− Company to Present 22 Abstracts in Oncology, Including 5 Oral Presentations, Demonstrating Takeda’s Enduring Commitment to Improving the Lives of Patients with Blood Cancers
CAMBRIDGE, Mass. & OSAKA, Japan-Monday 9 November 2020 [ AETOS Wire ]
(BUSINESS WIRE) -- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that it will present 22 company-sponsored abstracts at the 62nd American Society of Hematology (ASH) Annual Meeting, being held virtually December 5-8, 2020. The company’s scientific research at ASH will identify unique approaches in advancing the treatment of hematologic cancers, illustrative of its commitment to developing and providing transformative solutions for patient needs. Takeda will also be presenting data from its broader hematology portfolio and pipeline at the conference.
“At this year’s ASH, Takeda’s Oncology Research and Development updates underscore our commitment to transform existing treatment paradigms and investigate truly novel approaches that address critical needs for patients living with blood cancers, such as leukemias, lymphomas and myeloma,” said Chris Arendt, Head, Oncology Therapeutic Area Unit, Takeda. “Our pursuit to cure cancer is driven by our commitment to provide life-saving medicines to all patients, including those with limited or ineffective treatment options.”
Key data to be presented include:
Pevonedistat: A sub-analysis from the Phase 2 Pevonedistat-2001 trial will be presented in an oral session. The analysis, which focused on outcomes of the higher-risk myelodysplastic syndromes (MDS) subgroup of the study, showed that the combination of pevonedistat and azacitidine resulted in longer event-free survival, longer duration of response and delayed transformation to acute myeloid leukemia without increasing myelosuppression, compared to treatment with azacitidine alone. Additionally, the safety profile of pevonedistat and azacitidine in combination was comparable to azacitidine alone. Despite poor outcomes, there have been no novel advances in higher-risk MDS treatment in over 10 years and new, effective therapies with favorable safety profiles that do not worsen myelosuppression are needed.
ICLUSIG® (ponatinib): Data from the interim analysis of the OPTIC trial of ICLUSIG will be presented in an oral session. The data highlighted the revised benefit-risk of ICLUSIG, a third-generation tyrosine kinase inhibitor (TKI), with the use of a response-based dosing regimen in resistant chronic-phase chronic myeloid leukemia (CP-CML) patients, with or without mutations, who have experienced treatment failure with second-generation (2G) TKIs. Another oral presentation will feature a pooled sub-analysis highlighting patients from the PACE and OPTIC trials, comprising the largest patient population evaluation in a post-2G TKI setting. While CP-CML is often manageable, patients who have experienced treatment failure with prior 2G TKI therapy, especially those who are resistant to therapy, suffer from poor long-term outcomes, underscoring that there are still gaps in care for people living with CP-CML.
NINLARO™ (ixazomib): Results from the TOURMALINE-MM2 trial will be presented in an oral session. The study was designed to evaluate the addition of NINLARO to lenalidomide and dexamethasone in newly diagnosed transplant ineligible multiple myeloma patients. While the trial did not meet the threshold for statistical significance and the primary endpoint of progression-free survival (PFS) was not met, the study found the addition of NINLARO resulted in a 13.5 month increase in median PFS overall. In the prespecified expanded high-risk cytogenetics subgroup, the addition of NINLARO resulted in a median PFS of 23.8 months versus 18.0 months in the placebo arm. Newly diagnosed multiple myeloma patients are in need of additional proteasome inhibitor-based treatment options, as there are currently no approved options that are all-oral.
ADCETRIS® (brentuximab vedotin): Five-year follow up data from two Phase 3 frontline lymphoma studies will be featured as poster presentations. Data from the ECHELON-1 trial, which evaluated ADCETRIS in combination with doxorubicin, vinblastine and dacarbazine (ADCETRIS+AVD) for previously untreated, stage III/IV Hodgkin lymphoma shows that, with extended follow-up time, the addition of ADCETRIS to AVD demonstrates a robust and sustained treatment benefit, independent of disease stage, International Prognostic Index risk factor score and PET2 status compared to ABVD, the current standard of care. Positive final analyses from ECHELON-2 which evaluated ADCETRIS in combination with CHP (cyclophosphamide, doxorubicin, prednisone) (ADCETRIS+CHP) versus a standard care treatment in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma will also be presented. The safety profile of ADCETRIS in the ECHELON-1 and ECHELON-2 trials were consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
Accepted oncology abstracts include:
Note: all times listed are in Pacific Time
Efficacy and Safety of Pevonedistat Plus Azacitidine Vs Azacitidine Alone in Higher-Risk Myelodysplastic Syndromes (MDS) From Study P-2001 (NCT02610777). Abstract 653. Oral Presentation. Monday, December 7, 2020 – 11:30 a.m.
