On November 2, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that it will present a total of 18 company sponsored abstracts at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) , to be held in San Diego from December 1 to December 4, 2018 (Press release, Takeda, NOV 2, 2018, View Source [SID1234530662]). Takeda’s presentations will reveal new clinical trial data from the entire hematology portfolio of the company. In particular, Takeda will present data from phase 3 clinical trials of TOURMALINE-MM3 and ECHELON-2.

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"With the presentation of data from two phase 3 clinical trials as well as our products under development, Takeda continues to increase the evidence about new therapeutic options to improve the way cancer patients are treated," said Dr. Christophe Bianchi, President, Takeda Global Oncology Business Unit. «The positive data from the TOURMALINE-MM3 trial, the first and only placebo-controlled phase 3 study to evaluate a proteosome inhibitor in this setting, showed that with the use of NINLARO as a maintenance treatment after autologous stem cell transplantation, it improved progression-free survival in the control group, highlighting the potential use of NINLARO as maintenance therapy in a patient population where options are limited at this time. In turn, positive data from the ECHELON-2 trial showed that in patients with peripheral CD-30 positive T-cell lymphoma without prior treatment, ADCETRIS in combination with chemotherapy was superior to the control group in terms of progression-free survival and Survival in general, which represents an important milestone for ADCETRIS as a potential therapy in this environment where the standard of medical care has not changed in several decades ».

At this year’s ASH (Free ASH Whitepaper) meeting, for the first time in an oral session on Sunday, December 2 at 7:30 a.m. Pacific Standard Time, the data from the phase 3 TOURMALINE-MM3 trial that assesses the effect of NINLARO (ixazomib) as maintenance therapy in adult patients diagnosed with multiple myeloma who responded to high-dose therapies (HDT) and autologous stem cell transplantation (ASCT, for its acronym in English). The TOURMALINE-MM3 trial achieved its main endpoint when the use of NINLARO resulted in a statistically significant improvement in progression-free survival (PFS, for its acronym in English) versus placebo as assessed by the Independent Review Committee (IRC). No new safety signs were found in TOURMALINE-MM3 and the safety profile of NINLARO in the maintenance environment is consistent with previously reported results regarding the use of NINLARO as a single agent. At present, NINLARO is not approved for use as a single agent in the post-ASCT maintenance environment.

Data from the ECHELON-2 Phase 3 trial will be presented during an oral session on Monday, December 3 at 6:15 p.m. Pacific Standard Time. The trial demonstrated a statistically significant improvement in the PFS of ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) versus the control group, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The first-line data from ECHELON-2 were reported in October 2018. The results of the trial showed that the combined treatment with ADCETRIS plus CHP was superior to the control group in terms of PFS as evaluated by an Independent Review Center (IRF, for its acronym in English, risk index = 0.71, p value = 0.0110). All key secondary endpoints, including total survival, were statistically significant in favor of the ADCETRIS plus CHP group, along with the manageable safety profile. Currently ADCETRIS is not approved for the first line of treatment of PTCL (peripheral T-cell lymphoma).

The variety of Takeda in terms of research and development will be further exhibited through the different presentations focused on multiple myeloma, lymphoma, chronic myeloid leukemia and myelodysplastic syndromes (MDS).

Presentations of the 18 abstracts sponsored by Takeda Oncology were accepted at ASH (Free ASH Whitepaper) 2018, including:

Note: All times shown in the list are expressed in Pacific Standard Time.

ADCETRIS (brentuximab vedotina)

The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A + CHP) Versus CHOP in the Frontline Treatment of Patients with CD30 + Peripheral T-Cell Lymphomas . (ECHELON-2 trial: results of a randomized double-blind, active-phase phase 3 study of the drug brentuximab vedotin and CHP (A + CHP) versus CHOP in the first line of treatment in patients with T-cell lymphomas peripherals CD30 +). Summary 997. Oral presentation. Monday, December 3, 2018, 6:15 to 7:45 pm (San Diego Convention Center, Room 6F).
Older Patients (pts) with Previously Untreated Classical Hodgkin Lymphoma (cHL): A Detailed Analysis from the Phase 3 ECHELON-1 Study . (Elderly patients with classic Hodgkin’s lymphoma without previous treatment (cHL): Detailed analysis of the ECHELON-1 phase 3 study). Summary 1618. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice Irrespective of CD30 Level or Large Cell Transformation Status in the Phase 3 REACH Study . (Superior clinical benefit of the drug brentuximab vedotin for the treatment of mycosis fungoides versus medical choice regardless of the concentration of CD30 or the state of transformation of large cells in the phase 3 study REACH). Summary 1646. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 ECHELON-1 Study . (Brentuximab vedotin in adolescents and young adults (AYA) with stage III or IV Hodgkin lymphoma: Analysis of a subgroup of the phase 3 study ECHELON-1). Summary 1647. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study . (Brentuximab vedotin together with chemotherapy treatment in patients with classic late stage Hodgkin lymphoma (cHL): evaluation of modified progression free survival (mPFS) and traditional PFS in the phase 3 ECHELON-1 study). Summary 2904. Sunday, December 2, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
Resolution of Peripheral Neuropathy (PN) in Patients Who Received A + AVD or ABVD in the Phase 3 ECHELON-1 Trial . (Resolution of peripheral neuropathy (NP) in patients who received A + ADL or ABVD in the phase 3 trial ECHELON-1). Summary 2921. Sunday, December 2, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
Phase 1 Results From a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin plus Doxorubicin, Vinblastine and Dacarbazine (A + AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL) . (Phase 1 results of a phase 1/2 study to evaluate the safety, tolerability, and recommended phase 2 dose (RP2D) of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) in pediatric patients with Hodgkin’s lymphoma classic (cHL) in advanced stage recently diagnosed). Summary 1644. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Multiple myeloma / NINLARO (ixazomib)

Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial. (Maintenance therapy with oral proteasome inhibitor (PI) ixazomib significantly prolongs progression free survival (PFS) after autologous stem cell transplantation (ASCT) in patients with recently diagnosed multiple myeloma (NDMM). ): phase 3 trial TOURMALINE-MM3). Summary 301. Oral presentation. Sunday December 2, 2018, 7:30 a.m. to 9:00 a.m. (Marriott Marquis San Diego Marina, Grand Ballroom 7).
Addition of Ixazomib to an Rd Backbone Improves Clinical Benefit in Relapsed / Refractory Multiple Myeloma (RRMM) Patients (Pts) with Non-Canonical NF-KB Activation – Results from the TOURMALINE-MM1 Study . (The addition of ixazomib to a main treatment with Rd improves the clinical benefit in patients with refractory / recurrent multiple myeloma (RRMM) with activation of the noncanonical NF-KB pathway: results of the TOURMALINE-MM1 study). Summary 473. Oral presentation. Sunday, December 2, 2018, 4:30 a.m. to 6:00 p.m. (Marriott Marquis San Diego Marina, Grand Ballroom 7).
Patient Treatment Preferences for Relapsed / Refractory Multiple Myeloma: Are Patients Willing to Trade Off Efficacy for Tolerability? . (Preferred treatment of the patient with refractory or recurrent multiple myeloma: Are patients willing to sacrifice efficacy for tolerability?). Summary 614. Oral presentation. Monday, December 3, 2018, 7:00 a.m. to 8:30 a.m. (San Diego Convention Center, Room 11B).
Ixazomib Plus Lenalidomide-Dexamethasone (IRd) in Relapsed / Refractory Multiple Myeloma (MM) Patients (Pts) – Effectiveness in Routine Clinical Practice Is Similar to the Efficacy in the Phase 3 TOURMALINE-MM1 Trial: A Pooled Analysis from the INSIGHT MM Observational Study and the Czech Registry of Monoclonal Gammopathies (RMG). (Ixazomib in addition to lenalidomide and dexamethasone (IRd) in patients with refractory or recurrent multiple myeloma.) Effectiveness in routine clinical practice is similar to efficacy in the Phase 3 TOURMALINE-MM1 trial: a combined analysis based on the observational study INSIGHT-MM and the Czech Registry of Monoclonal Gammapathies (RMG)). Summary 1971. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Socio-Demographic Features and Societal Perspective of Relapse and / or Refractory Multiple Myeloma (RRMM) Patients in Spain: An Interim Analysis of CHARISMMA Study . (Sociodemographic characteristics and social perspective of patients with refractory or recurrent multiple myeloma (RRMM) in Spain: interim analysis of the CHARISMMA study). Summary 2300. Saturday, December 1, 2018, 6:15 a.m. to 8:15 p.m. (San Diego Convention Center, Room GH).
Transplant Status Does Not Impact the Selection of Induction Regimens for Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) in the INSIGHT MM Prospective, Observational Study . (The status of the transplant does not affect the selection of induction regimens for patients recently diagnosed with multiple myeloma (NDMM) in the observational and prospective INSIGHT MM study). Summary 3289. Sunday, December 2, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
Dynamic Changes in International Staging System As a Predictor of Survival Outcome in Patients with Advanced Multiple Myeloma . (Dynamic changes in the international classification system by stages as a predictor of survival outcomes in patients with advanced multiple myeloma). Summary 4438. Monday, December 3, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
ICLUSIG (ponatinib)

Real-World Comparisons of Cardiovascular Events between Different Tyrosine Kinase Inhibitors Among Patients with Chronic Myeloid Leukemia . (Comparisons of the usual clinical practice of cardiovascular events among different tyrosine kinase inhibitors among patients with chronic myeloid leukemia). Summary 3567. Sunday, December 2, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
Products in development (Lymphoma, multiple myeloma, myelodysplastic syndromes)

Patient Characteristics and Treatment Patterns in the First-Line and Second-Line Treatment of Diffuse Large B-Cell Lymphoma and Follicular Lymphoma in the United Kingdom, France, and Germany . (Characteristics of patients and treatment patterns in the first and second line of treatment of diffuse large B-cell lymphoma and follicular lymphoma in the United Kingdom, France and Germany). Summary 4234. Monday, December 3, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
A Single Administration of the Cytolytic CD38 Antibody TAK-079 to Healthy Subjects: Tolerability, Pharmacokinetics and Pharmacodynamics . (A single dose of TAK-079 antibody against the cytolytic CD38 antigen in healthy subjects: tolerability, pharmacokinetics, and pharmacodynamics). Summary 3249. Sunday, December 2, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
Assessing Patient-Reported Outcomes in People with Myelodysplastic Syndromes: Can a Customized Selection of Items from the EORTC Library Enhance the EORTC QLQ-C30? (Evaluation of the results reported by patients in people with myelodysplastic syndromes: Can the EORTC QLQ-C30 quality of life questionnaire be improved with a personalized selection of elements from the EORTC library (abbreviations in English of the European Organization for the Cancer Research and Treatment)?). Summary 4856. Monday, December 3, 2018, 6:00 a.m. to 8:00 p.m. (San Diego Convention Center, Room GH).
For more information, check the ASH (Free ASH Whitepaper) program here: View Source

About ADCETRIS
ADCETRIS is a drug-conjugated antibody (ADC) comprising an anti-CD30 monoclonal antibody bound by a protease-sensitive ligand to an agent that alters the microtubule network, monomethyl auristatin E ( MMAE), using patented Seattle Genetics technology. The ADC uses a binding system that is designed to be stable in the bloodstream but that releases MMAE after internalization in the tumor cells that express the CD30 antigen.

ADCETRIS injectable intravenous infusion has received authorization from the FDA for five indications in adult patients with: (1) stage III or IV non-pretreated classic Hodgkin lymphoma (LHc), in combination with chemotherapy, (2) LHc with high risk of recurrence or progression as consolidation after autologous hemopoietic stem cell transplantation (HMSTT), (3) LHc after failure of HMST or failure of at least two previous chemotherapy regimens with several agents in patients who are not suitable for TACMH, (4) LACGs after the failure of at least one previous chemotherapy regimen with several agents,and (5) anaplastic cutaneous primary large cell lymphoma (LACGpc) or mycosis fungoides (MF) with CD30 expression that has received prior systemic treatment.

