On November 7, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that a total of 18 sponsored abstracts will be presented at the 60th annual conference of the American Society of Hematology (ASH) (Free ASH Whitepaper), San Diego, December 1-4, 2018 (Press release, Takeda, NOV 7, 2018, View Source [SID1234530946]). Takeda’s presentations will include new clinical trial data covering his entire hematology portfolio. In particular, Takeda will present data from Phase 3 clinical trials TOURMALINE-MM3 and ECHELON-2.
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"With the presentation of data from two Phase 3 clinical trials and our portfolio of projects, Takeda continues to expand the evidence base for new treatment options that improve the way we treat cancer patients." some blood "
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"With the presentation of data from two Phase 3 clinical trials and our portfolio of projects, Takeda continues to expand the evidence base for new treatment options that improve the way we treat cancer patients." blood, "says Christophe Bianchi, MD, president of Takeda’s International Oncology Unit. "The positive data from the TOURMALINE-MM3 trial, the first and only placebo-controlled Phase 3 study evaluating a proteasome inhibitor in this context, showed that the use of NINLARO as maintenance therapy after autologous cell transplantation strains improved progression-free survival compared to the control group, highlighting the potential use of NINLARO as maintenance therapy in a patient population for which options are currently limited. In addition, the positive data from the ECHELON-2 trial demonstrated that in patients with previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in progression-free survival and overall survival in comparison with the control group, which represents an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " potential use of NINLARO as maintenance therapy in a patient population for which options are currently limited. In addition, the positive data from the ECHELON-2 trial demonstrated that in patients with previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in progression-free survival and overall survival in comparison with the control group, which represents an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " potential use of NINLARO as maintenance therapy in a patient population for which options are currently limited. In addition, the positive data from the ECHELON-2 trial demonstrated that in patients with previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in progression-free survival and overall survival in comparison with the control group, which represents an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " maintenance in a patient population for which options are currently limited. In addition, the positive data from the ECHELON-2 trial demonstrated that in patients with previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in progression-free survival and overall survival in comparison with the control group, which represents an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " maintenance in a patient population for which options are currently limited. In addition, the positive data from the ECHELON-2 trial demonstrated that in patients with previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in progression-free survival and overall survival in comparison with the control group, which represents an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " a previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in terms of progression-free survival and overall survival compared to the control group, which is an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " a previously untreated CD30 + T-cell lymphoma, ADCETRIS combined with chemotherapy gave better results in terms of progression-free survival and overall survival compared to the control group, which is an important step for ADCETRIS as a potential treatment in this context, where the standard of care has not changed for several decades. " has not changed for several decades. " has not changed for several decades. "
At this year’s ASH (Free ASH Whitepaper) conference, data from the TOURMALINE-MM3 Phase 3 trial, which assesses the effect of NINLARO (ixazomib) as maintenance therapy in adult patients with myeloma multiple responders to high-dose treatment and autologous stem cell transplantation (GATS) will be presented for the first time during an oral session on Sunday, December 2 at 7:30 am (Pacific Time). TOURMALINE-MM3 Trial Met its Primary Endpoint with NINLARO by Achieving a Statistically Significant Improvement in Progression-Free Survival (PFS) Versus Placebo, as Assessed by an Independent Review Committee (IRC) . No new safety signal was observed during the TOURMALINE-MM3 trial and the safety profile of NINLARO in the maintenance setting is consistent with previously reported results for the use of NINLARO as a single agent. NINLARO is currently not approved for use as a single agent in the post-GSC maintenance context.
Data from the Phase 3 ECHELON-2 trial will be presented during an oral session on Monday, December 3 at 6:15 pm (Pacific Time). The trial demonstrated a statistically significant improvement in SSP with ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) compared to the CHOP control group (cyclophosphamide, doxorubicin, vincristine, prednisone). ). The main data from ECHELON-2 were published in October 2018. The results of the trial showed that a combined ADCETRIS plus CHP treatment was superior to the control group for SSP, according to the assessment of a health center. independent review (risk ratio = 0.71, p value = 0.0110). All other key secondary endpoints, including overall survival, were statistically significant in favor of the ADCETRIS plus CHP group, as well as the manageable safety profile. ADCETRIS is currently not approved for the first-line treatment of peripheral T-cell lymphoma.
The scope and depth of Takeda’s R & D activities will be unveiled in more detail during several presentations on Multiple Myeloma, Lymphoma, Chronic Myeloid Leukemia and Myelodysplastic Syndromes (MDS).
18 abstracts sponsored by Takeda Oncology were accepted for presentation during the ASH (Free ASH Whitepaper) 2018:
Note: All times mentioned refer to Pacific Standard Time
ADCETRIS (brentuximab vedotine)
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 . Abstract 997. Oral presentation. Monday, December 3, 2018, 6:15 pm – 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 . Abstract 1618. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall GH).
Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice of CD30 Level or Large Cell Transformation Status in Phase 3 ALCANZA Study . Abstract 1646. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall 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 . Abstract 1647. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall 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 Phase 3 ECHELON-1 Study . Abstract 2904. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
Resolution of Peripheral Neuropathy (PN) in Patients Who Received A + AVD or ABVD in Phase 3 ECHELON-1 Trial . Abstract 2921. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
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) . Abstract 1644. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall GH).
Multiple myeloma / NINLARO (ixazomib)
Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolonged Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial . Abstract 301. Oral presentation. Sunday, December 2, 2018, 7:30 am – 9:00 am (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 . Abstract 473. Oral presentation. Sunday, December 2, 2018, 4:30 pm – 6:00 pm (Marriott Marquis San Diego Marina, Grand Ballroom 7).
Patient Treatment Preferences for Relapsed / Multiple Refractory Myeloma: Are Patients Willing to Trade Off Efficacy for Tolerability? . Abstract 614. Oral presentation. Monday, December 3, 2018, 7:00 – 8:30 (San Diego Convention Center, Room 11B).
