ORAL, ONCE-DAILY DOSING WITH IMBRUVICA (ibrutinib)

Transcription

1 ORAL, ONCE-DAILY DOSING WITH IMBRUVICA (ibrutinib) CLL/ SLL WM cgvhd INDICATIONS IMBRUVICA (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with: Chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL). CLL/SLL with 17p deletion. Waldenström s Macroglobulinemia (WM). Chronic graft versus host disease (cgvhd) after failure of one or more lines of systemic therapy. MCL Mantle cell lymphoma (MCL) who have received at least one prior therapy. MZL Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-cd20- based therapy. Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. WARNINGS AND PRECAUTIONS Hemorrhage, infections, cytopenias, atrial fi brillation, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity. Please see complete Important Safety Information on pages 6-7, and accompanying full Prescribing Information.

2 DOSAGE AND ADMINISTRATION IMBRUVICA single-agent dosing for CLL/SLL 1 CLL/SLL 3 capsules (420 mg) ONCE DAILY Continue IMBRUVICA treatment until disease progression or unacceptable toxicity IMBRUVICA + BR combination dosing for CLL/SLL 1 START CONCURRENTLY CLL/SLL 3 capsules (420 mg) ONCE DAILY Continue IMBRUVICA treatment until disease progression or unacceptable toxicity + BR up to 6 cycles Bendamustine was d at 70 mg/m 2 and rituximab was d at 375 mg/m 2 and 500 mg/m 2 * * Please refer to the full Prescribing Information for BR dosing details. IMBRUVICA single-agent dosing for WM 1 WM 3 capsules (420 mg) ONCE DAILY Continue IMBRUVICA treatment until disease progression or unacceptable toxicity IMBRUVICA dosing guidelines 1 Capsules should be swallowed whole with water at approximately the same time each day Patients should not open, break, or chew the capsules BR=bendamustine and rituximab, cgvhd=chronic graft versus host disease, CLL=chronic lymphocytic leukemia, MCL=mantle cell lymphoma, MZL=marginal zone lymphoma, SLL=small lymphocytic lymphoma, WM=Waldenström s Macroglobulinemia. 2 Please see complete Important Safety Information on pages 6-7, and accompanying full Prescribing Information.

3 IMBRUVICA single-agent dosing for MCL 1 MCL 4 capsules (560 mg) ONCE DAILY Continue IMBRUVICA treatment until disease progression or unacceptable toxicity IMBRUVICA single-agent dosing for MZL 1 MZL 4 capsules (560 mg) ONCE DAILY Continue IMBRUVICA treatment until disease progression or unacceptable toxicity IMBRUVICA single-agent dosing for cgvhd 1 cgvhd 3 capsules (420 mg) ONCE DAILY Continue IMBRUVICA until cgvhd progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cgvhd, discontinue IMBRUVICA considering the medical assessment of the individual patient Missed of IMBRUVICA 1 Patients should take IMBRUVICA as soon as possible on the SAME DAY, with a return to the regular schedule on the following day If a full day of treatment is missed, patients should NOT take extra capsules the next day to make up for the missed 3

4 DEFINITION OF PROGRESSIVE DISEASE (PD) PD during or after therapy is characterized by at least one of the following*: CLL WM International Workshop on CLL, 2008 Appearance of any new lesion or 50% increase in previously noted lymphadenopathy, hepatomegaly, or splenomegaly 2 In the absence of other objective evidence of PD, lymphocytosis alone should not be considered an indicator of PD 3 International Workshop on WM, % increase in serum IgM level from lowest value (requires confirmation) 4 MCL and MZL Revised Response Criteria for Malignant Lymphoma, 2007 Nodal masses: appearance of a new lesion(s) >1.5 cm in any axis, 50% increase in SPD of more than one node, or 50% increase in longest diameter of a previously identified node >1 cm in short axis 5 cgvhd Worsening in any 1 cgvhd domain by at least an absolute increase of 25% from baseline unless baseline values are within 25% of the scale used to score cgvhd 6 In addition, a new cgvhd manifestation also counts as progression 6 * The PD definitions above are adopted from their respective specified guidelines. 4 Please see complete Important Safety Information on pages 6-7, and accompanying full Prescribing Information.

