– Results from Phase 3 ECHELON-1 Trial of ADCETRIS® (brentuximab vedotin) in Frontline Advanced Hodgkin Lymphoma to be Featured in Plenary Session
– More than 10 Abstracts to Highlight Takeda’s Expanded Hematology-Oncology Portfolio in Lymphoma, Multiple Myeloma, Chronic Myeloid Leukemia and Acute Myeloid Leukemia
Cambridge, Mass. and Osaka, Japan, November 1, 2017 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that it will present a total of 11 company-sponsored abstracts at the 59th American Society of Hematology (ASH) Annual Meeting taking place in Atlanta from December 9 to 12, 2017. Takeda will present findings from Phase 3 and earlier-stage data from clinical studies across the company’s broadened oncology portfolio. Notably, data from the Phase 3 ECHELON-1 clinical trial evaluating ADCETRIS® (brentuximab vedotin) as part of a frontline combination chemotherapy regimen in patients with previously untreated advanced Hodgkin lymphoma will be featured in the Plenary Scientific Session.
“This year at ASH, we are presenting data that truly has the potential to change how patients with blood cancers are treated,” said Christophe Bianchi M.D., President, Takeda Global Oncology Business Unit. “The positive data from the ECHELON-1 trial represents a milestone in the frontline treatment of advanced Hodgkin lymphoma – a population in which one in three patients doesn’t achieve long-term remission after standard frontline therapy. Furthermore, the real-world data in multiple myeloma we will share will help the community to better understand discrepancies between effectiveness and efficacy in clinical trials versus real-world.”
Full data from the Phase 3 ECHELON-1 trial will be presented for the first time during the Plenary Scientific Session in partnership with Seattle Genetics. Topline data from ECHELON-1, which was reported in June 2017, demonstrated that the trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) versus the control arm. The two-year modified PFS rate for patients in the ADCETRIS arm was 82.1 percent compared to 77.2 percent in the control arm (HR=0.770; p-value=0.035). The safety profile of ADCETRIS+AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen. In addition, updated analyses of the Phase 3 ALCANZA data will be featured, showing that longer-term data continued to show significant clinical benefit for ADCETRIS versus investigator’s choice of methotrexate or bexarotene.
Takeda will also share data to help advance understanding of real-world versus clinical trial experiences in multiple myeloma as well as data on efficacy and safety of long-term NINLARO® (ixazomib) maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing a stem cell transplant. Additionally, the company will present five-year data from the pivotal Phase 2 PACE study of ICLUSIG® (ponatinib) and findings from investigational research of TAK-659 for non-Hodgkin lymphoma and acute myeloid leukemia.
Eleven Takeda-sponsored abstracts were accepted for presentation during ASH 2017, including:
Note: All times listed are in Eastern Standard Time
ADCETRIS (brentuximab vedotin):
Multiple Myeloma/NINLARO (ixazomib):
For more information, the ASH program is available here: https://ash.confex.com/ash/2017/webprogram/start.html
ADCETRIS® (brentuximab vedotin) 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 proprietary technology by Seattle Genetics. 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 was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. In June 2016, the European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT. ADCETRIS has received marketing authorization by regulatory authorities in 65 countries. See important safety information below.
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including the Phase 3 ALCANZA trial in CD30-positive cutaneous T cell lymphoma (CTCL) and two additional Phase 3 studies, one in frontline classical Hodgkin lymphoma (ECHELON-1) and one in frontline CD30-positive mature T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics 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 is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin is contraindicated as it causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in 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.
Patients should be closely monitored 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. ADCETRIS dosing should be held for any suspected case of PML and should be permanently discontinued if a diagnosis of PML is confirmed.
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored 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. ADCETRIS should be held 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, 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. New or worsening pulmonary symptoms should be promptly evaluated and treated appropriately.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, 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 emergence of possible serious and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered. If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. 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. These patients should be monitored closely and managed according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Patients should be monitored for symptoms of PN, 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. Complete blood counts should be monitored prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.
Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.
Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported. New or worsening GI symptoms should be promptly evaluated and treated appropriately.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Liver function should be tested prior to treatment initiation and routinely monitored in patients receiving ADCETRIS. 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. However, any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered 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. The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal or hepatic impairment should be closely monitored for adverse events.
Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated, she should be clearly advised on the potential risk to the fetus.
LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.
Serious adverse drug reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.
In the clinical studies of ADCETRIS, adverse reactions defined as very common (≥1/10) were: infection, upper respiratory tract infection, neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea, vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia, arthralgia, fatigue, chills, pyrexia, infusion-related reactions and weight decreased. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex, anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating polyneuropathy, ALT/AST increased, rash, and back pain.
BOXED WARNING WARNING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
Contraindication ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
Most Common (≥20%) Adverse Reactions
Relapsed classical HL and relapsed sALCL: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.
Classical HL post-auto-HSCT Consolidation: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).
Use in Specific Populations
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.
Advise males with female sexual partners of reproductive potential to use effective contraception during, and for at least 6 months after the final dose of ADCETRIS treatment.
Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.
NINLARO® (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as in relapsed or refractory systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review. In the U.S., NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.
The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of six ongoing pivotal trials – five, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:
In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.
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.
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
ICLUSIG is a kinase inhibitor. The primary target for ICLUSIG is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG was designed using ARIAD's computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. ICLUSIG targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs. ICLUSIG which received full approval from the FDA in November 2016, is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.
In the U.S., ICLUSIG is a kinase inhibitor indicated for the:
Limitations of use:
ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.
U.S. IMPORTANT SAFETY INFORMATION
Based on the Phase 2 48-month follow-up analysis (N=449), except where noted
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning.
Warnings and Precautions
Arterial Occlusions: Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of ICLUSIG-treated patients from the phase 1 and phase 2 trials. In the phase 2 trial, 33% (150/449) 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 multi-site vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193, 526, and 478 days, respectively. Patients with and without cardiovascular risk factors, some age 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing arterial occlusive events, interrupt or stop ICLUSIG.
Venous Thromboembolism: Venous thromboembolic events occurred in 6% (25/449) of ICLUSIG-treated patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. 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 ICLUSIG-treated patients (29/449). Nine percent of patients (39/449) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (14 patients each; 3%). 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: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in a patient within one week of starting ICLUSIG. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity 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. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity 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% (306/449) of ICLUSIG-treated patients. Fifty-three patients (12%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during ICLUSIG use and treat hypertension to normalize blood pressure. 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 occurred in 7% (31/449, 6% serious or grade 3/4) of ICLUSIG-treated patients. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449). The median time to onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. Check serum lipase every 2 weeks for the first 2 months and then 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 less than 1.5 x ULN.
Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent ICLUSIG 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to single agent 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-treated patients, ICLUSIG-treated patients 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: Peripheral and cranial neuropathy have occurred in ICLUSIG-treated patients. Overall, 20% (90/449) of ICLUSIG-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness (2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of ICLUSIG-treated patients (<1%, 3/449 - grade 3/4). Of the patients who developed neuropathy, 26% (23/90) 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 ICLUSIG-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of ICLUSIG-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. 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: Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with ICLUSIG. Hemorrhage occurred in 28% (124/449) of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449) each. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.
Fluid Retention: Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with ICLUSIG. One instance of brain edema was fatal. For fluid retention events occurring in >2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, <1%).
In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.
Cardiac Arrhythmias: Arrhythmias occurred in 19% (86/449) of ICLUSIG-treated patients, of which 7% (33/449) were grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being grade 3 or greater. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of ICLUSIG-treated patients.
Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients 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 (1 patient 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 as an adverse reaction in 59% (266/449) of ICLUSIG-treated patients and grade 3/4 myelosuppression occurred in 50% (226/449) of patients. The incidence of these events was greater in patients with AP-CML, 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% (31/449) 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): Postmarketing cases of reversible posterior leukoencephalopathy syndrome (RPLS—also known as Posterior Reversible Encephalopathy Syndrome (PRES)) 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 (MRI) 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.
Compromised Wound Healing and Gastrointestinal Perforation: Since ICLUSIG may compromise wound healing, interrupt ICLUSIG for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.
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: Overall, the most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
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: ICLUSIG can cause fetal harm when administered to pregnant women. Advise females to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. 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 six days after last dose.
For US Prescribing Information: http://www.iclusig.com/pi
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