Ixazomib Plus Lenalidomide-Dexamethasone (IRd) in Relapsed / Refractory Multiple Myeloma (MM) Patients (Pts) – Effectiveness in Routine Clinical Practice in TransMalcin-MM1 Trials: A Pooled Analysis from the INSIGHT MM Observational Study and the Czech Registry of Monoclonal Gammopathies (RMG) . Abstract 1971. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall GH).
Socio-Demographic Features and Societal Perspective of Relapse and / or Multiple Refractive Myeloma (RRMM) Patients in Spain: An Interim Analysis of CHARISMMA Study . Abstract 2300. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall 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 . Abstract 3289. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
Dynamic Changes in International Staging System. Predictor of Survival Outcome in Patients with Advanced Multiple Myeloma . Abstract 4438. Monday, December 3, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
ICLUSIG (ponatinib)
Real-World Comparisons of Cardiovascular Events Between Different Tyrosine Kinases Inhibitors Among Patients with Chronic Myeloid Leukemia . Abstract 3567. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
Portfolio of projects (lymphoma, multiple myeloma, myelodysplastic syndromes)
Patient Characteristics and Treatment Patterns in the First-Line and Second-Line Treatment of Large Diffuse B-Cell Lymphoma and Follicular Lymphoma in the United Kingdom, France, and Germany . Abstract 4234. Monday, December 3, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
A Single Administration of the Cytolytic CD38 Antibody TAK-079 to Healthy Subjects: Tolerability, Pharmacokinetics and Pharmacodynamics . Abstract 3249. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
Assessing Patient-Reported Outcomes in People with Myelodysplastic Syndromes: Can a Customized Selection of Items from the EORTC Library Enhance the EORTC QLQ-C30? Abstract 4856. Monday, December 3, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, GH Hall).
For more information, the ASH (Free ASH Whitepaper) program is available at View Source
About ADCETRIS
ADCETRIS is an antibody-drug conjugate (CAM) comprising an anti-CD30 monoclonal antibody bound by a protease cleavable linker to a microtubule-disrupting agent, auristatin monomethyl E (AMME), using proprietary technology. of Seattle Genetics. CAM uses a binding system designed to be stable in the blood but to release AMME during internalization in CD30 + tumor cells.
ADCETRIS Intravenous Injection has been approved by the FDA for five indications in adult patients with: (1) previously untreated Class III or IV classical Hodgkin’s lymphoma (LHc), in combination with chemotherapy, (2) high risk of relapse or progression, such as hematopoietic stem cell autograft (AGCSH) consolidation, (3) LHc after failure of GIST or failure of at least two prior multi-agent chemotherapy regimens in non-candidate patients at GATS, (4) LAGCs after failure of at least one prior multi-agent chemotherapy protocol, and (5) large-cell anaplastic primate cutaneous lymphoma (LcpAGC) or fungoid mycosis (MF) expressing the CD30 antigen,having received previous systemic therapy.
Health Canada granted conditional approval to ADCETRIS for relapsed or refractory Hodgkin lymphoma and LAGCs in 2013, and unconditional approval for consolidation therapy following autologous stem cell transplantation (GATS) in patients with Hodgkin’s lymphoma presenting with increased risk of relapse or progression.
ADCETRIS received a conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are as follows: (1) for the treatment of adult patients with recurrent or refractory CD30 + Hodgkin lymphoma following GATS, or further at least two previous therapies when GATS or multi-agent chemotherapy is not a therapeutic option, (2) for the treatment of adult patients with recurrent or refractory LAGCs, (3) for the treatment of patients adults with CD30 + Hodgkin lymphoma who have an increased risk of relapse or progression after GATS,and (4) for the treatment of adult patients with CD30 + T-cell cutaneous lymphoma (LCCT) after at least one prior systemic therapy.
ADCETRIS has received marketing authorization from regulatory authorities in more than 70 countries for the treatment of recurrent or refractory LH and LAGCs. Please see important safety information below.
ADCETRIS is being evaluated in more than 70 clinical trials, including a Phase 3 trial for the first-line treatment of Hodgkin lymphoma (ECHELON-1) and another Phase 3 trial for first-line treatment. intention of peripheral CD30 + T cell lymphoma (ECHELON-2), as well as trials for many other types of CD30 + malignancies.
Seattle Genetics and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has the rights to market ADCETRIS in the United States and Canada, and Takeda in the rest of the world. Seattle Genetics and Takeda jointly fund the development costs of ADCETRIS, in equal proportions, except in Japan, where Takeda assumes full responsibility for these costs.
Important safety information for ADCETRIS (brentuximab vedotine) (European Union)
Please refer to the summary of product characteristics before prescribing it.
CONTRAINDICATIONS
ADCETRIS is contraindicated in patients who are hypersensitive to brentuximab vedotine or its excipients. In addition, the combined use of ADCETRIS and bleomycin results in pulmonary toxicity.
SPECIAL WARNINGS AND PRECAUTIONS
Progressive Multifocal Leukoencephalopathy (PML): A reactivation of the John Cunningham virus (JCV) resulting in progressive multifocal leukoencephalopathy (PML) and death may occur in patients treated with ADCETRIS. Cases of PML have been reported in patients who received ADCETRIS after several previous chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from the reactivation of a latent John Cunningham (JCV) virus, the outcome of which is often fatal.
Patients should be closely monitored for the onset or aggravation of neurological, cognitive, or behavioral signs or symptoms that may be suggestive of PML. The suggested PML assessment includes neurology consultation, brain magnetic resonance imaging enhanced with gadolinium, and cerebrospinal fluid analysis for John Cunningham DNA polymerase chain reaction, or biopsy of the brain with John Cunningham virus evidence. A negative PCR test of the John Cunningham virus does not exclude PML. Additional monitoring and evaluation may be warranted if no alternative diagnosis can be established.
