On May 31, 2016 Syros Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) accepted the Company’s Investigational New Drug (IND) application to advance its lead drug candidate, SY-1425, a potent and selective retinoic acid receptor alpha (RARα) agonist, into a Phase 2 clinical trial in genomically defined subsets of patients with relapsed or refractory acute myeloid leukemia (AML) and relapsed high-risk myelodysplastic syndrome (MDS) identified through its platform (Press release, Syros Pharmaceuticals, MAY 31, 2016, View Source [SID:1234512905]). Syros is on track to initiate the Phase 2 clinical trial in mid-2016.

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"We’re delighted to reach this important milestone for patients and for Syros," said Nancy Simonian, MD, Chief Executive Officer of Syros. "SY-1425 represents a promising therapeutic approach for subsets of AML and MDS patients with a novel biomarker that we discovered using our proprietary gene control platform, and our goal is to rapidly advance this first-in-class therapy for these currently underserved patients. The achievement of this milestone marks our evolution into a clinical-stage company just three years since our founding. Our progress is a testament to our team and to our pioneering approach of systematically analyzing the non-coding region of the genome to advance a new wave of medicines designed to control the expression of disease-driving genes."

Using its gene control platform, Syros identified subsets of AML and MDS patients whose tumors have a highly specialized regulatory region of non-coding DNA, known as a superenhancer, associated with the RARA gene. Syros then identified a biomarker for the RARAassociated super-enhancer, which it found in approximately 25 percent of AML and MDS patient tissue samples. Preclinical studies show the RARA biomarker is predictive of response to treatment with SY-1425 in AML cell lines and patient-derived xenograft (PDX) models of AML. Treatment with SY-1425 was observed to inhibit cancer growth and prolong survival in PDX models of AML with the RARA biomarker but not in models of AML without the biomarker. These data provide meaningful evidence that patients with the RARA biomarker may be promising candidates for treatment with SY-1425 and support further development of SY-1425 in these genomically defined patient populations.

The Phase 2 clinical trial will be a multi-center, open-label trial exploring safety and efficacy in relapsed or refractory AML and relapsed high-risk MDS patients who have been prospectively selected using the Company’s RARA biomarker. The trial is expected to enroll approximately 40 patients. The primary endpoint of the trial will be overall response rate. The trial will also assess pharmacodynamic markers, duration of response, safety and tolerability, survival and biomarker predictability. Syros in-licensed SY-1425 to develop and commercialize SY-1425 in North America and Europe for all cancers. SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat a different form of AML known as acute promyelocytic leukemia (APL), in which it has a wellestablished efficacy and safety profile. Syros continues to research the role of the RARA super-enhancer in other cancers and plans to pursue additional indications upon achieving clinical proof-of-concept in AML and MDS.

On May 31, 2016 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that they have entered into a definitive agreement for Jazz Pharmaceuticals to acquire Celator for $30.25 per share in cash, or approximately $1.5 billion (Press release, Celator Pharmaceuticals, MAY 31, 2016, View Source [SID:1234512901]).

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The transaction with Celator is well-suited to advance Jazz Pharmaceuticals’ growth strategy.

VYXEOS is the first product candidate to demonstrate a statistically significant improvement in Overall Survival in patients with high-risk (secondary) AML1
U.S. FDA Breakthrough Therapy designation granted for VYXEOS2
U.S. FDA and European Commission Orphan Drug designation for VYXEOS for the treatment of AML
VYXEOS is an innovative product candidate based on the Celator CombiPlex platform
Anticipated long-lived exclusivity for VYXEOS
Broadens Jazz Pharmaceuticals’ hematology/oncology portfolio
Worldwide development and commercialization rights to VYXEOS
Synergies with Jazz Pharmaceuticals’ commercial expertise and infrastructure
Transaction expected to close in the third quarter of 2016
Transaction expected to be accretive to Non-GAAP adjusted EPS beginning in 2018 and beyond
1 Included secondary AML and de novo AML with a karyotype characteristic of myelodysplastic syndrome (MDS)
2 U.S. FDA Breakthrough Therapy designation granted for VYXEOS for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes
"Celator Pharmaceuticals is a strong strategic fit with Jazz Pharmaceuticals. VYXEOS will further diversify our product portfolio and is complementary to our clinical and commercial expertise in hematology/oncology," said Bruce Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals plc. "As Celator is currently preparing a regulatory submission in the U.S. for VYXEOS, this acquisition would add a new orphan product with the potential for short- and long-term revenue generation and expansion of our international commercial platform."

"The planned combination of Jazz and Celator is highly complementary, as both companies are dedicated to bringing differentiated therapies to patients who have high unmet medical needs," said Scott Jackson, chief executive officer of Celator Pharmaceuticals. "We believe that Jazz Pharmaceuticals’ clinical and commercial expertise in hematology/oncology and existing international infrastructure will help realize the value of VYXEOS as a treatment to patients with AML. After thoroughly evaluating our strategic options, our board of directors has unanimously determined that this all-cash transaction is in the best interest of our stockholders."