5 Transformation to a more aggressive histology (eg, Richter s transformation) 2 Occurrence of cytopenias attributable to CLL 2 Includes 2012 modification for lymphocytosis. 3 Progression in clinical features attributable to disease 4 Absolute increase of >5 g/l (0.5 g/dl) is required when the increase of IgM is the only applicable criterion. 4 Spleen, liver: >50% increase from nadir in the SPD of any previous lesions 5 Bone marrow: new or recurrent involvement 5 Lesions should be PET positive if observed in typical FDG-avid lymphoma or the lesion was PET positive before therapy. 5 Criteria for rating of different cgvhd-affected organ progression varies. In general, an increase 1 points or 2 points for certain organs on the NIH scale is considered progression except for change from 0 to 1 for skin, eye, esophagus, and upper/lower GI. Please note, this is not complete information of various organ progression ratings. Please refer to Pavletic 2006 et al. and Lee 2015 et al. for further details. 6,7 cgvhd=chronic graft versus host disease, CLL=chronic lymphocytic leukemia, FDG=fluorodeoxyglucose, GI=gastrointestinal, IgM=immunoglobulin M, MCL=mantle cell lymphoma, MZL=marginal zone lymphoma, NIH=National Institutes of Health, PET=positron emission tomography, SPD=sum of product diameters, WM=Waldenström s Macroglobulinemia. 5

6 IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: 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 benefi t-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. Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. 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. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fi brillation and atrial fl utter (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 fi brillation. Periodically monitor patients clinically for atrial fi brillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fi brillation should be managed appropriately, and if it persists, consider the risks and benefi ts of IMBRUVICA treatment and follow modifi cation guidelines. Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 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 antihypertensive treatment as appropriate. Second Primary Malignancies: Other malignancies (range, 3 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, 2 to 13%). 6

7 Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate. Embryo-Fetal Toxicity: Based on fi ndings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. 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. Advise men to avoid fathering a child during the same time period. ADVERSE REACTIONS B-cell malignancies: The most common adverse reactions ( 20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse reactions ( 5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%). Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions. cgvhd: The most common adverse reactions ( 20%) in patients with cgvhd were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%), muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%), and pneumonia (21%). The most common Grade 3 or 4 adverse reactions ( 5%) reported in patients with cgvhd were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%). Twenty-four percent of patients receiving IMBRUVICA in the cgvhd trial discontinued treatment due to adverse reactions. Adverse reactions leading to reduction occurred in 26% of patients. DRUG INTERACTIONS CYP3A Inducers: Avoid coadministration with strong CYP3A inducers. CYP3A Inhibitors: Dose adjustment may be recommended. SPECIFIC POPULATIONS Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA. Please see accompanying full Prescribing Information. 7

8 IMBRUVICA DOSE MODIFICATIONS FOR ADVERSE REACTIONS 1 Interrupt IMBRUVICA therapy for the following ARs: Grade 3 or greater non-hematologic ARs Grade 3 or greater neutropenia with infection or fever Grade 4 hematologic ARs For full modification guidance per indication, see below. If an AR listed above occurs, the IMBRUVICA may be modified as follows 1 : START at approved 1 ST 2 ND 3 RD 4 TH CLL/SLL WM cgvhd 420 mg Interrupt until resolution to Grade 1 or baseline RESUME at same Interrupt until resolution to Grade 1 or baseline RESUME at lower Interrupt until resolution to Grade 1 or baseline RESUME at lower DISCONTINUE if adverse reaction persists or reoccurs following 2 reductions 420 mg 280 mg 140 mg START at approved 1 ST 2 ND 3 RD 4 TH MCL MZL 560 mg Interrupt until resolution to Grade 1 or baseline RESUME at same Interrupt until resolution to Grade 1 or baseline RESUME at lower Interrupt until resolution to Grade 1 or baseline RESUME at lower DISCONTINUE if adverse reaction persists or reoccurs following 2 reductions 560 mg 420 mg 280 mg 8 Please see complete Important Safety Information on pages 6-7, and accompanying full Prescribing Information.