Be aware of symptoms of PML that the patient may not notice (eg, cognitive, neurological or psychiatric symptoms).
Pancreatitis: Cases of acute pancreatitis have been observed in patients treated with ADCETRIS. Fatal issues have been reported. Patients should be closely monitored for the onset or aggravation of abdominal pain, which may suggest acute pancreatitis. The patient’s assessment may include a medical examination, a laboratory evaluation for serum amylase and serum lipase, as well as abdominal imaging such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be suspended if there is suspicion of acute pancreatitis. Abandon ADCETRIS if a diagnosis of acute pancreatitis is confirmed.
Pulmonary toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonia, interstitial lung disease and acute respiratory distress syndrome, have been reported in patients treated with ADCETRIS. Although no causal association with ADCETRIS has been established, the risk of pulmonary toxicity can not be ruled out. Assess promptly and appropriately treat new or worsening lung symptoms. Consider suspension of administration during evaluation and until symptoms improve.
Serious and opportunistic infections : serious infections such as pneumonia, staphylococcal bacteremia, sepsis / septic shock (including fatal cases), shingles and opportunistic infections, such as Pneumocystis jiroveci pneumonia and oral candidiasis, have have been reported in patients treated with ADCETRIS. Patients should be closely monitored during treatment to check for the potential occurrence of serious and opportunistic infections.
Infusion Reactions (PRL): Immediate and delayed perfusion-related reactions, as well as cases of anaphylaxis, occurred with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis develops, ADCETRIS should be discontinued immediately and permanently, and appropriate medical treatment should be given. In case of RLP, discontinue the infusion and take appropriate medical care. The infusion can be restarted with a slower flow rate after symptoms disappear. Patients who have previously had PRP should be premedicated for subsequent infusions. PRRs are more common and more severe in patients with antibodies against ADCETRIS.
Tumor lysis syndrome (TLS): TLS cases have been reported with ADCETRIS. Patients with a rapidly proliferating tumor and a large tumor mass present a risk of SLT. These patients should be closely monitored and managed according to best medical practice.
Peripheral neuropathy (NP): Treatment with ADCETRIS can cause NP, sensory and motor. An NP caused by ADCETRIS is usually cumulative and reversible in most cases. Monitor the onset of NP symptoms in patients such as hypoesthesia, hyperaesthesia, paresthesia, discomfort, burning, neuropathic pain or weakness. In case of onset or aggravation of an NP, patients may need to delay and dose reduction or even discontinuation of ADCETRIS.
Hematologic Toxicity: ADCETRIS may cause Grade 3 or 4 anemia, thrombocytopenia, or prolonged neutropenia (≥ 1 week) Grade 3 or 4. Complete blood counts prior to administration of each dose.
Febrile neutropenia: Cases of febrile neutropenia have been reported. When developing febrile neutropenia, patients should be closely monitored for fever and treated according to best medical practice.
Stevens-Johnson Syndrome (SSJ): Cases of SSJ and toxic epidermal necrolysis (NET) have been reported with ADCETRIS. Fatal issues have been reported. Stop treatment with ADCETRIS if SSJ or NET develops and administer appropriate medical treatment.
Gastrointestinal (GI) complications : GI complications, some with fatal outcome, have been reported; they include cases of intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and hemorrhage. Evaluate and treat patients promptly if GI symptoms appear or worsen.
Hepatotoxicity: Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Severe cases of hepatotoxicity, some with fatal outcome, have also occurred. Check liver function before starting treatment and regularly monitor elevated liver enzyme levels in patients receiving ADCETRIS. Patients with hepatotoxicity may require a dose delay, dose modification, or even discontinuation of ADCETRIS.
Hyperglycemia: Cases of hyperglycemia have been reported in trials in patients with high body mass index (BMI), with or without a history of diabetes mellitus. Monitor serum glucose levels carefully in patients with hyperglycaemia. Antidiabetic treatment should be given as appropriate.
Renal and hepatic impairment: There is still limited experience in patients with renal and hepatic impairment. Available data indicate that AMME clearance may be affected by severe renal impairment, liver failure, and low serum albumin levels.
LCCT CD30 +: The extent of treatment effect in CD30 + LCCT subtypes other than fungoid mycosis (FM) and primary large-cell anaplastic cutaneous lymphoma (LcpAGC) is unclear due to lack of high quality evidence. In two single-group Phase II studies of ADCETRIS, disease activity was shown in subtypes of Sezary syndrome, lymphomatoid papulosis, and histology of mixed LCCT. These data suggest that efficacy and safety can be extrapolated to other CD30 + LCCT subtypes. Carefully evaluate the benefit / risk ratio for the patient, and proceed with caution with other types of LCCT CD30 +.
Sodium content of the excipients: ADCETRIS contains a maximum level of 2.1 mmol (or 47 mg) of sodium per dose. Consider this for patients on a low salt diet.
INTERACTIONS
Patients receiving a potent inhibitor of CYP3A4 and P-glycoprotein concurrently with ADCETRIS may be at increased risk for neutropenia and should be closely monitored. Joint administration of ADCETRIS with a CYP3A4 inducer did not affect the plasma exposure of ADCETRIS, but it appears to reduce the plasma concentrations of AMME metabolites that could be analyzed. ADCETRIS is not expected to alter exposure to drugs metabolized by CYP3A4 enzymes.
PREGNANCY: Counsel women of childbearing potential to use two effective methods of contraception during and up to 6 months after treatment with ADCETRIS. There are no data on the use of ADCETRIS in pregnant women. However, studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefits to the mother outweigh the potential risks to the fetus.
