On November 5, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that 18 corporate-sponsored abstracts will be presented at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) , which will be held December 1-20, 2018 in San Diego (Press release, Takeda, NOV 5, 2018, View Source [SID1234530741]). Takeda’s presentations will present new clinical trial data from the company’s hematology portfolio. In particular, Takeda reports results from the Phase 3 clinical trials TOURMALINE-MM3 and ECHELON-2.
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"By providing data from two Phase 3 clinical trials and from the Company’s pipeline, Takeda continues to expand the evidence base for new therapeutic options that improve the treatment of blood cancer patients," Dr. Takeda said. Christophe Bianchi, MD, President, Takeda Global Oncology Business Unit. "Positive results from the TOURMALINE-MM3 trial, the first and only placebo-controlled phase 3 trial to test a proteasome inhibitor in this setting, showed that NINLARO maintenance therapy after autologous stem cell transplantation improved progression-free survival compared to the control arm. Thus, NINLARO can potentially be used as a maintenance therapy in a patient group, currently limited treatment options are available. In addition, the positive results of the ECHELON-2 study demonstrated that ADCETRIS in combination with chemotherapy provided better progression-free survival and overall survival in patients with previously untreated CD30-positive peripheral T-cell lymphoma than the control arm. This is an important milestone for ADCETRIS as one possible treatment option in this setting, where standard care has been unchanged for several decades. " that ADCETRIS in combination with chemotherapy achieved better progression-free survival and overall survival in patients with previously untreated CD30-positive peripheral T-cell lymphoma than the control arm. This is an important milestone for ADCETRIS as one possible treatment option in this setting, where standard care has been unchanged for several decades. " that ADCETRIS in combination with chemotherapy achieved better progression-free survival and overall survival in patients with previously untreated CD30-positive peripheral T-cell lymphoma than the control arm. This is an important milestone for ADCETRIS as one possible treatment option in this setting, where standard care has been unchanged for several decades. "
At this year’s ASH (Free ASH Whitepaper) meeting, results of the Phase 3 TOURMALINE-MM3 study addressing the effect of NINLARO (ixazomib) maintenance therapy in adult patients with multiple myeloma responding to high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), examined, presented for the first time in a lecture. The lecture will be held on Sunday, December 2nd at 7:30 pm PT. The TOURMALINE MM3 trial achieved its primary endpoint with NINLARO, which led to a statistically significant improvement in progression-free survival (PFS) compared to placebo, assessed by an Independent Review Committee (IRC). There were no new safety signals in the TOURMALINE MM3 study and the safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy. NINLARO is not currently approved as a single agent for ASCT maintenance therapy.
Results of the Phase 3 ECHELON-2 study will be presented in a lecture on Monday, December 3 at 6:15 pm PT. The study found a statistically significant improvement in PFS for ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) compared to the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Main results of the ECHELON-2 study were reported in October 2018. Study results showed that combination therapy with ADCETRIS plus CHP for progression-free survival was superior to the control arm as assessed by an Independent Review Facility (IRF) (hazard ratio = 0.71, p = 0.0110). For all important secondary endpoints, including overall survival, there were statistically significantly better outcomes for the ADCETRIS-plus-CHP arm with a manageable safety profile. ADCETRIS is currently not approved as a PTCL frontline therapy.
The breadth and depth of Takeda’s research and development efforts will also be highlighted in several presentations focusing on multiple myeloma, lymphoma, chronic myeloid leukemia, and myelodysplastic syndromes (MDS).
Eighteen abstracts sponsored by Takeda were accepted for presentation at the ASH (Free ASH Whitepaper) Annual Meeting in 2018, including:
Note: All times are in Pacific Standard Time (PT).
ADCETRIS (Brentuximab Vedotin)
The ECHELON-2 study: Results of a randomized, double-blind, drug-controlled Phase 3 study of brentuximab vedotin and CHP (A + CHP) versus CHOP in the frontline treatment of patients with CD30-positive peripheral T-cell lymphoma . Abstract 997. Lecture. Monday, December 3, 2018, 6:15 – 7:45 pm (San Diego Convention Center, Room 6F).
