Imbruvica

/ Janssen

Mantle Cell Lymphoma: The recommended dose  for MCL is
560 mg (four 140 mg capsules) orally once daily.
Chronic Lymphocytic Leukemia: The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once daily.

Indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

None

Hemorrhage: Fatal bleeding events have occurred in patients who received ibrutinib. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% patients who received ibrutinib in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received ibrutinib. This drug may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.
Consider the benefit-risk of withholding it for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections: Fatal and non-fatal infections have occurred with this therapy. Grade 3 or greater infections occurred in 21% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with ibrutinib. Deaths due to cardiac causes or sudden deaths occurred in clinical trials. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events. Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure, and consider the risks and benefits of continued treatment.
Hypertension: Hypertension occurred in 19% of 1,476 patients who received ibrutinib in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months). Monitor blood pressure, initiate or adjust anti-hypertensive medication throughout treatment with Ibrutinib as appropriate.
Cytopenias: In 645 patients with B-cell malignancies who received ibrutinib as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements.
Second Primary Malignancies: Malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients who received ibrutinib in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).
Hepatotoxicity, Including Drug-Induced Liver Injury: Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including ibrutinib. Evaluate bilirubin and transaminases at baseline and throughout treatment. For patients who develop abnormal liver tests after ibrutinib, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold treatment. Upon confirmation of DILI, discontinue.
Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) has been infrequently reported. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity: Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.
See prescribing information for full details.

The following adverse reactions are discussed in more detail in the special precaution section above:
• Hemorrhage
• Infections
• Myelosuppression
• Renal Toxicity.
• Second Primary Malignancies.
Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.
For full details see prescribing information.

Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.
CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ⋅ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration it with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for
7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting dhis drug herapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate
CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A.
CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction. 

Pregnancy: Pregnancy Category D. Risk Summary Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
Nursing Mothers: 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.