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Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood.
IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies].
Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See ADVERSE REACTIONS]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.
Monitor complete blood counts monthly.
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see DOSAGE AND ADMINISTRATION].
Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.5 months (range, 0.03 to 18.40 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.
Second Primary Malignancies
Other malignancies (range, 5 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 13%).
Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryofetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with MCL, CLL or WM. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
- Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see WARNINGS AND PRECAUTIONS].
- Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see WARNINGS AND PRECAUTIONS].
- Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see WARNINGS AND PRECAUTIONS].
- Hypertension: Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which may require treatment with anti-hypertensive therapy [see WARNINGS AND PRECAUTIONS].
- Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see WARNINGS AND PRECAUTIONS].
- Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see WARNINGS AND PRECAUTIONS].
- Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for 1 month after the last dose of IMBRUVICA [see WARNINGS AND PRECAUTIONS].
- Inform patients to take IMBRUVICA orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see DOSAGE AND ADMINISTRATION].
- Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see DOSAGE AND ADMINISTRATION].
- Advise patients of the common side effects associated with IMBRUVICA [see ADVERSE REACTIONS]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
- Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see DRUG INTERACTIONS].
- Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been conducted with ibrutinib.
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).
Use In Specific Populations
IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including malformation [see Data]. 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.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at 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 resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL or WM administered the dose of 560 and 420 mg daily, respectively.
There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.
The development and health benefits of breastfeeding should be considered along with the mother's clinical need for IMBRUVICA and any potential adverse effects on the breastfed child from IMBRUVICA or from the underlying maternal condition.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating IMBRUVICA therapy.
Advise females of reproductive potential to avoid pregnancy while taking IMBRUVICA and for up to 1 month after ending treatment. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.
Advise men to avoid fathering a child while receiving IMBRUVICA, and for 1 month following the last dose of IMBRUVICA.
The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.
Of the 552 patients in clinical studies of IMBRUVICA, 69% were ≥ 65 years of age, while 24% were ≥ 75 years of age. No overall differences in effectiveness were observed between younger and older patients. Grade 3 or higher pneumonia occurred more frequently among older patients treated with IMBRUVICA [see Clinical Studies].
Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function.
The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment.
Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh class B and C) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/4/2016
Additional Imbruvica Information
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