Lactation (lactation): No data are available on the potential excretion of ADCETRIS or its metabolites in human milk. The risk to the newborn / infant can not be ruled out. Because of this potential risk, the decision should be made to stop breastfeeding or to give up / give up treatment with ADCETRIS.
FERTILITY: In non-clinical studies, treatment with ADCETRIS showed testicular toxicity; it is therefore likely to alter male fertility. Advise men treated with ADCETRIS not to conceive children during treatment, and up to six months after the last dose.
Effects on ability to drive and use machines: ADCETRIS may have a minor influence on the ability to drive and use machines.
ADVERSE REACTIONS
The most common adverse events (≥10%) were: infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, neuropathy Peripheral motor, infusion-related reactions, pruritus, constipation, dyspnoea, weight loss, myalgia and abdominal pain.
Serious adverse reactions to the drug included pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, Tumor lysis and Stevens-Johnson syndrome. Serious adverse drug reactions occurred in 12% of patients. The frequency of single serious adverse drug reactions was less than or equal to 1%.
Important safety information for the United States regarding ADCETRIS (brentuximab vedotine)
BOX: PROGRESSIVE MULTIFOCAL LEUCOENCÉPHALOPATHIE (PML)
JC virus infection with PML and death may occur in patients treated with ADCETRIS.
Contraindication
Joint use of ADCETRIS and bleomycin due to pulmonary toxicity (eg interstitial infiltration and / or inflammation).
Warnings and Precautions
Peripheral neuropathy (NP): ADCETRIS causes a NP of mainly sensory nature. Cases of peripheral motor neuropathy have also been reported. An ADCETRIS-induced NP is cumulative. Monitor the onset of symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning, neuropathic pain or weakness. Change the dose accordingly.
Anaphylaxis and Infusion Reactions : Infusion- related reactions (APRs), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during the infusion. In the case of RLP, the infusion should be discontinued and appropriate medical care provided. In case of anaphylaxis, discontinue the infusion immediately and definitively and administer appropriate medical treatment. Administer premedication to patients with a history of RPL prior to new infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic Toxicity: Severe prolonged neutropenia (≥1 weeks) and thrombocytopenia or grade 3 or 4 anemia may occur with ADCETRIS. Cases of febrile neutropenia have been reported with ADCETRIS. Perform a complete blood count before each dose of ADCETRIS. Consider more frequent monitoring for patients with grade 3 or 4 neutropenia. Monitor any febrile conditions in patients. If developing grade 3 or 4 neutropenia, consider dose delays, dose reductions, suspension of therapy, or G-CSF prophylaxis with subsequent doses.
Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia and sepsis or septic shock (including fatalities) have been reported in patients treated with ADCETRIS. Monitor patients carefully during treatment to check for possible emergence of bacterial, fungal or viral infections.
Tumor lysis syndrome: Carefully monitor patients with rapidly proliferating tumors and a large tumor burden.
Increased toxicity in severe renal impairment: The incidence of grade 3 or greater adverse events and deaths was higher in patients with severe renal impairment than in those with normal renal function. Avoid the use of this treatment in patients with severe renal impairment.
Increased toxicity in patients with moderate or severe hepatic impairment: The incidence of grade 3 or greater adverse events and deaths was higher in patients with moderate or severe hepatic impairment than in those with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment .
Hepatotoxicity : Serious and fatal cases have occurred in patients treated with ADCETRIS. These cases were consistent with hepatocellular lesions and included elevations of transaminases and / or bilirubin, occurred after the first dose of ADCETRIS or re-administration of the product. Pre-existing liver disease, elevated liver enzyme levels, and concomitant use of other medications may increase the risk. Monitor liver enzyme and bilirubin levels. Patients with new, worsening or recurrent hepatotoxicity may require a dose delay, dose modification, or discontinuation of ADCETRIS.
PML: JC virus infections resulting in PML and death have been reported in patients treated with ADCETRIS. The first onset of symptoms occurred at different times since the start of ADCETRIS treatment, with some cases occurring within 3 months of initial exposure. Potential contributing factors other than ADCETRIS include prior treatments and an underlying disease that may cause immunosuppression. Consider a diagnosis of PML in patients with signs and symptoms of recent onset central nervous system abnormalities. Suspend treatment with ADCETRIS if PML is suspected and discontinue if PML is confirmed.
Pulmonary toxicity: Non-infectious pulmonary toxicity events, some with fatal outcome, such as pneumonia, interstitial lung disease and acute respiratory distress syndrome, have been reported. Monitor the onset of signs and symptoms in patients, including cough and dyspnea. In case of new or worsening pulmonary symptoms, discontinue ADCETRIS during evaluation and until symptoms improve.
Serious Dermatologic Reactions: Cases of Stevens-Johnson syndrome (SSJ) and toxic epidermal necrolysis (NET), some with fatal outcome, have been reported with ADCETRIS. If SSJ or NET occur, stop ADCETRIS and administer appropriate medical treatment.
Gastrointestinal (GI) complications: Cases of acute pancreatitis, some with fatal outcome, have been reported in patients treated with ADCETRIS. Other serious and fatal GI complications reported in patients treated with ADCETRIS include perforations, bleeding, erosions, ulcers, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with pre-existing GI involvement may increase the risk of perforation. In case of new or worsening GI symptoms, promptly perform a diagnostic evaluation and administer appropriate treatment.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, it should be noted that ADCETRIS may harm the fetus. Inform women of childbearing potential of the potential risk to the fetus and advise them to avoid becoming pregnant during treatment with ADCETRIS, and for at least 6 months after the final dose of ADCETRIS. Most common side effects (≥20%): sensory peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory infection and pyrexia.
Drugs interactions
Concomitant use of potent inhibitors or inducers of CYP3A4, or P-gp inhibitors, may potentially affect exposure to auristatin monomethyl E (AMME).