Health Canada granted ADCETRIS authorization with conditions for recurrent or refractory Hodgkin’s lymphoma and the LACGs in 2013, and unconditional authorization for post-autologous stem cell transplantation (MAHT) treatment of patients with Hodgkin’s lymphoma with increased risk of recurrence or progression.

ADCETRIS received the conditional marketing authorization from the European Commission in October 2012. The indications authorized in Europe are: (1) for the treatment of adult patients with positive Hodgkin’s lymphoma for recurrent or refractory CD30 after TACM, or after at least two previous therapies when the TACM or the chemotherapy with several agents is not a treatment option, (2) the treatment of adult patients with recurrent or refractory ALCL, (3) for the treatment of adult patients with positive Hodgkin’s lymphoma for CD30 with increased risk of recurrence or progression following the TACM, and (4) for the treatment of adult patients with cutaneous T-cell lymphoma (CTCL) positive for CD30 after at leasta previous systemic therapy.

ADCETRIS has received marketing authorization from regulatory authorities in more than 70 countries for the treatment of recurrent or refractory Hodgkin’s lymphoma and for LACGs. See the important safety information below.

ADCETRIS is being widely evaluated in more than 70 clinical trials, including a phase 3 study as a first-line treatment of Hodgkin’s lymphoma (ECHELON-1) and another phase 3 study as a first-line treatment of peripheral T-cell positive lymphomas for CD30 (ECHELON-2), as well as assays in many other types of neoplasms that express the CD30 antigen.

Seattle Genetics and Takeda develop ADCETRIS together. Under the terms of the cooperation agreement, Seattle Genetics has the marketing rights in the US. UU and Canada, and Takeda has the commercialization rights of ADCETRIS in the rest of the world. Seattle Genetics and Takeda finance the cost of the joint development of ADCETRIS in equal parts, except in Japan, where Takeda is exclusively responsible for development costs.

Important safety information of ADCETRIS (brentuximab vedotina) (European Union)

See the Summary of Product Characteristics (SmPC) before prescribing.

CONTRAINDICATIONS

ADCETRIS is contraindicated in patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, the combined use of ADCETRIS with bleomycin is contraindicated since it causes pulmonary toxicity.

SPECIAL WARNINGS AND PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): in patients treated with ADCETRIS, who had previously received several chemotherapy regimens, reactivation of John Cunningham virus (VJC) was reported, resulting in progressive multifocal leukoencephalopathy (PML) and, in some cases, to the death. PML is a rare demyelinating disease of the central nervous system that causes a reactivation of latent VJC and is usually fatal.

Patients should be monitored closely for neurological, cognitive or behavioral signs or symptoms, new or worsening, which may be indicative of PML. The suggested evaluation of PML includes consultation of neurology, magnetic resonance imaging of the brain contrasted with gadolinium, and analysis of cerebrospinal fluid to detect VJC DNA by polymerase chain reaction (PCR) or a brain biopsy with evidence of VJC. A negative CPR to VCJ does not exclude a LMP. Additional monitoring and evaluation must be ensured if there is no alternative diagnosis. Dosing of ADCETRIS should be discontinued if a case of PML is suspected and should be permanently discontinued if the diagnosis of PML is confirmed.

Pay attention to symptoms of PML that may go unnoticed by the patient (eg, cognitive, neurological, or psychiatric).

Pancreatitis: acute pancreatitis has been observed in patients treated with ADCETRIS. Some fatal case has been reported. Patients who present or worsen abdominal pain, which may suggest acute pancreatitis, should be monitored closely. The patient’s evaluation may include a physical examination, laboratory tests to evaluate serum amylase and lipase, and abdominal imaging studies, such as ultrasound and other appropriate diagnostic methods. The use of ADCETRIS should be discontinued in any case of suspected acute pancreatitis. If the diagnosis of acute pancreatitis is confirmed, treatment with ADCETRIS should be stopped.

Pulmonary toxicity: cases of pulmonary toxicity were reported, some with fatal outcome, including pneumonitis, interstitial lung disease and acute respiratory distress syndrome (ARDS), in patients receiving ADCETRIS. Although a causal association has not been established with the use of ADCETRIS, the risk of pulmonary toxicity can not be ruled out. New or aggravated pulmonary symptoms should be evaluated and treated promptly and appropriately. It may be necessary to suspend the dose during the evaluation and until the symptoms improve.

Severe and opportunistic infections: in patients treated with ADCETRIS, serious infections were reported, in particular, pneumonia, staphylococcal bacteremia, sepsis / septic shock (with fatal outcome) and herpes zoster and opportunistic infections, in particular, Pneumocystis jiroveci pneumonia and candidiasis oral. Patients should be monitored with great attention during treatment to detect the onset of opportunistic and serious infections.

Reactions related to the infusion (RRI): Immediate and delayed infusion-related reactions (RRI) have been reported with the use of ADCETRIS, as well as anaphylactic reactions. Patients should be carefully monitored during and after the infusion. If an anaphylactic reaction occurs, the administration of ADCETRIS should be stopped immediately and permanently and appropriate medical treatment should be administered. If a reaction related to the infusion occurs, the infusion should be interrupted and appropriate medical treatment instituted. The infusion can be restarted at a slower rate after resolution of the symptoms. Patients who have suffered a reaction related to the previous infusion should be premedicated before the next infusions.

Tumor lysis syndrome (TLS): cases of TLS have been reported with ADCETRIS. Patients with tumors of rapid proliferation and high tumor burden are at risk of having an SLT. These patients should be closely monitored and their symptoms should be managed in accordance with the best medical practices.

