Onset of Action | Onset of clinical effect occurs within 1-2 weeks of starting oral therapy, with improvement in symptoms (e.g., lymphadenopathy) noted. |
| Duration of Action | Duration of action corresponds to the dosing interval (twice daily) with continuous BTK occupancy; effects persist for the duration of therapy. |
| Molecular Weight | 440.5 |
Adults: 560 mg orally once daily (4 capsules of 140 mg each) for mantle cell lymphoma; 420 mg once daily (3 capsules of 140 mg) for chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, or chronic graft-versus-host disease.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for creatinine clearance ≥25 mL/min. Insufficient data for patients with CrCl <25 mL/min or on dialysis. |
| Liver impairment | Child-Pugh class A: No adjustment. Child-Pugh class B: Reduce dose to 280 mg once daily. Child-Pugh class C: Reduce dose to 140 mg once daily. |
| Pediatric use | Adolescents (≥12 years): 420 mg once daily; weight-based dosing not established. For pediatric patients <12 years: not approved. |
| Geriatric use | No specific dose adjustment; monitor for cardiac adverse events (atrial fibrillation, hypertension) and bleeding risk due to higher incidence in elderly. |
| 1st trimester | Avoid due to potential fetal harm based on animal studies showing developmental toxicity. |
| 2nd trimester | Avoid; limited human data but embryofetal toxicity observed in animals. |
| 3rd trimester | Avoid; may cause fetal hematologic toxicity and interfere with B-cell development. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause bleeding infections and atrial fibrillation.
| Placental transfer | Evidence of placental transfer in animals; likely crosses human placenta given molecular weight and protein binding. |
| Breastfeeding | Unknown if excreted in human milk; due to potential serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment and for at least 1 week after last dose. |
| Lactation Rating | L5 |
| Teratogenic Risk | Based on animal studies and mechanism of action (BTK inhibition), ibrutinib is expected to cause fetal harm. In animal reproduction studies, ibrutinib was teratogenic and embryotoxic at exposures below the human AUC at the clinical dose. There are no adequate and well-controlled studies in pregnant women. Use during first trimester may cause structural abnormalities; second and third trimester use may impair fetal B-cell development and hematopoiesis. |
| Fetal Monitoring | Monitor complete blood counts (CBC) for anemia, neutropenia, thrombocytopenia; liver function tests (ALT, AST, bilirubin); blood pressure for hypertension; cardiac monitoring for atrial fibrillation/flutter; monitor for signs of infection, bleeding, and tumor lysis syndrome; fetal growth monitoring by ultrasound if exposure occurs during pregnancy. |
| Fertility Effects | Ibrutinib may impair fertility in females of reproductive potential based on animal studies showing ovarian effects at clinically relevant exposures. Reversibility unknown. In male patients, no specific fertility studies in humans; animal studies did not show impairment of male fertility. |
■ FDA Black Box Warning
Hemorrhage: Fatal bleeding events have occurred in patients receiving ibrutinib. Major hemorrhage (e.g., gastrointestinal, intracranial) has been reported. Monitor for signs of bleeding. Consider benefit-risk of holding ibrutinib for 3-7 days pre- and post-surgery depending on procedure.
| Common Effects | mantle cell lymphoma |
| Serious Effects |
Hypersensitivity to ibrutinib or any excipientConcurrent use with St. John's wort or strong CYP3A4 inducers
| Precautions | Hemorrhage: Increased risk of bleeding, especially in patients on anticoagulants or antiplatelet agents. Avoid concomitant use of warfarin., Infections: Fatal and serious infections (including bacterial, viral, fungal) have occurred. Consider prophylaxis in patients at increased risk., Cytopenias: Grade 3/4 neutropenia, thrombocytopenia, and anemia have occurred. Monitor blood counts monthly., Cardiac arrhythmias: Atrial fibrillation and atrial flutter have been reported. Monitor cardiac function, especially in patients with cardiac risk factors., Hypertension: New-onset or worsening hypertension has been reported. Monitor blood pressure and manage appropriately., Second primary malignancies: Other malignancies (including skin cancers) have occurred. Perform skin cancer monitoring., Tumor lysis syndrome: Risk is increased in patients with high tumor burden. Monitor and manage appropriately., Hepatotoxicity: Elevations in liver enzymes have been observed. Monitor hepatic function. |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and starfruit as they can increase drug levels and toxicity. Take with a full glass of water; may be taken with or without food but avoid high-fat meals as they may increase absorption variability. |
| Clinical Pearls | Monitor for atrial fibrillation (occurrence ~6-16%, higher risk in elderly). Obtain baseline ECG and monitor for bleeding due to antiplatelet effect (avoid concurrent anticoagulants unless necessary). Check for tumor lysis syndrome risk, especially in high tumor burden. Ibrutinib is a strong CYP3A4 inhibitor; avoid co-administration with sensitive CYP3A4 substrates or adjust doses. Monitor for hypertension and myelosuppression. |
| Patient Advice | Take exactly as prescribed; do not miss doses or stop without consulting your doctor. · Take capsules whole with water at the same time each day; do not open or chew. · Avoid grapefruit, Seville oranges, and starfruit during treatment. · Report any unusual bleeding, bruising, or black/tarry stools immediately. · Contact your healthcare provider if you experience irregular heartbeat, chest pain, or dizziness. · Use effective contraception during treatment and for 1 month after last dose. · Do not take with strong CYP3A4 inhibitors unless directed; avoid St. John's wort. |
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