Elderly patients with previously untreated classic Hodgkin’s lymphoma (cHL): An in-depth analysis of the Phase 3 ECHELON-1 study . Abstract 1618. Saturday, December 1, 2018, 6:15 – 8:15 pm (San Diego Convention Center, Hall GH).
Superior clinical benefit of brentuximab vedotin in mycosis fungoides versus physician’s choice, regardless of CD30 grade or large cell transformation status in the 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 with stage III or IV Hodgkin’s lymphoma: A subgroup analysis of the Phase 3 ECHELON-1 study . Abstract 1647. Saturday, December 1, 2018, 6:15 – 8:15 pm (San Diego Convention Center, Hall GH).
Brentuximab Vedotin plus chemotherapy in patients with advanced classical Hodgkin’s lymphoma (cHL): testing of modified progression-free survival (mPFS) and conventional PFS in the Phase 3 ECHELON-1 study . Abstract 2904. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
Regression of peripheral neuropathies (PN) in patients receiving A + AVD or ABVD in the Phase 3 ECHELON-1 study . Abstract 2921. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
Phase 1 results of a phase 1/2 study evaluating the safety, tolerability and recommended Phase 2 dose (RP2D) of brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A + AVD) in pediatric patients with advanced, new diagnosed classical Hodgkin’s lymphoma (cHL) . Abstract 1644. Saturday, December 1, 2018, 6:15 – 8:15 pm (San Diego Convention Center, Hall GH).
Multiple Myeloma / NINLARO (Ixazomib)
Maintenance therapy with oral proteasome inhibitor (PI) Ixazomib causes significant progression-free survival (PFS) after autologous stem cell transplantation (ASC) in patients with newly diagnosed multiple myeloma (NDMM): Phase 3 TOURMALINE-MM3 study . Abstract 301. Lecture. 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 patients with relapsed / refractory multiple myeloma (RRMM) with non-canonical NF-κB activation – results of the TOURMALINE MM1 study . Abstract 473. Lecture. Sunday, December 2, 2018, 4:30 – 6:00 pm (Marriott Marquis San Diego Marina, Grand Ballroom 7).
Treatment preferences of patients with relapsed / refractory multiple myeloma: Are patients ready for a compromise between efficacy and tolerability? Abstract 614th Lecture. Monday, December 3, 2018, 7:00 am – 8:30 am (San Diego Convention Center, Room 11B).
Ixazomib plus lenalidomide-dexamethasone (IRd) in patients with relapsed / refractory multiple myeloma (MM) – day-to-day efficacy is similar to efficacy in the Phase 3 TOURMALINE-MM1: a pooled analysis of the INSIGHT MM and the Czech Register Monoclonal gammopathies (RMG) . Abstract 1971. Saturday, December 1, 2018, 6:15 – 8:15 pm (San Diego Convention Center, Hall GH).
Socio-demographic characteristics and societal perspective in patients with relapsed and / or refractory multiple myeloma (RRMM) in Spain: an interim analysis of the CHARISMMA study . Abstract 2300. Saturday, December 1, 2018, 6:15 pm – 8:15 pm (San Diego Convention Center, Hall GH).
Transplant status without influence on the choice of induction schemes in patients with newly diagnosed multiple myeloma (NDMM) in the prospective observational study INSIGHT MM . Abstract 3289. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
Dynamic changes in the International Staging System as a 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, Hall GH).
ICLUSIG (Ponatinib)
Comparing cardiovascular events in various tyrosine kinase inhibitors in patients with chronic myeloid leukemia from clinical practice . Abstract 3567. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
Pipeline (lymphoma, multiple myeloma, myelodysplastic syndromes)
Patient characteristics and treatment patterns in first- and second-line therapy in diffuse large 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, Hall GH).
