Adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy. However, most people will not have to pay this much because most insurance plans and Medicare cover the cost of this medicine. BTK=Bruton's tyrosine kinase, CLL=chronic lymphocytic leukemia, DDI=drug-drug interaction, SLL=small lymphocytic lymphoma. This Instructions for Use contains information about how to prepare and give a dose of Imbruvica Oral Suspension. Mantle Cell Lymphoma and Marginal Zone Lymphoma. Prophylaxis for infections were managed per institutional guidelines with 79% of patients receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole derivatives. Patients age 12 years and older were treated with Imbruvica 420 mg orally once daily, and patients age 1 year to less than 12 years were treated with Imbruvica 240 mg/m2 orally once daily [see Clinical Studies (14.5)]. Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients. The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were White. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Imbruvica was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. IMBRUVICA may cause serious side effects, including: The most common side effects of IMBRUVICA in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include: The most common side effects of IMBRUVICA in adults or children 1 year of age and olderwith cGVHD include: Diarrhea is a common side effect in people who take IMBRUVICA. IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. This site is published by Pharmacyclics LLC which has developed the content in conjunction with Janssen Biotech, Inc. Any information that is collected on this site may be shared between Pharmacyclics LLC and Janssen Biotech, Inc. 1 bottle of Imbruvica (called bottle in this Instructions for Use) with pre-inserted bottle adapter (called adapter in this Instructions for Use). Store the bottle between 36F and 77F (2C and 25C). The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Swallow the tablet or capsule whole and do not crush, chew, break, or open it. Each 420 mg tablet is a yellow green to green oblong tablet debossed with ibr on one side and 420 on the other side. Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients who received Imbruvica in clinical trials [see Adverse Reactions (6.1)]. 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. However, some of these cases were in the setting of disease progression. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. The safety and efficacy of Imbruvica in patients with MCL who have received at least one prior therapy were evaluated in Study 1104 (NCT01236391), an open-label, multi-center, single-arm trial of 111 previously treated patients. You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA. de Rooij MFM, Kuil A, Geest CR, et al. 5Ucd.)sz? rGGvt40v4 Y &d"Y 9&v2 n[K}".^w^M W))@cb2[Df . Increased ibrutinib concentrations may increase the risk of drug-related toxicity. CI = confidence interval; ORR = overall response rate. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were White. Please see the fullImportant Product Information. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio; NE = not evaluable. By blocking this protein, IMBRUVICA may help kill and reduce the number of cancer cells and may also slow the spread of the . By clicking "OK" below you will be taken to a website that may contain links or references to other websites to which our Privacy Policy may not apply. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Includes 2 events with a fatal outcome. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Each 140 mg tablet is a yellow green to green round tablet debossed with ibr on one side and 140 on the other side. Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. 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% of 2,838 patients who received IMBRUVICA in 27 clinical trials. The body system and individual ADR preferred terms are sorted in descending frequency order. Imbruvica is indicated for the treatment of adult patients with Waldenstrms macroglobulinemia (WM). Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with Imbruvica. Hypertension occurred in 19% of 1,476 patients who received Imbruvica in clinical trials. The IMBRUVICA Copay Card cannot be used by patients receiving prescription reimbursement under any federal, state, or government-funded insurance programs, including Medicare Part D, Medicare Advantage Plan, Medicaid, Medigap, VA, DOD, and TRICARE, or where prohibited by law or the patients health insurance provider. Adults and children 1 year of age and older with chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy. Clinical Studies and Model-Informed Approaches. Patients should not take extra doses to make up the missed dose [see Dosage and Administration (2.1)]. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with Imbruvica [see Adverse Reactions (6.1)]. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. When you have support, such as help understanding your insurance coverage and potential ways to pay for IMBRUVICA, you may feel more confident during treatment. Each Imbruvica carton contains (see Figure A): This Instructions for Use has been approved by the U.S. Food and Drug Administration. Cardiac Arrhythmias, Cardiac Failure, and Sudden Death:Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Concomitant treatment with supportive care therapies for cGVHD was permitted. Hypertension: 1L= first-line; CI=confidence interval, Clb=chlorambucil, CLL=chronic lymphocytic leukemia, HR=hazard ratio, I=IMBRUVICA, IRC=independent review committee, OS=overall . 