Peripheral neuropathy (NP): treatment with ADCETRIS can cause PN, both sensory and motor. The NP induced by ADCETRIS is usually cumulative and reversible in most cases. Patients should be monitored for NP symptoms, such as hypesthesia, hyperesthesia, paraesthesia, malaise, burning sensation, neuropathic pain, or weakness. In the case of patients experiencing a new NP or a worsening of their NP, a delay and reduction in the dose or interruption of ADCETRIS may be required.

Haematological toxicities : ADCETRIS can cause grade 3 or 4 anemia, thrombocytopenia and prolonged grade 3 or 4 neutropenia (equal to or greater than one week). Complete blood counts should be monitored before administration of each dose.

Febrile neutropenia: cases of febrile neutropenia have been reported. In that case, patients should be monitored closely to detect fever due to neutropenia and treated according to the best medical practices.

Stevens-Johnson syndrome (SJS): with ADCETRIS, cases of SJS and toxic epidermal necrolysis (NET) were reported. Deadly cases were reported. In case of SJS or NET, treatment with ADCETRIS should be interrupted and adequate medical treatment administered.

Gastrointestinal complications (CGI): Gastrointestinal complications, including fatal cases, such as intestinal obstruction, ileus, enterocolitis, neutropenic colitis, gastric erosion, ulcer, perforation and hemorrhage were reported. New or aggravated gastrointestinal symptoms should be evaluated quickly and treated appropriately.

Hepatotoxicity: Increases in the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal cases, have also been reported. Liver function should be evaluated before starting treatment and routine controls should be performed in patients receiving ADCETRIS. Patients who experience hepatotoxicity may require a delay or modification of the dose or an interruption of ADCETRIS.

Hyperglycaemia: Cases of hyperglycaemia have been reported during trials in patients with a high body mass index (BMI) with or without a history of diabetes mellitus. In all patients who experience a hyperglycemic event, their serum glucose must be closely monitored. A diabetes treatment should be administered when appropriate.

Renal and hepatic insufficiency: the experience in patients with renal and hepatic insufficiency is limited. The available data indicate that the elimination of MMAE could be affected by severe renal insufficiency, hepatic insufficiency and by low serum concentrations of albumin.

LCCT positive for CD30: the size of the effect of treatment on subtypes of CD30 positive to CD30 other than mycosis fungoides (MF) and cutaneous primary anaplastic large cell lymphoma (LACGpc) is unclear due to lack of evidence of high level. In two ADCETRIS phase II studies with a single group, the activity of the disease manifested itself in subtypes of Sézary syndrome (SS), lymphomatoid papulosis (PL) and mixed histology CTCL. These data suggest that efficacy and safety can be extrapolated to other CD30-positive subtypes of CTCL. The efficacy and safety of each patient should be carefully evaluated and carefully administered in other types of patients with CD30-positive CTCL.

Sodium content in the excipients: ADCETRIS contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. This should be taken into account in patients with a low sodium diet.

INTERACTIONS
Patients who concomitantly receive a potent inhibitor of CYP3A4 and glycoprotein P (P-gp) with ADCETRIS may be at increased risk of neutropenia and should be closely monitored. The concomitant administration of ADCETRIS with CYP3A4 inducers did not alter the plasma exposure of ADCETRIS; however, it apparently reduced the plasma concentrations of the MMAE metabolites analyzed. ADCETRIS is not expected to alter exposure to drugs metabolized by CYP3A4 enzymes.

PREGNANCY: women of childbearing age should use two effective contraceptive methods during treatment with ADCETRIS and up to 6 months after treatment. No data are available on the use of ADCETRIS in pregnant women; however, studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus.

BREASTFEEDING (breastfeeding): no data are available on the excretion of ADCETRIS or its metabolites in human milk; therefore, the risk in newborns and infants can not be excluded. In case of possible risks, the decision must be made to interrupt breastfeeding or to suspend or refrain from receiving treatment with ADCETRIS.

FERTILITY: in non-clinical studies, treatment with ADCETRIS has caused testicular toxicity and can alter male fertility. Men treated with this medication are advised not to father a child during treatment and for up to 6 months after receiving the last dose of ADCETRIS.

Effects on the ability to drive and use machines: ADCETRIS may slightly affect the ability to drive and use machines.

UNDESIRABLE EFFECTS
The most frequent adverse reactions (≥10%) were: infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, reactions related to infusion, pruritus, constipation, dyspnea, weight loss, myalgia and abdominal pain.

Serious adverse reactions to the medication were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, lysis syndrome tumor and Stevens-Johnson syndrome. Serious adverse reactions to the drug occurred in 12% of patients. The frequency of serious and unique adverse reactions to the medication was ≤1%.

Important safety information for ADCETRIS (brentuximab vedotina) in the United States

BOX OF WARNINGS: PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY (LMP)

In patients treated with ADCETRIS, infection with the JC virus can occur, which can lead to PML and even death.

Contraindications
The combined use of ADCETRIS with bleomycin is contraindicated, as it causes pulmonary toxicity (eg, interstitial infiltration or inflammation).

Warnings and precautions

Peripheral neuropathy (NP): treatment with ADCETRIS causes a peripheral neuropathy that is predominantly sensitive. Cases of peripheral motor neuropathy were also reported. Peripheral neuropathy induced by ADCETRIS is cumulative. Control patients to detect symptoms: hypesthesia, hyperesthesia, paraesthesia, malaise, burning sensation, pain or neuropathic weakness. Implement dose modifications if appropriate.

Anaphylaxis and infusion reactions: with ADCETRIS, reactions related to the infusion, including anaphylaxis, have occurred. Control patients during infusion. If a reaction related to the infusion occurs, stop it and implement appropriate medical treatment. If anaphylaxis occurs, stop the infusion immediately and permanently and administer the appropriate medical treatment. Patients who have suffered a previous reaction related to the infusion should be premedicated to receive the following infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Haematological toxicities : Anemia or thrombocytopenia of grade 3 or 4 and prolonged severe neutropenia (≥ 1 week) may occur with ADCETRIS. Cases of febrile neutropenia with ADCETRIS were also reported. Monitor the complete blood count before each dose of ADCETRIS and consider more frequent monitoring in patients with grade 3 or 4 neutropenia. Monitor patients for fever. If grade 3 or 4 neutropenia appears, consider delaying, reducing or stopping doses or using prophylaxis with G-CSF.