9 DISCONTINUATION AND DOSE REDUCTION RATES IN REGISTRATION STUDIES Approximately 6% (CLL/SLL), 14% (MCL), 10% (WM and MZL), and 26% (cgvhd) of patients had a reduction due to ARs 1 4% to 10% (CLL/SLL), 9% (MCL), 9% (WM and MZL), and 24% (cgvhd) of patients discontinued due to ARs 1 Most frequent ARs leading to discontinuation were: CLL/SLL: pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia (1% each) 1 MCL: subdural hematoma (1.8%) 1 WM and MZL: interstitial lung disease, diarrhea, and rash (1.6% each) 1,8 cgvhd: fatigue (7.1%) and pneumonia (4.8%) 1,8 AR=adverse reaction, cgvhd=chronic graft versus host disease, CLL=chronic lymphocytic leukemia, MCL=mantle cell lymphoma, MZL=marginal zone lymphoma, SLL=small lymphocytic lymphoma, WM=Waldenström s Macroglobulinemia. 9

10 SPECIAL CONSIDERATIONS FOR IMBRUVICA DOSING 1 Dose Modifications for CYP3A inhibitors* B-Cell Malignancies Coadministered Drug Moderate CYP3A inhibitor Posaconazole at s less than or equal to 200 mg BID Voriconazole at any Posaconazole at s greater than 200 mg BID Other strong CYP3A inhibitors Chronic Graft Versus Host Disease Moderate CYP3A inhibitor Posaconazole immediate-release tablet 200 mg BID or delayed-release tablet 300 mg QD Voriconazole at any Posaconazole at other higher s Other strong CYP3A inhibitors Monitor for adverse reactions and follow modification guidance as needed 1 Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A 1 The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers 1 Hemorrhage 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 postsurgery, depending on the type of surgery and the risk of bleeding. 1 These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this category. 10 Please see complete Important Safety Information on pages 6-7, and accompanying full Prescribing Information.

11 The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. 1 Recommended IMBRUVICA Dose 140 mg once daily Interrupt as recommended Avoid concomitant use If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA 420 mg once daily Modify as recommended 280 mg once daily Modify as recommended Avoid concomitant use If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA Hepatic impairment 1 The recommended is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A) Avoid the use of IMBRUVICA in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) * Examples of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin. Examples of moderate CYP3A inhibitors include: aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil. Please refer to Section 2.3 of the full Prescribing Information for details on modifications. Examples of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John s wort. Please note that the induction potency of St. John s wort may vary widely based on preparation. 11

12 YOU&i Support Program Personalized support The YOU&i support program helps your patients learn about access to IMBRUVICA, find affordability support options, and sign up for information and resources to support them along their treatment journey. Learn more about the YOU&i Support Program: Call Monday - Friday, 8 AM - 8 PM ET References: 1. IMBRUVICA (ibrutinib) Prescribing Information. Pharmacyclics LLC Hallek M, Cheson BD, Catovsky D, et al; for the International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood. 2008;111(12): Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes. Blood. 2012;e-letter. 4. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124(9): Cheson BD, Pfi stner B, Juweid ME, et al. International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5): Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12(3): Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versushost disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21(6): Data on fi le. Pharmacyclics LLC. To learn more, visit IMBRUVICAHCP.com Pharmacyclics LLC 2017 Janssen Biotech, Inc /17 PRC-02694