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). Do not open, break, or chew IMBRUVICA capsules. If you have commercial insurance, you may be eligible to pay as little as $0 per prescription of IMBRUVICA with the IMBRUVICA Copay Card. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Monitor blood pressure in patients treated with Imbruvica, initiate or adjust anti-hypertensive medication throughout treatment with Imbruvica as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration (2.2)]. Gently insert tip of the syringe into the adapter. Overall response rate as assessed by investigators in patients with del 17p was 88.9% in the Imbruvica arm versus 18.8% in the ofatumumab arm. Patents, which are listed in FDA's Orange Book (available athttps://www.accessdata.fda.gov/scripts/cder/ob/default.cfm). How long can you stay on Imbruvica (ibrutinib)? Waldenstrms Macroglobulinemia and Marginal Zone Lymphoma. Tumor lysis syndrome: Responses were seen across all organs involved for cGVHD (skin, mouth, gastrointestinal tract, and liver). If the dose is more than the marking on the syringe, split the dose between syringes as prescribed. Burger JA, Buggy JJ. Adverse reactions leading to dose reduction occurred in 26% of patients. Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. Avoid the use of Imbruvica in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilberts syndrome) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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% of 2,838 patients who received Imbruvica in 27 clinical trials. The median treatment duration was 51 months (range, 0.2 to 98 months) for CLL/SLL, 11 months (range, 0 to 87 months) for MCL, and 47 months (range, 0.3 to 61 months) for WM. The median number of prior treatments was 4 (range, 1 to 7 treatments). Your risk of bleeding may increase if you are also taking a blood thinner medicine. Each mL contains 70 mg of ibrutinib. At baseline, 20% of patients had 11q deletion. CI = confidence interval; HR = hazard ratio; NE = not evaluable; R = rituximab. If you have a government insurance plan, potential financial support for IMBRUVICA may be available through an independent foundation.. Imbruvica is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion. Retain in original package until dispensing. An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase of 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor support) in 65% of patients in the Imbruvica + R group and 39% of patients in the placebo + R group. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. At the same time throw away any used or unused syringes. The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were White. The median duration of response was 33 months (range, 2.4 to 60.2+ months). Hold the middle of the syringe and carefully remove it from the bottle (see. Embryo-fetal toxicity: In 645 patients with B-cell malignancies who received Imbruvica 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 [see Adverse Reactions (6.1)]. Adult patients with Waldenstrm's macroglobulinemia (WM). Initiation of new systemic cGVHD therapy while on study was not permitted. Shake well before each use Median Duration of Response, months (95% CI). The BTK protein sends important signals that tell B cells to mature and produce antibodies. have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes. No ramp-up dosing needed at therapy initiation The IRC review demonstrated an ORR of 69%. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). This indication is approved under accelerated approval based on overall response rate. 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. The trial enrolled 249 patients with CLL and 20 patients with SLL. Monitor and evaluate patients for fever and infections and treat appropriately. In the randomized population, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm. Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with Imbruvica. ": Heart problems. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure. Thirty-two percent of patients had 17p deletion. Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. w(yzB# Ia!- d|HVpiPgPb!r%:R@:%PHJ:O#P>F0lbRreG!%cEF&B"t>-Gph}X!"%8. Avoid use of Imbruvica in patients with severe hepatic impairment (Child-Pugh class C). Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in Imbruvica-treated patients compared to the control arm, respectively. Rules and maximum limits apply. If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change your IMBRUVICA dose. Do not open, break, or chew the capsules. b Based on all responders in the study, calculated from first response to progression, death, or new systemic therapies for cGVHD. Do not breastfeed during treatment with Imbruvica and for 1 week after the last dose. For any questions about the Pharmacyclics Privacy Policy, please visit www.pharmacyclics.com. Advise patients of the common side effects associated with Imbruvica [see Adverse Reactions (6)]. The trial enrolled 373 patients with CLL and 18 patients with SLL. Patients currently using the IMBRUVICA Copay Card are not eligible for retroactive billing or reimbursement of previous copays. Patients with cGVHD: Avoid use of IMBRUVICA in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilberts syndrome). 551 0 obj <> endobj Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, Hypertension occurred in 19% of 1,476 patients who received Imbruvica in clinical trials. The data described below reflect exposure to Imbruvica in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy [see Clinical Trials (14.5)]. Adults with marginal zone lymphoma (MZL) who require a medicine by mouth or injection (systemic therapy) and have received a certain type of prior treatment. Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent Imbruvica 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of 10% with a median duration of treatment of 15.6 months are presented in Table 7 and Table 8. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. PFS and ORR were assessed by an IRC. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were White. This works out to $13,546 for a supply of 28 tablets/capsules. Patients (n=391) were randomized 1:1 to receive either Imbruvica 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals. Data sources include IBM Watson Micromedex (updated 1 Nov 2022), Cerner Multum (updated 25 Oct 2022), ASHP (updated 12 Oct 2022) and others. Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A inducer) decreased the Cmax of ibrutinib by more than 13-fold and AUC by more than 10-fold. Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 ng/mL to 1000 ng/mL. Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may inhibit BCRP and P-gp transport at clinical doses. Ask your pharmacist how to properly dispose of the medicine. Make sure the syringe is clean and dry before use. Populations pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Across clinical trials, 3.1% of 2,838 patients who received Imbruvica without antiplatelet or anticoagulant therapy experienced major hemorrhage. Both ibrutinib and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses. The HELIOS study, a randomized, double-blind, placebo-controlled phase 3 study of Imbruvica in combination with bendamustine and rituximab (BR) (NCT01611090), was conducted in patients with previously treated CLL or SLL. Products regulation Blood donation Lab services Who we are E-services. You are leaving the patient and caregiver site and entering the US Healthcare professional site. 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. Increases in creatinine 1.5 to 3 times the upper limit of normal (ULN) occurred in 9% of patients. The half-life of ibrutinib is 4 hours to 6 hours. 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). The most common (20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. The most common adverse reactions in patients with CLL/SLL receiving Imbruvica ( 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Your use of the information on this site is subject to the terms of theLegal Noticeand newPrivacy Policyof Pharmacyclics LLC. IMBRUVICA (ibrutinib) capsules, for oral use IMBRUVICA (ibrutinib) tablets, for oral use IMBRUVICA (ibrutinib) oral suspension Initial U.S. Approval: 2013 -----RECENT MAJOR CHANGES-----Indications and Usage, cGVHD (1.6) 8/2022 The risk of major bleeding is higher if you're also taking antiplatelet medications or blood thinners. * Based on laboratory measurements and adverse reactions. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. * Based on laboratory measurements per IWCLL criteria and adverse reactions. Advise women not to breastfeed during treatment with Imbruvica and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Take IMBRUVICA 1 time a day at about the same time each day. Study 1118 included 63 patients with previously treated WM who received single agent Imbruvica. Imbruvica (Page 2 of 12) Pharmacyclics LLC 24 August 2022 2.2 Dosage Modifications for Adverse Reactions For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Do not take extra doses of Imbruvica to make up for a missed dose. Adverse reactions and laboratory abnormalities described below in Table 17 and Table 18 reflect exposure to Imbruvica with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with Imbruvica. The oral suspension bottle is provided in a carton with two 3 mL reusable oral dosing syringes: NDC 57962-007-12. The mechanism for the bleeding events is not well understood. Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL). Imbruvica (ibrutinib) tablets for oral use are available in the following dosage strengths: 140 mg, 280 mg, 420 mg, and 560 mg. Each tablet contains ibrutinib (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. With IMBRUVICA, there's a once-daily oral treatment option available to treat adults with previously treated MCL 1. Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Advise the patients and caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Do not cut, crush, or chew the tablets. CYP3A Inducers: Avoid coadministration with strong CYP3A inducers. The safety of Imbruvica has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria. For any questions about the Pharmacyclics Privacy Policy, please visit www.pharmacyclics.com. Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Serious adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis. If there is fluid on top of the adapter you may wipe it with clean disposable tissue. Verify pregnancy status in females of reproductive potential prior to initiating Imbruvica. Do not breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.. Take IMBRUVICA 1 time a day at about the same time each day. IMBRUVICA (ibrutinib) is a prescription medicine used to treat: It is not known if IMBRUVICA is safe and effective in childrenunder 1 year of age. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Abstract 923. Efficacy results for del 17p CLL/SLL are shown in Table 28. a IRC evaluated. Figure 6: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in E1912.
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