A single dose of the cytolytic CD38 antibody TAK-079 in healthy volunteers: tolerability, pharmacokinetics, and pharmacodynamics . Abstract 3249. Sunday, December 2, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
Review patient-reported outcomes in patients with myelodysplastic syndromes: Can a tailor-made selection of EORTC library items improve the EORTC QLQ-C30? Abstract 4856. Monday, December 3, 2018, 6:00 pm – 8:00 pm (San Diego Convention Center, Hall GH).
For more information, the ASH (Free ASH Whitepaper) program is available here: View Source
About ADCETRIS
ADCETRIS is an ADC derived from a monoclonal anti-CD30 antibody that uses proprietary technology from Seattle Genetics to bind a protease cleavable linker to monomethylauristatin E (MMAE), a microtubule-disrupting agent. The linker system of the ADC is designed to remain stable in the bloodstream. Only after internalization of the conjugate into the CD30-positive tumor cells MMAE is released.
The ADCETRIS intravenous infusion injection has received FDA approval for five indications for the treatment of adult patients: (1) untreated classical Hodgkin lymphoma (cHL) stage III or IV, in combination with chemotherapy, (2) high cHL Recurrence or progression risk as a consolidation after autologous hematopoietic stem cell transplantation (auto-HSCT); (3) cHL after auto HSCT failure or failure of at least two prior polychemotherapy regimens in patients not eligible for auto HSCT;(4) sALCL after failure of at least one prior polychemotherapy and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) in patients who have previously received systemic therapy.
Health Canada approved ADCETRIS for relapsed or refractory Hodgkin’s lymphoma and sALCL in 2013, and granted ADCETRIS full approval for autologous stem cell transplantation (ASCT) consolidation therapy in patients with Hodgkin’s lymphoma at increased risk of recurrence or progression.
ADCETRIS received conditional marketing approval from the European Commission in October 2012. The indications approved in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin’s lymphoma after ASCT or after at least two previous therapies, when ASCT or polychemotherapy are not treatment options, (2) for the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin’s lymphoma who are at increased risk of recurrence or progression after ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell Lymphoma (CTCL) after at least one previous systemic therapy.
ADCETRIS has been approved by the regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin’s lymphoma and sALCL. Please observe the following important safety instructions.
ADCETRIS is currently being extensively studied in more than 70 ongoing clinical trials, including a Phase 3 study for first-line treatment in Hodgkin’s lymphoma (ECHELON-1) and another Phase 3 trial for use as a frontline therapy CD30-positive peripheral T-cell lymphoma (ECHELON-2) as well as studies on numerous other types of CD30-positive malignancies.
Seattle Genetics and Takeda jointly develop ADCETRIS. Under the terms of the cooperation agreement, Seattle Genetics holds the marketing rights to ADCETRIS in the US and Canada, while Takeda owns the marketing rights in the rest of the world. Seattle Genetics and Takeda are sharing the co-development costs of ADCETRIS in equal parts, with the sole exception of Japan being responsible for development costs.
Important Safety Information of ADCETRIS (Brentuximab Vedotin) (European Union)
Please refer to the Specialist Information (SmPC) before a prescription.
CONTRAINDICATIONS
ADCETRIS is contraindicated in patients with hypersensitivity to brentuximab vedotin and its other ingredients. In addition, the concomitant use of ADCETRIS and bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS AND PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): In ADCETRIS-treated patients, reactivation of the John Cunningham virus (JCV) may lead to progressive multifocal leukoencephalopathy (PML) and subsequent death. PML has been reported in patients who received ADCETRIS after receiving several other chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system, which is caused by a reactivation of a latent JCV and often leads to death.
Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms that may indicate PML. PML suspicion options include neurological examination, brain gadolinium contrast MRI, and CSF DNA CSF analysis by polymerase chain reaction or brain biopsy with detection of JCV. A negative JCV PCR does not rule out PML. If no alternative diagnosis can be made, further follow-up and clarification may be indicated. The administration of ADCETRIS should be suspended whenever PML is suspected, and ADCETRIS must be discontinued if the PML diagnosis is confirmed.