A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy. Abstract 988. Poster Presentation. Saturday, December 5, 2020.
Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes. Abstract 2191. Poster Presentation. Sunday, December 6, 2020.
Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and OPTIC. Abstract 647. Oral Presentation. Monday, December 7, 2020 – 11:30 a.m.
Outcome by Mutation Status and Line of Treatment in OPTIC, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML. Abstract 48. Oral Presentation. Saturday, December 5, 2020 – 8:15 a.m.
A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL).Abstract 2842. Poster Presentation. Monday, December 7, 2020.
Ponatinib Versus Imatinib with Reduced-Intensity Chemotherapy in Patients with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL): PhALLCON Study. Abstract 1026. Poster Presentation. Saturday, December 5, 2020.
Treatment of Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Using Tyrosine Kinase Inhibitors in Combination with Chemotherapy: A Patient-Centered Benefit-Risk Assessment. Abstract 3471. Poster Presentation. Monday, December 7, 2020.
The Phase 3 TOURMALINE-MM2 Trial: Oral Ixazomib, Lenalidomide, and Dexamethasone (IRd) Vs Placebo-Rd for Transplant-Ineligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM). Abstract 551. Oral Presentation. Monday, December 7, 2020 – 7:45 a.m.
Progression-Free Survival (PFS) Benefit Demonstrated and Quality of Life (QoL) Maintained across Age and Frailty Subgroups with the Oral Proteasome Inhibitor (PI) Ixazomib Vs Placebo As Post-Induction Maintenance Therapy in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Analysis of the TOURMALINE-MM4 Phase 3 Trial. Abstract 1381. Poster Presentation. Saturday, December 5, 2020.
Prognostic Importance of Measurable Residual Disease (MRD) Kinetics and Progression-Free Survival (PFS) Benefit in MRD+ Patients (Pts) with Ixazomib Vs Placebo As Post-Induction Maintenance Therapy: Results from the Multicenter, Double-Blind, Phase 3 TOURMALINE-MM4 Trial in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Pts. Abstract 2318. Poster Presentation. Sunday, December 6, 2020.
In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study. Abstract 3200. Poster Presentation. Monday, December 7, 2020.
Effectiveness and Safety of Ixazomib-Based Therapy in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated Outside the Clinical Trial Setting Via an Early Access Program (EAP) in Europe: Second Interim Analysis of the ‘Use Via Early Access to Ixazomib’ (UVEA-IXA) Study. Abstract 2292. Poster Presentation. Sunday, December 6, 2020.
Real-Life-Setting Effectiveness of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma: The REMIX Study. Abstract 1377. Poster Presentation. Saturday, December 5, 2020.
Real-World Treatment Patterns and Outcomes of Proteasome Inhibitor (PI: Bortezomib [V], Carfilzomib [K], or Ixazomib [I])-Lenalidomide/Dexamethasone (Rd)-Triplets By Prior Lenalidomide-Exposure in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Engaged in Routine Care in the United States (US). Abstract 3242. Poster Presentation. Monday, December 7, 2020.
TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma. Abstract 3197. Poster Presentation. Monday, December 7, 2020.
Mezagitamab Induces Immunomodulatory Effect in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Abstract 316. Oral Presentation. Sunday, December 6, 2020 – 10:30 a.m.
ADCETRIS® (brentuximab vedotin) and Lymphoma
Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study. Abstract 2973. Poster Presentation. Monday, December 7, 2020.
The ECHELON-2 Trial: 5-year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma. Abstract 1150. Poster Presentation. Saturday, December 5, 2020.
Nodal Peripheral T-cell Lymphoma with T Follicular-Helper Phenotype: A Different Entity? Results of the Spanish Retrospective REAL-T Study. Abstract 2972. Poster Presentation. Monday, December 7, 2020.
Results from the International, Multi-Center, Retrospective B-HOLISTIC Study: Describing Treatment Pathways and Outcomes for Classical Hodgkin Lymphoma. Abstract 2979. Poster Presentation. Monday, December 7, 2020.