Use in specific populations
Moderate or severe hepatic insufficiency or severe renal insufficiency: increased exposure to AMME and adverse reactions. Avoid using this medicine.
Advise men with female sexual partners of childbearing potential to use effective contraception while taking ADCETRIS, and for at least 6 months after the last dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid breastfeeding while taking ADCETRIS.
For important additional safety information, including the BOX, please refer to ADCETRIS Complete Prescription Information at www.seattlegenetics.com or www.ADCETRIS.com .
About ICLUSIG (ponatinib) tablets
ICLUSIG is a kinase inhibitor targeting primarily BCR-ABL1 protein, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). ICLUSIG is an anti-cancer drug developed using a computational and structural drug design platform, specifically designed to inhibit the activity of BCR-ABL1 protein and its mutations. ICLUSIG targets not only the native BCR-ABL1 protein, but also mutations that lead to resistance to BCR-ABL1 treatment, including the most resistant T315I mutation.. This mutation has been associated with resistance to all other approved ITKs. ICLUSIG, which received full FDA approval in November 2016, is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.
In the United States, ICLUSIG is indicated for:
Treatment of adult patients with chronic, accelerated or blast phase CML (PC-CML, CML-PA or CML-PB), or Ph + ALL, for whom no other tyrosine kinase (ITK) is indicated.
Treatment of adult patients with T315I + CML (PC, PA or PB) or Ph + T315I + ALL.
Limitations: ICLUSIG is not indicated or recommended for the treatment of patients with newly diagnosed chronic phase CML.
IMPORTANT INFORMATION REGARDING ICLUSIG (ponatinib) SAFETY (UNITED STATES)
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE AND HEPATOTOXICITY
Please refer to the complete prescription information for the full framed warning.
Arterial occlusions have been observed in at least 35% of patients treated with ICLUSIG (ponatinib), including fatal cases of myocardial infarction, stroke, large brain artery stenosis, severe peripheral vascular disease as well as the need to perform urgent procedures for revascularization. These disorders have occurred in patients with or without a cardiovascular risk factor, including patients younger than 50 years of age. Discontinue or stop immediately ICLUSIG treatment in case of arterial occlusion. Any decision to resume treatment based on ICLUSIG should be based on an assessment of the benefits and risks it represents.
Venous thromboembolism occurred in 6% of patients treated with ICLUSIG. Monitor the signs of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients developing severe venous thromboembolism.
Heart failure, fatal in some cases, occurred in 9% of patients treated with ICLUSIG. Monitor the heart function. Discontinue or discontinue ICLUSIG therapy if heart failure develops or worsens.
Hepatotoxicity, liver failure and death have occurred in patients treated with ICLUSIG. Monitor liver function. Discontinue ICLUSIG treatment in case of suspected hepatotoxicity.
WARNINGS AND PRECAUTIONS
Arterial Occlusions:chez au moins 35 % des patients traités par ICLUSIG dans les essais de phases 1 et 2, des occlusions artérielles ont été observées, y compris des cas mortels d’infarctus du myocarde, d’accident vasculaire cérébral, de sténose des gros vaisseaux du cerveau et de maladie vasculaire périphérique grave. Dans l’essai de phase 2, 33 % des patients (150 sur 449) traités par ICLUSIG ont subi un événement d’occlusion artérielle de type cardiovasculaire (21 %), vasculaire périphérique (12 %) ou cérébrovasculaire (9 %); certains patients ont subi plus d’un type d’événement. Des événements mortels ou mettant la vie en danger sont survenus dans les 2 semaines suivant le début du traitement, à des doses quotidiennes de seulement 15 mg. ICLUSIG est également susceptible de provoquer une occlusion vasculaire récurrente ou multi-sites. Des patients ont dû subir des interventions de revascularisation. Le délai médian d’apparition des premiers événements d’occlusion artérielle de type cardiovasculaire, cérébrovasculaire et périphérique était de 193, 526 et 478 jours, respectivement. Des patients avec ou sans facteur de risque cardiovasculaire, certains âgés de 50 ans ou moins, ont subi ces événements. Les facteurs de risque les plus courants observés avec ces événements étaient l’hypertension, l’hyperlipidémie et des antécédents de maladie cardiaque. Les événements d’occlusion artérielle étaient plus fréquents avec l’âge et chez les patients présentant des antécédents d’ischémie, d’hypertension, de diabète ou d’hyperlipidémie. Chez les patients soupçonnés de développer des événements d’occlusion artérielle, il convient d’interrompre ou de cesser la prise d’ICLUSIG.
Venous thromboembolism: Venous thromboembolic events occurred in 6% of patients (25 out of 449) treated with ICLUSIG with an incidence rate of 5% (13 out of 270 LMC-PC), 4% (3 out of 85 LMC-PA) , 10% (6 of 62 LMC-PB) and 9% (3 of 32 Ph + ALL). These events include: deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with loss of vision. Consider dose modification or discontinuation of ICLUSIG in patients with severe venous thromboembolism.
Heart failure :fatal or severe heart failure or left ventricular dysfunction occurred in 6% of patients (29 out of 449) treated with ICLUSIG. Nine percent of patients (39 out of 449) had heart failure or left ventricular dysfunction in all grades. The most frequently reported heart failure events were congestive heart failure and decreased ejection fraction (14 patients each, 3%). Monitor for signs or symptoms suggestive of heart failure and treat as clinically indicated, including discontinuation of ICLUSIG. Consider interruption of treatment in case of
Hepatotoxicity:ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant liver failure leading to death occurred in one patient within the first week of starting ICLUSIG. Two other fatal cases of acute liver failure have occurred. Fatalities have occurred in patients with CML-PB or Ph + ALL. Cases of severe hepatotoxicity occurred in all disease cohorts, with 11% of patients (50 of 449) suffering from grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were ASAT elevations. or ALT (54% all grades, 8% grade 3 or 4, 5% did not experience a reversal at the last follow-up), bilirubin and alkaline phosphatase. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity was three months. Monitor liver function at baseline, then at least once a month or as clinically indicated. Discontinue treatment, reduce dose or discontinue ICLUSIG as clinically indicated.