Attention should be paid to symptoms of PML that may not be noticed by the patient (eg cognitive, neurological or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been reported in ADCETRIS-treated patients, sometimes with fatal outcome. Patients should be monitored closely for newly occurring or worsening abdominal pain, which may indicate acute pancreatitis. Patient examinations should include physical examinations, laboratory tests for serum amylase and serum lipase, and abdominal imaging such as ultrasound and other appropriate diagnostic methods. If acute pancreatitis is suspected, ADCETRIS should be discontinued. If the diagnosis of acute pancreatitis is confirmed, ADCETRIS should be discontinued permanently.
Pulmonary toxicity: Cases of pulmonary toxicity such as pneumonitis, interstitial lung disease and acute respiratory distress syndrome (ARDS) have been reported in patients receiving ADCETRIS, some of which are fatal. Although a causal relationship with ADCETRIS is not established, the risk of pulmonary toxicity can not be excluded. New or worsening pulmonary symptoms should be clarified immediately and treated accordingly. During the clarification and until the improvement of the symptoms, an interruption of the administration should be considered.
Serious infections and opportunistic infections: ADCETRIS-treated patients have experienced severe infections such as pneumonia, staphylococcal bacteremia, sepsis or septic shock (including fatal outcomes) and herpes zoster, and opportunistic infections such as Pneumocystis pneumonia ( Pneumocystis jiroveci ) and oral candidosis. Patients should be monitored carefully for possible signs of severe or opportunistic infection during treatment.
Infusion-Related Reactions (IRR): In the ADCETRIS therapy, immediate and delayed infusion reactions as well as anaphylactic reactions have occurred. Patients should be monitored carefully during and after an infusion. If an anaphylactic reaction occurs, the administration of ADCETRIS should be stopped immediately and for good medical treatment. In the case of an IRR, the infusion should be discontinued and appropriate medical measures should be taken. The infusion may be restarted at a slower rate once symptoms have resolved. Patients already experiencing an infusion-related reaction should be appropriately premedicated for subsequent infusions.
Tumor lysis syndrome (TLS): Cases of TLS have been reported in ADCETRIS. Patients with rapidly proliferating tumors and high tumor burden are at risk for TLS. These patients should be closely monitored and treated with the most appropriate medical procedures.
Peripheral neuropathy (PN): Treatment with ADCETRIS may cause sensory or motor PN. ADCETRIS-induced peripheral neuropathy is typically cumulative and, in most cases, reversible. Patients should be monitored for signs of PN, such as hypoaesthesia, hyperesthesia, paraesthesia, malaise, burning sensation, neuropathic pain or weakness. In patients who experience a new or worsening PN, the dose may need to be delayed and reduced or ADCETRIS discontinued.
Hematologic Toxicities : ADCETRIS may have Grade 3 or 4 anemia, thrombocytopenia, and persistent (or more than one week) neutropenia of Grade 3 or 4. Prior to administration of each dose, the large blood count should be monitored.
Febrile Neutropenia: Cases of febrile neutropenia have been reported. Patients should be closely monitored for fever and treated with the most appropriate medical procedures if febrile neutropenia develops.
Stevens-Johnson syndrome (SJS): Cases of SJS and toxic epidermal necrolysis (TEN) have been reported in ADCETRIS therapy, some of them fatal. If an SJS or TEN occurs, treatment with ADCETRIS must be discontinued and appropriate medical treatment initiated.
Gastrointestinal complications: Gastrointestinal complications, sometimes fatal, have been reported, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosions, ulcers, perforations and bleeding. New or worsening gastrointestinal complaints should be clarified immediately and treated accordingly.
Hepatotoxicity: Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels have been reported, including severe cases of liver toxicity, some of which are fatal. Liver function should be monitored in patients receiving ADCETRIS before initiating therapy and then periodically for elevated liver function. In patients with hepatotoxicity, a delay or change in dose or discontinuation of ADCETRIS therapy may be required.