Characteristics and Treatment Response of Newly Diagnosed Advanced-Stage and Relapsed/Refractory Hodgkin Lymphoma in Taiwan: A Nationwide Retrospective Study. Abstract 3479. Poster Presentation. Monday, December 7, 2020.
Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor, which blocks modifications of select proteins. Pevonedistat treatment disrupts cell cycle progression and cell survival, leading to cell death in cancers including leukemias. Pevonedistat in combination with azacitidine demonstrated antitumor activity in preclinical studies and was well tolerated, with promising clinical activity, in a Phase 1 study of patients with AML. Pevonedistat is currently being evaluated in Phase 3 studies as a first-line treatment for patients with HR-MDS, HR-CMML, and AML, who are ineligible (unfit) for transplant or intensive induction chemotherapy and is also being explored in a Phase 2 study in unfit AML in a triple combination with azacitidine and venetoclax.
About ICLUSIG® (ponatinib) tablets
ICLUSIG is a kinase inhibitor targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG inhibits native BCR-ABL1, as well as all BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with CP, accelerated phase, or blast phase CML or Ph+ ALL for whom no other TKI therapy is indicated, and treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.
IMPORTANT SAFETY INFORMATION (U.S.)
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning.
Arterial occlusion has occurred in at least 35% of ICLUSIG® (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
Heart Failure, including fatalities occurred in 9% of ICLUSIG-treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.
WARNINGS AND PRECAUTIONS
Arterial Occlusions: The 35% of patients reported to have arterial occlusive events (AOEs) in the boxed warning included patients from both phase 1 and phase 2 trials. In the phase 2 trial, 33% of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event. Some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multisite vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first AOE ranged from 193-526 days. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. AOEs were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing AOEs, interrupt or stop ICLUSIG.
Venous Thromboembolism: Venous thromboembolic events, including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss, occurred in 6% of patients with an incidence rate of 5% (CP-CML), 4% (AP-CML), 10% (BP-CML), and 9% (Ph+ ALL). Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of patients in the phase 2 trial. The most common heart failure events (each 3%) were congestive cardiac failure and decreased ejection fraction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.
Hepatotoxicity: Hepatotoxic events were observed in 29% of patients (11% were grade 3 or 4). Severe hepatotoxicity occurred in all disease cohorts. Three patients with BP-CML or Ph+ ALL died: one with fulminant hepatic failure within one week of starting ICLUSIG and two with acute liver failure. The most common forms were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. The median time to onset of event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.
Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% of patients, of which 12% were serious and included hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline BP <140/90 mm Hg, 80% developed treatment-emergent hypertension (44% Stage 1 and 37% Stage 2). In 132 patients with Stage 1 hypertension at baseline, 67% developed Stage 2. Monitor and manage BP elevations during ICLUSIG use and treat hypertension to normalize BP. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.
Pancreatitis: Pancreatitis was reported in 7% of patients (6% were serious or grade 3/4). Many of these cases resolved within 2 weeks with dose interruption or reduction of ICLUSIG. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Check serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with ICLUSIG and evaluate patients for pancreatitis. Do not consider restarting ICLUSIG until patients have complete resolution of symptoms and lipase levels are <1.5 x ULN.
Increased Toxicity in Newly Diagnosed CP-CML: In a prospective, randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib, ICLUSIG exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
Neuropathy: Overall, 20% of patients experienced a peripheral neuropathy event of any grade (2% were grade 3/4). The most common were paresthesia (5%), neuropathy peripheral (4%), hypoesthesia (3%), dysgeusia (2%), muscular weakness (2%), and hyperesthesia (1%). Cranial neuropathy developed in 2% of patients (<1% grade 3/4). Of the patients who developed neuropathy, 26% developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting ICLUSIG and evaluate if neuropathy is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2%. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14%. Visual blurring occurred in 6%. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.
Hemorrhage: Hemorrhage occurred in 28% of patients (6% serious, including fatalities). The incidence of serious bleeding events was higher in patients with AP- or BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% each. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.
Fluid Retention: Fluid retention occurred in 31% of patients. The most common events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%). Serious events occurred in 4%. One instance of brain edema was fatal. Serious treatment-emergent events included: pleural effusion (2%), pericardial effusion (1%), and edema peripheral (<1%). Monitor patients for fluid retention and manage as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.