Hypertension:Treatment-related elevation of systolic or diastolic blood pressure occurred in 68% of patients (306 out of 449) treated with ICLUSIG. Fifty-three patients (12%) experienced treatment-related symptomatic hypertension as a serious adverse event, including a hypertensive crisis. Patients may require urgent clinical intervention because of hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic blood pressure <140 mm Hg and initial diastolic blood pressure <90 mm Hg, 80% (229 of 285) experienced treatment-related hypertension; 44% (124 of 285) developed stage 1 hypertension and 37% developed stage 2 hypertension. Of 132 patients with stage 1 hypertension at the start of treatment, 67% (88 of 132) developed hypertension. Stage 2. Elevations of blood pressure should be monitored and managed during ICLUSIG therapy and hypertension should be treated to normalize blood pressure. Discontinue treatment, reduce dose or discontinue ICLUSIG if hypertension can not be controlled with medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. Of 132 patients with stage 1 hypertension at the start of treatment, 67% (88 of 132) developed stage 2 hypertension. Elevations of blood pressure should be monitored and managed during treatment with ICLUSIG and appropriate to treat hypertension to normalize blood pressure. Discontinue treatment, reduce dose or discontinue ICLUSIG if hypertension can not be controlled with medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. Of 132 patients with stage 1 hypertension at the start of treatment, 67% (88 of 132) developed stage 2 hypertension. Elevations of blood pressure should be monitored and managed during treatment with ICLUSIG and appropriate to treat hypertension to normalize blood pressure. Discontinue treatment, reduce dose or discontinue ICLUSIG if hypertension can not be controlled with medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. Elevations of blood pressure should be monitored and managed during treatment with ICLUSIG and hypertension should be treated to normalize blood pressure. Discontinue treatment, reduce dose or discontinue ICLUSIG if hypertension can not be controlled with medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. Elevations of blood pressure should be monitored and managed during treatment with ICLUSIG and hypertension should be treated to normalize blood pressure. Discontinue treatment, reduce dose or discontinue ICLUSIG if hypertension can not be controlled with medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. reduce the dose or discontinue ICLUSIG if hypertension can not be controlled by medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis. reduce the dose or discontinue ICLUSIG if hypertension can not be controlled by medication. In the event of significant deterioration, labile or treatment-resistant hypertension, discontinue therapy and consider a diagnosis of renal artery stenosis.
Pancreatitis:pancreatitis occurred in 7% of patients (31 out of 449, 6% of grade or grade 3/4) treated with ICLUSIG. The incidence of treatment-related lipase elevation was 42% (16% grade 3 or higher). Pancreatitis led to suspension or discontinuation of treatment in 6% of patients (26 of 449). The median time to onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis resolved within two weeks of discontinuation or dose reduction. Check serum lipase every two weeks for the first two months, then monthly or as clinically indicated. Consider additional control of serum lipase in patients with a history of pancreatitis or alcohol abuse. It may be necessary to stop treatment or reduce the dose. In cases where elevations of lipase are accompanied by abdominal symptoms, discontinue ICLUSIG therapy and evaluate patients for possible pancreatitis. Do not consider restarting ICLUSIG until complete resolution of symptoms in patients and a return to lipase lower than 1.5 times ULN. In cases where elevations of lipase are accompanied by abdominal symptoms, discontinue ICLUSIG therapy and evaluate patients for possible pancreatitis. Do not consider restarting ICLUSIG until complete resolution of symptoms in patients and a return to lipase lower than 1.5 times ULN. In cases where elevations of lipase are accompanied by abdominal symptoms, discontinue ICLUSIG therapy and evaluate patients for possible pancreatitis. Do not consider restarting ICLUSIG until complete resolution of symptoms in patients and a return to lipase lower than 1.5 times ULN.
Increased toxicity in newly diagnosed chronic phase CML:In a prospective randomized clinical trial of first-line therapy in patients with newly diagnosed chronic phase CML (COC), a 45-mg daily dose of ICLUSIG monotherapy doubled the risk of adverse events serious as compared to a daily dose of 400 mg imatinib monotherapy. The median duration of treatment exposure was less than 6 months. The trial was discontinued for safety reasons in October 2013. Arterial and venous occlusions and thromboses occurred at least twice as often in the ICLUSIG group as in the imatinib group. Compared with patients treated with imatinib, those treated with ICLUSIG showed a higher incidence of myelosuppression, pancreatitis, hepatotoxicity, heart failure, hypertension, and cutaneous and subcutaneous tissue disorders. ICLUSIG is not indicated or recommended for the treatment of patients with newly diagnosed PC-CML.
Neuropathy:cases of peripheral and cranial neuropathy have occurred in patients treated with ICLUSIG. In total, 20% of patients (90 out of 449) treated with ICLUSIG experienced peripheral neuropathy, all grades combined (2%, grade 3/4). The most common peripheral neuropathies reported were paresthesia (5%, 23 of 449 patients), peripheral neuropathy (4%, 19 of 449), hypesthesia (3%, 15 of 449), dysgeusia (2% , 10 of 449), muscle weakness (2%, 10 of 449) and hyperesthesia (1%, 5 of 449). Cranial neuropathy developed in 2% of patients (10 out of 449) treated with ICLUSIG (<1%, 3 out of 449 patients – grade 3/4). Among the patients who developed neuropathy, the disease occurred in the first month of treatment in 26% (23 out of 90). Monitor for symptoms of neuropathy such as hypoesthesia, hyperaesthesia, paresthesia, discomfort, burning, neuropathic pain, or weakness. Consider discontinuing ICLUSIG and monitoring for signs of neuropathy.