Hyperglycaemia: There have been cases of hyperglycaemia in patients with an increased body mass index (BMI) with or without a history of diabetes mellitus. In patients experiencing a hyperglycaemic event, serum glucose levels should be monitored closely. If necessary, appropriate antidiabetic treatment should be used.
Renal and hepatic impairment: There is limited experience in patients with impaired renal and hepatic function. Available data suggest that MMAE excretion could be compromised by severe renal or hepatic dysfunction and low serum albumin concentrations.
CD30-positive CTCL: The extent of treatment effect on CD30-positive CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to a lack of evidence at high evidence levels. Disease activity was demonstrated in two single-arm Phase 2 studies of ADCETRIS in Sézary syndrome (SS) subtypes, lymphomatoid papulosis (LyP), and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated for other CD30-positive CTCL subtypes. A careful risk-benefit assessment should be made for each patient, and caution should be exercised in other types of CD30-positive CTCL patients.
Sodium content of excipients : ADCETRIS contains a maximum of 2.1 mmol (47 mg) sodium per dose. This should be considered in patients with controlled sodium diet.
INTERACTIONS
Patients receiving strong CYP3A4 and P-gp inhibitors concomitantly with ADCETRIS may be at increased risk of neutropen- sation, so these patients should be closely monitored. The concomitant administration of ADCETRIS and a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but appeared to reduce the plasma concentration of MMAE metabolites that could be analyzed. It is not expected that ADCETRIS will affect exposure to medicinal products metabolised by CYP3A4 enzymes.
PREGNANCY: Women of childbearing potential are advised to use two reliable birth control methods during and up to six months after treatment with ADCETRIS. So far, there are no data on the use of ADCETRIS in pregnant women. However, animal studies have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the potential benefit to the mother is significantly greater than the potential risk to the unborn child.
TERM: There is no data on whether ADCETRIS or its metabolites are excreted in breast milk. Therefore, a risk for the newborn / infant can not be excluded. Given the potential risk, a decision should be made as to whether weaning or discontinuation / abandonment of ADCETRIS therapy is more advisable.
FERTILITY: In non-clinical studies, treatment with ADCETRIS has been found to cause testicular toxicity and may therefore affect male fertility. Men treated with ADCETRIS are advised not to father a child 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.
UNWANTED REACTIONS
The most common adverse reactions (> 10%) were infection, peripheral sensory neuropathy, nausea, fatigue, diarrhea, fever, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, Constipation, dyspnea, weight loss, myalgia and abdominal pain.
Serious adverse reactions included pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, fever, motor and sensory peripheral neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome and Stevens-Johnson syndrome. Severe adverse reactions occurred in 12 percent of patients. The frequency of unique severe adverse reactions was ≤1 percent.
Important Safety Information for ADCETRIS (Brentuximab Vedotin) (USA)
FRAGRANTED WARNING: PROGRESSIVE MULTIFOCALE LEUKENCE PEPHALOPATHY (PML)
Patients receiving ADCETRIS may experience infection with the JC virus, resulting in PML and, subsequently, death.
Contraindication
Co-administration of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity (eg, interstitial infiltration and / or inflammation).
Warnings and Precautions
Peripheral Neuropathy (PN): Treatment with ADCETRIS causes a predominantly sensory PN. Cases of motor PN have also been reported. A PN triggered by ADCETRIS is cumulative. Patients should be monitored for the occurrence of symptoms such as hypoaesthesia, hyperesthesia, paraesthesia, discomforting and burning sensations, neuropathic pain or weakness. If these symptoms occur, appropriate dose changes should be made.
Anaphylactic and infusion-related reactions: Infusion reactions (IRR), including anaphylactic reactions, have occurred in association with ADCETRIS. Patients should be monitored during the infusion. In the case of an IRR, the infusion should be discontinued and appropriate medical measures should be taken. In an anaphylactic reaction, the infusion should be discontinued immediately and a suitable medical treatment should be performed. Patients who previously had an infusion reaction should be prepared for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.