Transaction Closing
The transaction is structured as a tender offer and second step merger. The closing of the tender offer is conditioned upon customary conditions, including the tender of a majority of the outstanding shares of Celator common stock and expiration or termination of the Hart Scott Rodino waiting period. The transaction is expected to close in the third quarter of 2016.

Certain stockholders of Celator holding approximately 18.4 percent of Celator’s outstanding shares of common stock, including executive officers, members of the Celator board of directors and certain investment funds affiliated with the members of the board of directors, have agreed to tender their shares in the tender offer.

Financing
Jazz Pharmaceuticals expects to finance the transaction with a combination of cash on hand and borrowings under its senior secured credit facility.

Advisors
Jazz Pharmaceuticals’ financial advisor for the transaction is RBC Capital Markets, and its primary legal advisor is Cooley LLP.

Celator Pharmaceuticals’ financial advisor for the transaction is MTS Health Partners, and its primary legal advisor is Kirkland and Ellis LLP.

On May 31, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported initiation of the Phase 1/2 clinical trial of AP32788, an investigational tyrosine kinase inhibitor (TKI) designed as a targeted therapy for patients with non-small cell lung cancer (NSCLC) with specific mutations in EGFR or HER2 (Press release, Ariad, MAY 31, 2016, View Source [SID:1234512888]).

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AP32788 targets tumors driven by EGFR or HER2 kinases and was designed to achieve selective inhibition of these kinases with exon 20 mutations. There are currently no approved targeted treatment options available for the approximately four to nine percent of EGFR-mutated lung tumors with exon 20 insertion mutations in NSCLC patients.1 Additionally, approximately two percent of NSCLC patients2 have HER2 mutations, with the majority having exon 20 insertion mutations.

"In the preclinical data presented at the AACR (Free AACR Whitepaper) meeting last month, AP32788 demonstrated the ability to inhibit all tested EGFR and HER2 mutants, including exon 20 insertion mutants," stated Tim Clackson, Ph.D., president of research and development and chief scientific officer of ARIAD. "We are pleased to be advancing AP32788, the next promising cancer medicine in the ARIAD pipeline, into clinical study for patients who currently have no targeted treatment options in these orphan oncology disease subsets."

Clinical Trial Design

The trial will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The initial Phase 1 dose-escalation trial segment will include patients with advanced NSCLC. Patients enrolled in this multicenter study will be refractory to standard available therapies. The primary objective of the Phase 1 segment of the trial is to determine the safety, tolerability, pharmacokinetic profile, and recommended Phase 2 dose (RP2D) of orally administered AP32788. ARIAD expects to enroll approximately 20 to 30 patients in this portion of the trial.

The Phase 2 expansion phase of the trial will include four histologically and molecularly defined patient cohorts, including:

NSCLC patients with EGFR exon 20 activating insertions with no active, measurable central nervous system (CNS) metastases;
NSCLC patients with HER2 exon 20 activating insertions or point mutations with no active, measurable CNS metastases;
NSCLC patients with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; and,
NSCLC with other targets against which AP32788 has shown preclinical activity (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations) with or without active, measurable CNS metastases.
The Phase 2 segment of the trial is planned to enroll approximately 80 patients and will evaluate anti-tumor activity of AP32788 in these molecularly defined patient populations.

"While there are approved TKIs for use in NSCLC patients with common EGFR activating mutations, there is a need for targeted treatment options to address the subset of patients with EGFR exon 20, HER2, and other uncommon EGFR mutations," said Robert C. Doebele, M.D., Ph.D., associate professor, division of medical oncology, University of Colorado. "This trial will evaluate the safety, tolerability and optimal dose of AP32788, and the potential activity in NSCLC patients who currently have no targeted treatment options."

ARIAD’s Phase 1/2 clinical trial of AP32788 is expected to enroll patients at up to seven centers during the dose-escalation phase. Additional centers will be activated for enrollment of the expansion cohorts. More information about the clinical trial evaluating AP32788 can be found at View Source

EGFR mutations represent the largest known, targetable subset of NSCLC. While the most common types of EGFR mutation are addressed by approved TKI therapies, there are no targeted treatment options available for the approximately 4 to 9 percent of EGFR-mutated lung tumors with exon 20 insertion mutations. In addition, patients with HER2 mutations, mostly exon 20 insertion mutations, comprise approximately 2 percent of NSCLC patients and also have no currently approved targeted treatment options. ARIAD estimates that there are approximately 6,000 patients in the United States living with EGFR exon 20 or HER2 point mutations, based on a broader data set of 175,000 patients with stage IIIb or IV NSCLC living in the U.S. in 2015, according to Kantar Health.

About AP32788

AP32788 is an investigational oral tyrosine kinase inhibitor (TKI) of activating mutations in EGFR and HER2. The molecule was designed to address the unmet need in patients with non-small cell lung cancer (NSCLC) driven by exon 20 insertion mutations in EGFR and HER2, and is ARIAD’s fourth internally discovered oncology candidate to advance into clinical development.