Serious and opportunistic infections: In patients treated with ADCETRIS, infections such as pneumonia, bacteremia and sepsis / septic shock (including fatal cases) were reported. Closely monitor patients during treatment to detect the appearance of possible bacterial, mycotic or viral infections.

Tumor lysis syndrome: closely monitor patients with tumors of rapid proliferation and high tumor burden.

Increased toxicity in the presence of severe renal impairment: the frequency of adverse reactions of grade 3 or higher and deaths was higher in patients with severe renal impairment compared to patients with normal renal function. Avoid administration of ADCETRIS in patients with severe renal impairment.

Greater toxicity in the presence of moderate or severe hepatic insufficiency: the frequency of adverse reactions of grade 3 or higher and deaths was higher in patients with moderate or severe hepatic insufficiency compared to patients with normal hepatic function. Avoid administration of ADCETRIS in patients with moderate or severe hepatic impairment .

Hepatotoxicity : with ADCETRIS, there have been serious and even fatal cases of hepatotoxicity. The cases were compatible with hepatocellular injury and included increased transaminases or bilirubin and appeared after the first dose of ADCETRIS or after reintroduction of the drug. The risk of hepatotoxicity may also increase in the case of pre-existing liver diseases, high initial levels of liver enzymes and concomitant medications. Control liver enzymes and bilirubin. In the case of patients who present hepatotoxicity for the first time, its worsening or recurrence, consider the possibility of delaying, modifying or interrupting ADCETRIS doses.

Progressive multifocal leukoencephalopathy (PML): in patients treated with ADCETRIS, JC virus infections that caused PML and death were reported. The onset of symptoms occurred at different times, from the beginning of therapy with ADCETRIS, and in some cases they occurred 3 months after the initial exposure. In addition to treatment with ADCETRIS, other possible factors that cause PML include previous therapies and an underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient who has recent signs and symptoms of central nervous system abnormalities. Suspend the administration of ADCETRIS if PML is suspected and interrupt its administration if the diagnosis of PML is confirmed.

Pulmonary toxicity: cases of non-infectious pulmonary toxicity, including pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported, some with fatal results. Monitor patients for signs and symptoms of pulmonary toxicity, such as dyspnea and cough. In case of appearance or worsening of pulmonary symptoms, stop the administration of ADCETRIS during the evaluation and until the symptoms improve.

Severe dermatological reactions: with ADCETRIS, cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (NET), including fatal cases, have been reported. If a case of SJS or NET occurs, discontinue treatment with ADCETRIS and administer appropriate medical treatment.

Gastrointestinal complications (CGI): In patients treated with ADCETRIS, cases of acute pancreatitis, including fatal outcomes, have been reported. Other serious and fatal GI complications have also been reported in patients treated with ADCETRIS, including perforation, hemorrhage, gastric erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. In case of pre-existing lymphoma and CGI, the risk of perforation could increase. In the event that a patient presents new CGI or its worsening, an immediate diagnostic evaluation should be performed and adequate treatment administered.

Embryo-Fetal Toxicity: Based on the mechanism of action and studies performed on animals, ADCETRIS can cause fetal harm. Warn women of childbearing age about the potential risk to the fetus and that they should avoid pregnancy during treatment with ADCETRIS and for at least 6 months after the final dose of ADCETRIS. Most frequent adverse reactions (≥20%): peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection and pyrexia.

Drug Interactions
Concomitant use of potent inhibitors or inducers of CYP3A4, or P-gp inhibitors, could affect exposure to monomethyl auristatin E (MMAE).

Use in specific populations
Patients with moderate or severe hepatic impairment and patients with severe renal impairment: increased exposure to MMAE and more adverse reactions appear. Avoid its use.

Men with sexual partners of childbearing age should be advised to use effective contraception during treatment with ADCETRIS and for at least 6 months after the final dose of ADCETRIS.

Patients should be advised to report immediately if they become pregnant and to avoid breastfeeding while receiving ADCETRIS.

For more important safety information, including the WARNING BOX, see the complete prescription information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com .

About ICLUSIG (ponatinib) in tablets

ICLUSIG is a kinase inhibitor. The main objective of Iclusig is BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and in acute lymphoblastic leukemia with positive Philadelphia chromosome (Ph + ALL). ICLUSIG has been designed using the ARIAD structure-based drug design computing platform, specifically to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG is used to treat both native BCR-ABL1 and mutations resistant to BCR-ABL1 treatment, including the strongest T315I mutation of all. INCLUSIG is the only approved tyrosine kinase inhibitor that demonstrates activity against the mutation of the T315I gatekeeper of BCR-ABL1 .This mutation has been associated with resistance to other approved tyrosine kinase inhibitors. ICLUSIG, which received full approval from the FDA in November 2016, also obtained approval in the European Union, Australia, Switzerland, Israel, Canada and Japan.

In the USA UU., ICLUSIG is indicated for:

Treatment of adult patients with chronic myeloid leukemia or Ph + ALL in chronic phase, accelerated phase or blast phase, for whom another therapy with tyrosine kinase inhibitors (TKI) is not indicated.
Treatment of adult patients with chronic myeloid leukemia with presence of T315I mutation (chronic phase, accelerated phase or blast phase) or acute lymphoblastic leukemia with positive Philadelphia chromosome (Ph + ALL) and presence of T315I mutation.
Limitations of use: ICLUSIG is not indicated or recommended for the treatment of recently diagnosed patients with CML in the chronic phase.

IMPORTANT SAFETY INFORMATION (US) OF ICLUSIG (ponatinib)

CAUTION: BLOOD OCCLUSION, VENOUS THROMBOEMBOLIS, CARDIAC INSUFFICIENCY, and HEPATOTOXICITY

See the prescription for complete information on the warning box.