Hematologic Toxicities : Under ADCETRIS, persistent (≥ 1 week) severe neutropenia and thrombocytopenia or Grade 3 or 4 anemia may occur. Cases of febrile neutropenia with ADCETRIS have been reported. Before each dose of ADCETRIS, a large blood count should be taken. Patients with Grade 3 or 4 neutropenia may be more likely to monitor more frequently. Patients should be monitored for fever. If Grade 3 or 4 neutropenia develops, delay or decrease in dose, discontinuation of therapy, or G-CSF prophylaxis should be considered at later doses.
Severe infections and opportunistic infections: Patients receiving ADCETRIS have been reported to have infections such as pneumonia, bacteremia and sepsis, or septic shock (including fatal cases). Patients should be monitored closely for possible bacterial, fungal or viral infections during treatment.
Tumor lysis syndrome: Patients with rapidly proliferating tumors and high tumor burden should be monitored closely.
Increased toxicity in severe renal insufficiency: Adverse reactions of grade 3 or higher and deaths were more common in patients with severe renal insufficiency than in patients with normal renal function. The use of ADCETRIS should be avoided in patients with severe renal insufficiency.
Increased toxicity in moderate or severe hepatic insufficiency: Grade 3 or higher adverse reactions and deaths were more common in patients with moderate or severe hepatic insufficiency than in patients with normal liver function. The use of ADCETRIS should be avoided in patients with moderate or severe hepatic insufficiency .
Hepatotoxicity : Patients receiving ADCETRIS have experienced severe cases of hepatotoxicity, some of which are fatal. The cases were consistent with hepatocellular damage, including elevated transaminase and / or bilirubin levels, and occurred after the first dose of ADCETRIS or re-exposure. Already existing liver disease, elevated baseline liver enzymes and concomitant medications may also increase the risk. Liver enzyme and bilirubin levels should be monitored. Patients with new, worsening or recurrent hepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS therapy.
Progressive multifocal leukoencephalopathy (PML): In ADCETRIS-treated patients, infections with the JC virus have been reported, leading to PML and subsequently death. The first symptoms occurred at various times after initiation of ADCETRIS therapy, with some occurring within three months of the first exposure. Other contributing factors besides ADCETRIS therapy include previous therapies as well as underlying diseases that could cause immunosuppression. The diagnosis of PML should be considered in all patients with emerging signs and symptoms of central nervous system disorders.
Pulmonary toxicity: Events of non-infectious pulmonary toxicity such as pneumonitis, interstitial lung disease and acute respiratory distress syndrome, among them fatal, have been reported. Patients should be monitored for signs and symptoms of pulmonary toxicity, including coughing and dyspnoea. In the case of new or worsening pulmonary symptoms, the administration of ADCETRIS should be discontinued during the evaluation until symptom relief.
Serious dermatological reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), among them fatal, have been reported with ADCETRIS. If an SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical treatment initiated.
Gastrointestinal complications: ADCETRIS-treated patients have been reported to have acute pancreatitis, including fatalities. Other fatal and severe gastrointestinal complications including perforation, bleeding, erosions, ulcers, intestinal obstruction, enterocolitis, neutropenic colitis and ileus have been reported in ADCETRIS-treated patients. Lymphoma with pre-existing gastrointestinal involvement may increase the risk of perforation. If new or worsening gastrointestinal symptoms appear, a diagnostic evaluation should be made immediately and appropriate treatment should be initiated.
Embryo-fetal toxicity: Based on the mechanism of action and studies in animals, ADCETRIS may cause unborn life. Women of child-bearing potential are advised not to become pregnant during treatment with ADCETRIS and at least six months after the last dose of ADCETRIS. The most common (> 20%) adverse reactions: peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection and fever.
Interaction with other medicinal products
Co-administration of potent CYP3A4 inhibitors or inducers and P-gp inhibitors may influence exposure to monomethylauristatin E (MMAE).
Use in special populations
Moderately or severely impaired hepatic function or severely impaired renal function: MMAE exposure and adverse reactions are increased. An application should be avoided.