Ocular toxicity:serious cases of ocular toxicity resulting in blindness or blurred vision have occurred in patients treated with ICLUSIG. Cases of retinal toxicity, including macular edema, retinal vein occlusion and retinal hemorrhage, were observed in 2% of patients treated with ICLUSIG. Conjunctival irritation, corneal abrasion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Blurred vision occurred in 6% of patients. Other ocular toxicities include cases of cataract, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis and ulcerative keratitis. Perform full eye exams at the beginning of treatment and periodically during treatment.
Haemorrhage: Severe bleeding, including some fatal, occurred in 6% of patients (28 out of 449) treated with ICLUSIG. Hemorrhagic events occurred in 28% of patients (124 of 449). The incidence of severe bleeding was higher in patients with CML-BP, CML-PB or Ph + ALL. Gastrointestinal haemorrhage and subdural hematoma were the most common serious bleeding events, occurring in 1% of patients (4 of 449). Most, but not all, bleeding episodes have occurred in patients with Grade 4 thrombocytopenia. Discontinue ICLUSIG for severe or severe bleeding and evaluate.
Fluid retention: Severe cases of fluid retention occurred in 4% of patients (18 out of 449) treated with ICLUSIG. A case of cerebral edema has been fatal. Of the fluid retention events occurring in at least 2% of patients (seen on treatment), severe cases include: pleural effusion (7 of 449, 2%), pericardial effusion (4 of 449, 1%) and peripheral edema (2 of 449, <1%).
In total, fluid retention occurred in 31% of patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral edema (3%).
Monitor the appearance of signs of fluid retention and manage patients according to clinical indications. Discontinue treatment, reduce dose or discontinue ICLUSIG as clinically indicated.
Cardiac Arrhythmias: Arrhythmias occurred in 19% of patients (86 out of 449) treated with ICLUSIG, of which 7% (33 out of 449) were Grade 3 or higher. An arrhythmia of ventricular origin was reported in 3% (3 of 86) of all arrhythmias, one case being grade 3 or higher. Symptomatic bradyarrhythmias leading to pacemaker implantation occurred in 1% of patients (3 out of 449) treated with ICLUSIG.
Most common atrial fibrillation – arrhythmia – occurred in 7% of patients (31 of 449), approximately half of whom 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 prolongation of the QT interval on the electrocardiogram, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia , complete atrioventricular block, cardiorespiratory arrest, loss of consciousness and sinus node dysfunction (1 patient each, 0.2%). In 27 patients, the event led to hospitalization.
In patients with signs and symptoms suggestive of a slow heartbeat (fainting, dizziness) or rapid heartbeat (chest pain, palpitations or dizziness), discontinue ICLUSIG and make an assessment.
Myelosuppression: Myelosuppression was reported as an adverse event in 59% of patients (266 out of 449) treated with ICLUSIG and grade 3/4 myelosuppression occurred in 50% of patients (226 out of 449). The incidence of these events was more frequent in patients with CML-PA, CML-PB or Ph + ALL than in patients with CML-PC.
Severe (grade 3 or 4) myelosuppression was observed early in treatment, with a median onset of onset of 1 month (range less than 1 month to 40 months). Perform a complete blood count every two weeks in the first three months, then once a month thereafter or as clinically indicated. Then adjust the dose accordingly.
Tumor lysis syndrome: Two patients (<1%, one patient with CML-PA and one patient with CML-PB) treated with ICLUSIG developed a severe tumor lysis syndrome. Hyperuricemia occurred in 7% of patients (31 of 449). Due to the risk of tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high levels of uric acid before starting ICLUSIG therapy.
Posterior Reversible Leukoencephalopathy Syndrome (SLEPR): cases of reversible posterior leukoencephalopathy syndrome (SLEPR – also known as reversible posterior encephalopathy syndrome [SEPPR]) have been reported in post-marketing ICLUSIG-treated patients. SLEPR is a neurological disorder that may have signs and symptoms such as seizures, headaches, decreased alertness, impaired mental functioning, vision loss, and other visual and neurological disorders. Hypertension is often present and the diagnosis is made with positive findings on magnetic resonance imaging (MRI) of the brain. If the SLEPR is diagnosed,
Compromised wound healing and gastrointestinal perforation: Because ICLUSIG may compromise wound healing, discontinue treatment for at least one week before the scheduled date of major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days after cholecystectomy.
Embryo-fetal toxicity: Based on its mechanism of action and the results of animal studies, ICLUSIG may 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 below human exposure at the recommended human dose. Pregnant women should be informed of the potential risk to the fetus. Advise women of childbearing potential to use effective contraception during ICLUSIG therapy and for 3 weeks after the last dose.
ADVERSE REACTIONS
Most Common Adverse Reactions : Overall, the most common non-hematologic adverse events (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue , hypertension, pyrexia, arthralgia, nausea, diarrhea, elevated lipase, vomiting, myalgia and extremity pain. Hematologic adverse events include thrombocytopenia, anemia, neutropenia, lymphopenia and leukopenia.
To report ADVERSE SIDE EFFECTS, contact Takeda at 1-844-T-1POINT (1-844-817-6468) or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
INTERACTIONS WITH THIS MEDICATION Potent
CYP3A inhibitors: Avoid concomitant use of ICLUSIG, or reduce the dose if concomitant administration can not be avoided.
Potent inducers of CYP3A: Avoid concomitant use.