On May 31, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission (EC) has approved the subcutaneous (SC) formulation of MabThera (rituximab) for people with previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL) (Press release, Hoffmann-La Roche , MAY 31, 2016, View Source [SID:1234512871]). The approved dose for CLL is 1600mg. Following the approval of MabThera SC (1400 mg) for common forms of non-Hodgkin lymphoma in March 2014, this is the second European approval for the formulation.

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"MabThera SC provides patients with significantly faster treatment administration and the opportunity to enjoy more time outside the clinical setting compared to intravenous delivery of the medicine," said Sandra Horning, M.D., Chief Medical Officer and Head, Global Product Develop ment. "Today’s approval in CLL means the benefit of MabThera SC can be offered to even more patients."
The European approval was based primarily on data from the phase Ib SAWYER study, in which previously untreated CLL patients received either MabThera SC (1600 mg) or intravenous MabThera (500mg/m2) in combination with chemotherapy (fludarabine and cyclophosphamide), a current standard of care. SAWYER demonstrated treatment with MabThera SC resulted in comparable levels of the medicine in the blood (serum concentrations), as well as efficacy and safety, to intravenous MabThera, and results were recently published in The Lancet Haematology1.

About MabThera
MabThera is a therapeutic monoclonal antibody that binds to a particular protein – the CD20 antigen – on the surface of normal and malignant B-cells. It then recruits the body’s natural defences to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.

MabThera first received FDA approval for the treatment of relapsed indolent non-Hodgkin Lymphoma (NHL) in 1997 and was the first targeted cancer medicine approved by the U.S. Food and Drug Administration (FDA). MabThera was approved in the EU in June 1998, and has since been used to treat more than 2.7 million people with specific blood cancers. For more than 15 years, the efficacy and safety of MabThera has been documented in more than 300 phase II/III clinical studies. MabThera has been approved for the treatment of several blood cancers, specifically, certain types of NHL and for chronic lymphocytic leukemia (CLL). It continues to be studied in other types of blood cancers and disease areas where CD20-positive cells are believed to play a role.
MabThera is known as Rituxan in the United States, Japan and Canada. Genentech, a member of the Roche Group, and Biogen collaborate on Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where MabThera is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd.

About Chronic Lymphocytic Leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world2. CLL mainly affects men and the median age at diagnosis is about 70 years3 . Worldwide, the incidence of all leukaemias is estimated to be over 350,0002 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia4.

On May 31, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported that the European Commission (EC) approved IMBRUVICA (ibrutinib) as a first-line treatment option for adult patients with chronic lymphocytic leukemia (CLL), expanding upon the initial EC approval in October 2014 for certain patients with CLL (Press release, AbbVie, MAY 31, 2016, View Source [SID:1234512870]).

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This decision comes just one month after the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an opinion in favor of the use of IMBRUVICA for the treatment of adult patients with first-line chronic lymphocytic leukemia (CLL) in the European Union (EU).

The broadened indication is based on data from the Phase 3 RESONATE-2 (PCYC-1115) trial, which also served as the basis for the March 2016 U.S. approval in the first-line CLL/SLL treatment setting and the May 2016 update to the U.S. Prescribing Information to include positive overall survival data.1

This approval marks a number of significant landmarks for IMBRUVICA: this is the drug’s fifth treatment indication in the EU and this approval means that IMBRUVICA is now available to treat all lines of CLL in the EU. Patients with treatment-naive CLL, relapsed/refractory CLL and those with the genetic mutations del 17p or TP53, can all now benefit from treatment with single-agent IMBRUVICA.

IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world. IMBRUVICA is already approved in Europe to treat adult patients with relapsed/refractory mantle cell lymphoma (MCL), adult patients with CLL who have received at least one prior therapy or who have del 17p or TP53 mutations, and adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or as a first-line treatment for WM patients unsuitable for chemo-immunotherapy.2

The approval was based on data from the Phase 3, randomized, open-label RESONATE-2 (PCYC-1115) trial, which were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2015 and simultaneously published in The New England Journal of Medicine (NEJM). After a median of 18 months of follow-up, IMBRUVICA was associated with a significant improvement in several efficacy endpoints versus chlorambucil in patients aged 65 or older with newly diagnosed CLL. Specifically, IMBRUVICA was associated with a 90% progression-free survival rate (PFS; the primary endpoint) versus 52% for chlorambucil. Moreover, IMBRUVICA showed statistically significant prolonged overall survival (OS; a key secondary endpoint). The safety of IMBRUVICA in the treatment-naïve CLL patient population was consistent with previously reported studies.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored study which enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included overall response rate (ORR; based on the same iWCLL criteria), OS and safety.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).1 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.1,[3] IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1

IMBRUVICA is approved in the U.S. to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia (WM). Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.1

IMBRUVICA is approved in the EU to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), previously untreated adult patients with chronic lymphocytic leukaemia (CLL) or those who have received at least one prior therapy, and adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or first line patients unsuitable for chemo-immunotherapy.2

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

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 benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – 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 (eg, 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 follow dose modification 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 antihypertensive medications and/or initiate antihypertensive 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.

Embryo-Fetal Toxicity – Based on findings 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.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia*(41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia 21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and nuetropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source