Arterial occlusion has occurred in at least 35% of patients treated with ICLUSIG (ponatinib), which includes fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease and the need for urgent procedures of revascularization. Patients with and without cardiovascular risk factors, including patients younger than 50 years, experienced these events. Interrupt or stop ICLUSIG immediately if arterial occlusion occurs. A risk-benefit consideration must be made before retaking ICLUSIG.
Venous thromboembolism has occurred in 6% of patients treated with ICLUSIG. Monitor that there is no presence of thromboembolism. Consider modifying the dose or discontinuing the use of ICLUSIG in patients who develop severe venous thromboembolism.
Heart failure, including death, occurred in 9% of patients treated with ICLUSIG. Monitor cardiac function Interrupting or stopping the use of ICLUSIG if new heart insufficiencies appear or existing insufficiencies worsen.
Hepatotoxicity, liver failure and death have occurred in patients treated with ICLUSIG. Monitor liver function. Discontinue the use of ICLUSIG if hepatotoxicity is suspected.
WARNINGS AND PRECAUTIONS
Arterial occlusions:arterial occlusion, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, has occurred in at least 35% of patients treated with ICLUSIG in phase 1 and phase 2 clinical trials In the phase 2 trials, 33% (150/449) of the patients treated with ICLUSIG experienced a cardiovascular (21%), peripheral (12%) or cerebrovascular (9%) event; some patients suffered more than one type of event. Fatal and potentially fatal events occurred 2 weeks after starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent vascular occlusion or in several places. Patients have required revascularization procedures. The mean time for the onset of the first arterial cardiovascular, cerebrovascular and peripheral vascular occlusive events was 193, 526 and 478 days, respectively. Patients with and without cardiovascular risk factors, some 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia and a history of heart disease. Occlusive arterial events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes or hyperlipidemia.

Venous thromboembolism: venous thromboembolism events occurred in 6% of patients treated with ICLUSIG, with an incidence rate of 5% (13/270 CML-CF), 4% (3/85 CML-FA), 10% (6/62 LMC-FB) and 9% (3/32 LLA Ph +). These events include: deep vein thromboembolism, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with loss of vision. Consider modifying the dose or discontinuing the use of ICLUSIG in patients who develop severe venous thromboembolism.

Heart failure:fatal or severe heart failure, or left ventricular dysfunction has occurred in 6% of patients treated with ICLUSIG (29/499). Nine percent of patients (39/449) suffered some degree of heart failure or left ventricular dysfunction. Heart failure events reported most frequently were congestive heart failure and decreased ejection fraction (14 patients each, 3%). Supervise patients and verify that there are no signs or symptoms of heart failure; if they exist, treat according to clinical indications, which may include the interruption of ICLUSIG. Consider discontinuing use if the patient develops severe heart failure.

Hepatotoxicity:ICLUSIG can cause hepatotoxicity, which includes liver failure and death. Fulminant and fatal hepatic failure occurred only in one patient, one week after beginning treatment with ICLUSIG. Two additional fatal cases of acute liver failure also occurred. Fatal cases occurred in patients with CML-FB or Ph + ALL. Severe hepatotoxicity occurred in all cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were increases in AST or ALT (54% in all grades, 8% in grade 3 or 4, 5% without reversion at the last follow-up), bilirubin and alkaline phosphatase. Hepatotoxicity events were observed in 29% of patients. The mean time for the onset of hepatotoxicity was 3 months. Monitor liver function at the beginning of treatment and then once a month, at least, or according to clinical indications. Interrupt, reduce or suspend the use of ICLUSIG according to clinical indication.

Hypertension:the increase in systolic or diastolic blood pressure (BP), emerging from treatment, occurred in 68% (306/449) of the patients treated with ICLUSIG. Fifty-three patients (12%) experienced symptomatic hypertension emerging from treatment as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headaches, chest pains or shortness of breath. In patients with a base systolic BP of <140 mm Hg and a base diastolic BP of <90 mm Hg, 80% (229/285) suffered from hypertension emerging from the treatment; 44% (124/285) developed stage 1 hypertension and 37% stage 2 hypertension. In 132 patients with stage 1 hypertension as a basis, 67% (88/132) developed stage 2 hypertension. Monitor and control blood pressure increases during the use of ICLUSIG, and treat hypertension to normalize blood pressure. Reduce the dose, interrupt or stop the use of ICLUSIG if the hypertension is not medically controlled. In the event of a significant worsening, labile or refractory hypertension, discontinue treatment and consider performing an evaluation of renal artery stenosis. and treat hypertension to normalize blood pressure. Reduce the dose, interrupt or stop the use of ICLUSIG if the hypertension is not medically controlled. In the event of a significant worsening, labile or refractory hypertension, discontinue treatment and consider performing an evaluation of renal artery stenosis. and treat hypertension to normalize blood pressure. Reduce the dose, interrupt or stop the use of ICLUSIG if the hypertension is not medically controlled. In the event of a significant worsening, labile or refractory hypertension, discontinue treatment and consider performing an evaluation of renal artery stenosis.

Pancreatitis:Pancreatitis occurred in 7% (31/449, 6% severe or grade 3/4) of patients treated with ICLUSIG. The incidence of the increase in the lipase emerging from the treatment was 42% (16% grade 3 or higher). Pancreatitis resulted in suspension or interruption of treatment in 6% of patients (26/449). The mean time for the onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis were resolved in 2 weeks by interrupting or reducing the dose. Verify serum lipase levels every 2 weeks during the first 2 months and then monthly, or according to clinical indications. Consider additional supervision of serum lipase levels in patients with a history of pancreatitis or excessive alcohol consumption. An interruption or reduction of the dose may be necessary. In cases in which the increase in lipase is accompanied by abdominal symptoms, discontinue treatment with ICLUSIG and verify that the patient does not have pancreatitis. Do not consider restarting the use of ICLUSIG until the patient’s symptoms have healed and the lipase levels are less than 1.5 x ULN. stop treatment with ICLUSIG and verify that the patient does not have pancreatitis. Do not consider restarting the use of ICLUSIG until the patient’s symptoms have healed and the lipase levels are less than 1.5 x ULN. stop treatment with ICLUSIG and verify that the patient does not have pancreatitis. Do not consider restarting the use of ICLUSIG until the patient’s symptoms have healed and the lipase levels are less than 1.5 x ULN.