Use in Specific Populations
Women and Men of Childbearing Potential : ICLUSIG may be harmful to the fetus when administered to a pregnant woman. Advise women to use effective contraception during ICLUSIG treatment and for 3 weeks after the last dose. Ponatinib is likely to affect fertility in women and it is not known if these effects are reversible. Confirm pregnancy in women of childbearing potential before initiating treatment with ICLUSIG.
Breast-feeding: Counsel women not to breast-feed while taking ICLUSIG and for six days after taking the last dose.
US Dosage Information: View Source
About NINLARO capsules (ixazomib)
NINLARO (ixazomib) is an oral proteasome inhibitor that is also studied in the continuum of multiple myeloma treatment frameworks as well as systemic light chain amyloidosis (AL). He was the first oral proteasome inhibitor to start Phase 3 clinical trials and receive approval. NINLARO was approved by the US Food and Drug Administration (the "FDA") in November 2015 following a priority review and by the European Commission in November 2016. In the United States 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 orphan drug designation for multiple myeloma, both in the United States and Europe, in 2011, and for AL amyloidosis, both in the United States and Europe, in 2012. ixazomib received the FDA’s revolutionary treatment designation for Recurrent or Refractory Systemic Light Chain Amyloidosis (AL), a related ultra-orphan disease, in 2014. The Japanese Ministry of Health, Labor and Welfare granted the orphan drug designation to ixazomib in 2016.
Ixazomib’s comprehensive clinical development program, TOURMALINE, includes a total of six ongoing pivotal trials – five that together address each large population of multiple myeloma patients, and one for light chain amyloidosis:
TOURMALINE-MM1, who studies ixazomib versus placebo in combination with lenalidomide and dexamethasone for recurrent and / or refractory multiple myeloma
TOURMALINE-MM2, who studies ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, who studies ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma after initial treatment and autologous stem cell transplantation (GATS)
TOURMALINE-MM4, who studies ixazomib compared to placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone GATS; this study is in the patient recruitment phase
TOURMALINE-MM5, which studies the dual therapy ixazomib plus dexamethasone compared to the dual therapy pomalidomide plus dexamethasone in patients with recurrent and / or refractory multiple myeloma who became resistant to lenalidomide
TOURMALINE-AL1, who studies ixazomib in combination with dexamethasone compared to a selection of physician-selectable regimens in patients with recurrent or refractory AL amylase; this study is in the recruitment phase of patients.
For more information on Phase 3 studies actively recruiting, please visit: View Source
In addition to the TOURMALINE program, ixazomib is evaluated in multiple therapeutic combinations for various patient populations in investigator-initiated studies at the global level.
NINLARO (ixazomib) Capsules : Important Safety Information Globally
WARNINGS AND SPECIAL PRECAUTIONS
Thrombocytopenia: cases of thrombocytopenia have been reported with NINLARO (28% vs. 14% in NINLARO and placebo regimens, respectively) with platelet nadirs generally occurring between days 14 and 21 of each 28-day cycle and re-establishment at baseline by beginning of the next cycle. Thrombocytopenia caused no increase in bleeding events or platelet transfusions. During treatment with NINLARO, check platelet count at least once a month and consider more frequent control during the first three cycles. Manage with dosage changes and platelet transfusions in accordance with standard medical guidelines.
Gastrointestinal toxicities : Cases of gastrointestinal toxicities were reported in NINLARO and placebo regimens, including diarrhea (42% vs. 36%, respectively), constipation (34% vs. 25%), nausea (26% vs. 21%) and vomiting (22% versus 11%), occasionally requiring the use of anti-diarrheal and antiemetic drugs, along with supportive care.
Peripheral neuropathy: Cases of peripheral neuropathy have been reported with NINLARO (28% versus 21% in NINLARO and placebo regimens, respectively). The most commonly reported adverse event was sensory peripheral neuropathy (19% and 14% in NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Monitor the onset of peripheral neuropathy symptoms and adjust the dosage if necessary.
Peripheral edema: Cases of peripheral edema have been reported with NINLARO (25% versus 18% in NINLARO and placebo regimens, respectively). Assess underlying causes in patients and provide supportive care as needed. Adjust the dose of dexamethasone according to your prescribing information or that of NINLARO in case of severe symptoms.
Skin reactions: 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 rash reported in both diets was maculopapular and macular rash. Manage rashes by providing supportive care, altering dosage, or stopping treatment.
Hepatotoxicity: Rare cases of liver injury, hepatocellular injury, hepatic steatosis and drug-induced cholestatic hepatitis have been reported with NINLARO. Regularly monitor liver enzymes and adjust the dose in case of grade 3 or 4 symptoms.
Pregnancy: NINLARO may be harmful to the fetus. Counsel men and women of childbearing potential to take contraceptive measures during treatment and for 90 days after taking the last dose of NINLARO. Women of childbearing potential should avoid pregnancy while taking NINLARO because of the potential danger to the fetus. Women taking hormonal contraceptives should also use a barrier contraceptive method.
Breast-feeding: It is not known if NINLARO or its metabolites are excreted in breast milk. There may be potential side effects in breastfed children and therefore breastfeeding should be discontinued.
SPECIAL PATIENT POPULATIONS
Hepatic impairment: reduce the initial dose of NINLARO to 3 mg in patients with moderate or severe hepatic impairment.
Renal Insufficiency: Reduce the initial dose of NINLARO 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable, so it can be given without regard to the date of dialysis.
INTERACTIONS
WITH THIS MEDICATION Concomitant use of strong inducers of CYP3A and NINLARO is not recommended.
ADVERSE REACTIONS
The most commonly reported adverse reactions (≥ 20%) in the NINLARO regimen and more common than in the placebo diet were diarrhea (42% vs. 36%, respectively), 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% versus 16%). Serious adverse events reported in at least 2% of patients include thrombocytopenia (2%) and diarrhea (2%). For each adverse event, one or more of the three drugs was discontinued in less than 1% of patients on the NINLARO regimen.