依鲁替尼Imbruvica/伊布替尼ibrutinib

[Function and Indications] Ibrutinib Imbruvica is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior treatment. This indication is based on the overall response rate. Improvement in survival or disease-related symptoms has not been determined.

[Model and Specification] Capsules, 140 mg/120 tablets/box.

[Usage and Dosage] Oral, once a day, 4 tablets each time (i.e. 560 mg).

[Clinical Studies]
Mechanism of Action:
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with the cysteine ​​residue in the BTK active site, resulting in inhibition of BTK enzyme activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The role of BTK is to activate pathways required for B-cell trafficking, chemotaxis, and adhesion through B-cell surface receptor signals. Nonclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
> 90% occupancy of BTK active sites on peripheral mononuclear cells was observed up to 24 hours after ibrutinib doses ≥ 2.5 mg/kg/day (≥ 175 mg/day for a mean body weight of 70 kg) in patients with relapsed B-cell lymphoma.

PRECAUTIONS
5.1 Bleeding
Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria) occurred in 5% of MCL patients. Overall, bleeding events including bruising of any grade occurred in 48% of MCL patients treated with 560 mg daily.
The mechanism of bleeding events is not fully understood.
Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapy.
The benefit-risk of considering withholding ibrutinib for at least 3 to 7 days before and after surgery depends on the type of surgery and the risk of bleeding [see Clinical Studies (14.1)].
5.2 Infections
Fatal and non-fatal infections have occurred with IMBRUVICA treatment. At least 25% of patients with MCL had NCI Common Terminology for Adverse Events (CTCAE) Grade 3 or greater infections [see Adverse Reactions (6)]. Monitor patients for fever and infections and evaluate promptly.
5.3 Myelosuppression
Treatment-emergent Grade 3 or 4 pancytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%), and anemia (9%). Monitor complete blood counts monthly.
5.4 Renal Toxicity
Fatal and serious cases have occurred with IMBRUVICA treatment. Treatment-emergent increases in creatinine levels to 1.5 times the upper limit of normal occurred in 67% of patients and 1.5 to 3 times the upper limit of normal in 9% of patients. Monitor creatinine levels regularly. Maintain hydration.
5.5 Second Primary Malignancies
Other malignancies have occurred in patients with MCL treated with IMBRUVICA (5%), including skin cancer (4%), and other cancers (1%).
5.6 Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib was teratogenic in rats at exposures reported in patients with MCL receiving ibrutinib at a dose of 560 mg daily. Decreased fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

[Adverse Reactions and Contraindications]
The following adverse reactions are discussed in more detail in other sections of the labeling:
● Hemorrhage [see Warnings and Precautions (5.1)]
● Infection [see Warnings and Precautions (5.2)]
● Myelosuppression [see Warnings and Precautions (5.3)]
● Renal toxicity [see Warnings and Precautions (5.4)]
● Second primary malignancies [see Warnings and Precautions (5.5)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of another drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

[Pregnant Use] It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

[Pediatric Use] The safety and effectiveness of IMBRUVICA in pediatric patients have not been established.

[Drug Interactions]
8.6 Renal Impairment
Less than 1% of ibrutinib is renally excreted. Ibrutinib exposure was not altered in patients with creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Ibrutinib is metabolized in the liver and exposure to ibrutinib is expected to be significantly increased in patients with hepatic impairment. IMBRUVICA clinical trials excluded patients with serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) ≥ 3.0 × upper limit of normal (ULN). There are insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3)].

[Manufacturer] Ibrutinib Imbruvica was developed by Janssen Pharmaceuticals (janssen)