Cardiac Arrhythmias: Arrhythmias occurred in 19% of patients (7% were grade ≥3). Arrhythmia of ventricular origin was reported in 3% of all arrhythmias, with one case being grade ≥3. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% of patients. Atrial fibrillation was the most common arrhythmia (7%), approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (2%), tachycardia and bradycardia (each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (each 0.2%). For 27 patients, the event led to hospitalization. In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt ICLUSIG and evaluate.
Myelosuppression: Myelosuppression was reported in 59% of patients (50% were grade 3/4). The incidence of these events was greater in patients with AP- or BP-CML, and Ph+ ALL than in patients with CP-CML. Severe myelosuppression (grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated and adjust the dose as recommended
Tumor Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with ICLUSIG.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Post-marketing cases of RPLS have been reported in ICLUSIG-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present, and diagnosis is made with supportive findings on magnetic resonance imaging of the brain. If RPLS is diagnosed, interrupt ICLUSIG treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.
Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.
Most Common Adverse Reactions: The most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Strong CYP3A Inhibitors: Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.
Strong CYP3A Inducers: Avoid concurrent use.
USE IN SPECIFIC POPULATIONS
Females and Males of Reproductive Potential: Ponatinib may impair fertility in females and it is not known if these effects are reversible. Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days after last dose.
For more information about ICLUSIG, visit www.ICLUSIG.com. For the Prescribing Information including the Boxed Warning for arterial occlusion, venous thromboembolism, heart failure, and hepatoxicity, please visit https://www.iclusig.com/pdf/ICLUSIG-Prescribing-Information.pdf.
About NINLARO™ (ixazomib) capsules
NINLARO™ (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.
NINLAROTM (ixazomib): GLOBAL IMPORTANT SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.
Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.
Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms
Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.
Thrombotic microangiopathy, sometimes fatal, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TPP/HUS and stop NINLARO if diagnosis is suspected. If the diagnosis of TPP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TPP/HUS is not known.
Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.
Pregnancy- NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.
Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.
SPECIAL PATIENT POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.
Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.
Co-administration of strong CYP3A inducers with NINLARO is not recommended.
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.
For European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdf
For US Prescribing Information: https://www.ninlarohcp.com/pdf/prescribing-information.pdf
For Canada Product Monograph: http://www.takedacanada.com/ninlaropm
About ADCETRIS® (brentuximab vedotin)
ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen's proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.
ADCETRIS for injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.
Health Canada granted ADCETRIS approval with conditions in 2013 for patients with (1) HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and (2) sALCL after failure of at least one multi-agent chemotherapy regimen. Non-conditional approval was granted for (3) post-ASCT consolidation treatment of patients with HL at increased risk of relapse or progression in 2017, (4) adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy in 2018, (5) for previously untreated patients with Stage IV HL in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and (6) for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.
ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (4) for the treatment of adult patients with previously untreated sALCL in combination with cyclophosphamide, doxorubicin and prednisone (CHP), (5) for the treatment of adult patients with relapsed or refractory sALCL, and (6) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.
In Japan, ADCETRIS received its first approval in January 2014 for relapsed or refractory Hodgkin lymphoma and ALCL, and untreated Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in September 2018, and Peripheral T-cell lymphomas in December 2019. In December 2019, ADCETRIS obtained additional dosage & administration for the treatment of relapsed or refractory Hodgkin lymphoma and Peripheral T-cell lymphomas in pediatric. The current wording of approved indication in Japan package insert is for the treatment of patients with CD30 positive: Hodgkin lymphoma and Peripheral T-cell lymphomas.
ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries/ regions for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.
ADCETRIS is being evaluated broadly in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies.
Seagen and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.
ADCETRIS (brentuximab vedotin) Important Safety Information (European Union)
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed.
Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms (e.g., cough, dyspnoea) appropriately. Consider holding dosing during evaluation and until symptomatic improvement.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and manage according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically an effect of cumulative exposure to ADCETRIS and is reversible in most cases. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.
Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been reported with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.
When ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose.
Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs and administer appropriate medical therapy.
Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported with ADCETRIS. Promptly evaluate and treat patients if new or worsening GI symptoms occur.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Test liver function prior to treatment initiation and routinely monitor during treatment. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use with caution in other CD30+ CTCL patient types.
Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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