Increased toxicity in chronic phase CML recently diagnosed:In a prospective randomized clinical trial in the first line of treatment of patients recently diagnosed with CML in chronic phase (CF), the single agent ICLUSIG 45 mg, once a day, increased the risk of serious adverse reactions compared to the agent single imatinib 400 mg, once a day. The mean exposure to the treatment was less than 6 months. The clinical trial was suspended for safety reasons in October 2013. Thrombosis and arterial and venous occlusions occurred with at least twice the frequency by the use of ICLUSIG compared to imatinib. Compared with patients treated with imatinib, patients treated with ICLUSIG had a higher incidence of myelosuppression, pancreatitis, hepatotoxicity, heart failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated or recommended for the treatment of patients with recently diagnosed CML-FC.

Neuropathy:cases of peripheral and cranial neuropathy have occurred in patients treated with ICLUSIG. In general, 20% (90/449) of the patients treated with ICLUSIG suffered a peripheral neuropathy event of any degree (2% grade 3/4). The most common peripheral neuropathies that were reported were paresthesia (5%, 23/449), peripheral neuropathy (4%, 19/449), hypesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscle weakness (2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of patients treated with ICLUSIG (<1%, 3/449, grade 3/4). Of the patients who developed neuropathy, 26% (23/90) developed it during the first month of treatment. Supervise patients and verify that there are no symptoms of neuropathies such as hypesthesia, hyperesthesia, paraesthesia, malaise, burning sensation, neuropathic pain or weakness. Consider interrupting the use of ICLUSIG and perform an evaluation if a neuropathy is suspected.

Ocular toxicity:There have been serious cases of ocular toxicity that have generated blindness or blurred vision in patients treated with ICLUSIG. Retinal toxicity, including macular edema, retinal vein occlusion, and retinal hemorrhage, occurred in 2% of patients treated with ICLUSIG. 14% of patients suffered ocular irritation, erosion or abrasion of the cornea, dry eye, conjunctivitis, subconjunctival hemorrhage, hyperemia and edema or eye pain. Blurred vision occurred in 6% of patients. Other ocular toxicity events include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperemia, iritis, iridocyclitis, and ulcerative keratitis.

Hemorrhage: severe bleeding events occurred that may include death in 6% (28/449) of patients treated with ICLUSIG. 28% (124/449) of the patients suffered hemorrhage. The incidence of severe bleeding events was higher in patients with CML-FA, CML-FB and Ph + ALL. The most common serious bleeding events were gastrointestinal hemorrhage and subdural hematoma, with 1% (4/449) each. The majority of bleeding events, but not all, occurred in patients with grade 4 thrombocytopenia. Discontinue the use of ICLUSIG if severe or severe bleeding occurs and assess the situation.

Fluid retention: the fluid retention events considered serious occurred in 4% (18/449) of the patients treated with ICLUSIG. A case of cerebral edema proved fatal. Among the fluid retention events that occurred in> 2% of patients (emerging from treatment), severe cases include: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and peripheral edema (2/449, <1%).

In total, 31% of patients suffered fluid retention. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral inflammation (3%).

Supervise fluid retention in patients and treat it according to the clinical indication. Discontinue, reduce or suspend the use of ICLUSIG according to clinical indications.

Cardiac arrhythmias: arrhythmias occurred in 19% (86/449) of the patients treated with ICLUSIG, of which 7% (33/449) was grade 3 or higher. Ventricular arrhythmia was reported in 3% (3/86) of all arrhythmias, with only one case of grade 3 or higher. 1% (3/449) of the patients treated with ICLUSIG suffered from symptomatic bradyarrhythmias that led to the implantation of a pacemaker.

Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/499) of the patients, approximately half was grade 3 or 4. Other arrhythmias of grade 3 or 4 included syncope (9 patients, 2.0 %), tachycardia and bradycardia (2 patients each, 0.4%), and prolongation of the QT interval measured in electrocardiogram, atrial flutter, supraventricular tachycardia, atrial tachycardia, total atrioventricular block, cardiorespiratory arrest, loss of consciousness and dysfunction

In patients with signs and symptoms suggesting a slow heart rate (fainting, dizziness) or a rapid heart rate (chest pain, palpitations or dizziness), discontinue the use of ICLUSIG and assess the situation.

Myelosuppression: myelosuppression was reported as an adverse reaction in 59% (266/499) of the patients treated with ICLUSIG and myosuppression of degree 3/4 occurred in 50% (226/449) of the patients. The incidence of these events was higher in patients with CML-FA, CML-FB and Ph + ALL than in patients with CML-FC.

Severe myelosuppression (grade 3 or 4) was observed in the early phases of treatment, with a mean time to start this one month (range <1-40 months). Obtain a complete blood count every 2 weeks for the first 3 months and then monthly, or according to clinical indications, and adjust the dose as recommended.

Tumor lysis syndrome: two patients (<1%, one with CML-FA and one with CML-FB) treated with ICLUSIG developed severe tumor lysis syndrome. 7% (31/449) of the patients developed hyperuricemia. Due to the potential of patients with advanced disease to develop the tumor lysis syndrome, ensure adequate hydration and treat high levels of uric acid before starting treatment with ICLUSIG.

Posterior reversible leukoencephalopathy syndrome (RPLS): post-marketing cases of reversible posterior leukoencephalopathy syndrome (RPLS, also known as posterior reversible encephalopathy syndrome [SERP]) have been reported in patients treated with ICLUSIG. SLPR is a neurological disorder that can present signs and symptoms such as seizures, headaches, decreased mental alertness, altered mental functioning, loss of vision and other visual and neurological disorders. Usually hypertension is present and the diagnosis can be made with the findings of a magnetic resonance imaging of the brain. If the patient is diagnosed with SLPR,

Compromised healing and gastrointestinal perforation: since the use of ICLUSIG can compromise wound healing, discontinue ICLUSIG at least 1 week before any major surgical intervention. One patient suffered from severe gastrointestinal perforation (fistula), 38 days after a cholecystectomy.

Embryonic and fetal toxicity: Based on this mechanism of action and the findings of animal studies, ICLUSIG can cause fetal harm if administered to a pregnant woman. In animal reproduction studies, the oral administration of ponatinib to pregnant rats during organogenesis caused adverse effects on development at a lower exposure rate than the recommended dose for humans. Inform women about the potential risks to the fetus. Advise women with reproductive potential to use effective contraception during treatment with ICLUSIG and up to 3 weeks after the last dose.

ADVERSE REACTIONS
Most common adverse reactions: in general, the most common non-haematological adverse reactions (≥20%) were abdominal pain, rash, constipation, headaches, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea , diarrhea, increased lipase, vomiting, myalgia and pain in the extremities. Adverse hematological reactions included thrombocytopenia, anemia, neutropenia, lymphopenia and leukopenia.

To report any ADVERSE REACTION SUSPECT, contact Takeda at 1-844-T-1POINT (1-844-817-6468), or the FDA at 1-800-FDA-1088 or log on to www.fda.gov/ MedWatch .

DRUG INTERACTIONS
Potent inhibitors of CYP3A: avoid simultaneous use or reduce the dose of ICLUSIG if simultaneous use can not be avoided.
Potent inducers of CYP3A: avoid concomitant use.

Use in specific populations
Men and women with reproductive potential: ICLUSIG can cause fetal harm if administered to a pregnant woman. Advise women to use effective contraception during treatment with ICLUSIG and up to 3 weeks after the last dose. Ponatinib can impair fertility and it is not known if these effects are reversible. Verify the pregnancy status of women with reproductive potential before starting treatment with ICLUSIG.

Breastfeeding: advise women not to breastfeed during treatment with ICLUSIG and up to 6 days after the last dose.

For information on prescription in the US UU., Visit: View Source

About NINLARO (ixazomib) in capsules

NINLARO (ixazomib) is an oral inhibitor of the proteasome that is also studied through the continuity of multiple myeloma treatment frameworks, as well as systemic light chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter phase 3 clinical trials and receive approval. NINLARO was approved by the US Food and Drug Administration (FDA). UU in November 2015 after a priority review and by the European Commission in November 2016. In the USA. and Europe, 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 received the name of orphan drug in multiple myeloma, both in the USA. UU as in Europe in 2011 and for AL amyloidosis in the USA. UU and Europe in 2012. Ixazomib received the condition of innovative therapy from the US FDA. UU for relapsed or refractory systemic light chain (AL) amyloidosis, a related ultra-orphan disease, in 2014. The Ministry of Health, Labor and Welfare of Japan gave the name of orphan drug to ixazomib in 2016.

Ixazomib’s comprehensive clinical development program, TOURMALINE, includes a total of six ongoing central studies: five are jointly investigating each major population of patients with multiple myeloma, and one in light chain amyloidosis:

TOURMALINE-MM1, investigates ixazomib vs. placebo in combination with lenalidomide and dexamethasone in multiple myeloma with recurrence and / or refractory
TOURMALINE-MM2, investigates ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigates ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem cell transplantation (ASCT)
TOURMALINE-MM4, investigate ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who were not subjected to ASCT; this study is currently recruiting
TOURMALINE-MM5, investigates ixazomib plus dexamethasone vs. pomalidomide plus dexamethasone in patients with relapsed and / or refractory multiple myeloma who have become resistant to lenalidomide
TOURMALINE-AL1, investigates ixazomib plus dexamethasone vs. physician’s choice of selected regimens in patients with relapsed or refractory light chain amyloidosis; this study is currently recruiting
For more information about active enrollment in phase 3 studies, visit: View Source

In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for several patient populations in studies initiated by the researcher globally.

NINLARO (ixazomib) in capsules: important global information on safety

SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28% vs. 14% in NINLARO and placebo regimens, respectively) with platelet nadires that usually occur between days 14-21 of each 28-day cycle and recovery at level basal for the start of the next cycle. It did not result in an increase in bleeding 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 according to 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%), which occasionally required the use of antiemetic and antidiarrheal medications, as well as supportive care.

Peripheral neuropathy has been 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 described in each regimen (<1%). Monitor patients for symptoms of peripheral neuropathy and adjust the dose as needed.

Peripheral edema with NINLARO has been reported (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as needed. Adjust the dose of dexamethasone according to your prescription information or the dose of NINLARO for severe symptoms.

Skin reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of eruption reported in both regimens was the maculopapular and macular eruption. Handle the rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, hepatic injury induced by medications, hepatocellular injury, hepatic steatosis and cholestatic hepatitis with NINLARO were rarely reported. Monitor liver enzymes regularly and adjust the dose for grade 3 or 4 symptoms.

Pregnancy – NINLARO can cause fetal harm. Advise female and male patients with reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women with the potential to become pregnant should avoid becoming pregnant while taking NINLARO, because of the potential danger to the fetus. Women who take oral contraceptives should use an additional barrier method of contraception.

Lactation – It is unknown if NINLARO or its metabolites are excreted through human milk. There could be potential adverse events in breastfeeding infants and, consequently, breastfeeding should be discontinued.

SPECIAL POPULATIONS OF PATIENTS
Hepatic impairment: reduce the initial dose of NINLARO to 3 mg in patients with moderate or severe hepatic impairment.

Renal impairment: reduce the initial dose of NINLARO to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialysable and, consequently, it can be administered without considering the time of dialysis.

DRUG INTERACTIONS
It is not recommended to administer NINLARO in conjunction with strong CYP3A inducers.

ADVERSE REACTIONS
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and higher 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 were discontinued in ≤ 1% of patients in the NINLARO regimen.