Men with sex partners of child-bearing potential are advised to use effective contraceptive methods during treatment with ADCETRIS and at least six months after the last dose of ADCETRIS.
Patients should be advised to report pregnancy immediately and not to breastfeed while receiving ADCETRIS.
Other important safety information, including special warnings (BOXED WARNING), can be found in the full prescribing information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com .
About ICLUSIG (ponatinib) tablets
ICLUSIG is a kinase inhibitor targeting primarily BCR-ABL1, a pathologically altered tyrosine kinase expressed in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). ICLUSIG is a targeted cancer therapeutics engineered specifically to inhibit the activity of BCR-ABL1 and its mutations using a computer-aided and structure-based drug design platform. Not only does ICLUSIG target the native form of BCR-ABL1, but also therapy-resistant mutations, including the T315I mutation, which is the least responsive to any of the mutations. ICLUSIG is the only approved TKI,, This mutation has been linked to resistance to all other TKIs. ICLUSIG, which was fully approved by the FDA in November 2016, is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.
In the US, ICLUSIG is indexed to:
Treatment of adult patients with CML in the chronic, accelerated or blast phase (CP-CML, AP-CML or BP-CML) or Ph + ALL, in which no other tyrosine kinase inhibitor (TKI) is indicated.
Treatment of adult patients with T315I-positive CML (CP, AP or BP) or T315I-positive Ph + ALL.
Limitations of use: Treatment with ICLUSIG is not indicated and recommended for patients with newly diagnosed CP-CML.
IMPORTANT SAFETY INSTRUCTIONS FOR ICLUSIG (ponatinib) (USA)
WARNING: ARTERIAL CLOSURE, VENOUS THROMBOEMBOL, HEART FAILURE AND LIVER TOXICITY
The detailed Special Warnings (Boxed Warning) can be found in the full prescribing information.
At least 35 percent of ICLUSIG (ponatinib) -treated patients had arterial occlusions, including fatal myocardial infarction, stroke, large cerebral stenosis, severe peripheral vascular disease, and the need for emergency revascularization surgery. Patients with and without cardiovascular risk factors, including patients younger than 50, were affected by these events. If arterial occlusion occurs, treatment with ICLUSIG should be discontinued or discontinued immediately. The decision whether to resume treatment with ICLUSIG should be based on a risk-benefit assessment.
Venous thromboembolism occurred in 6 percent of ICLUSIG-treated patients. Patients should be monitored for signs of thromboembolism. In patients who develop severe venous thromboembolism, dose adjustment or discontinuation of ICLUSIG should be considered.
Heart failure, including fatal cases, was found in 9 percent of ICLUSIG-treated patients. Accordingly, the heart function is to be monitored. In the event of a new onset or worsening of heart failure, treatment with ICLUSIG should be discontinued or discontinued.
Hepatotoxicity, liver failure and death were observed in ICLUSIG-treated patients. Accordingly, liver function should be monitored. If liver toxicity is suspected, treatment with ICLUSIG should be discontinued.
WARNINGS AND PRECAUTIONS
Arterial occlusions:At least 35 percent of ICLUSIG-treated patients in Phase 1 and 2 trials had arterial occlusions, including fatal myocardial infarction, stroke, large cerebral stenosis, and severe peripheral artery disease. In the Phase 2 study, 33 percent (150/449) of ICLUSIG-treated patients had a cardiovascular (21%), peripheral (12%), or cerebrovascular (9%) arterial occlusive event; Some patients suffered more than 1 type of such event. Fatal and life-threatening events occurred within 2 weeks after initiation of therapy, even at doses as low as 15 mg per day. ICLUSIG may also cause recurrent or multi-site occlusion. Patients required revascularization procedures. The median time to onset of the first cardiovascular, cerebrovascular and peripheral vascular occlusive events was 193, 526 and 478 days, respectively. Patients with and without cardiovascular risk factors, including patients up to 50 years of age, were affected by these events. The most common risk factors associated with these events were hypertension, hyperlipidemia and history of heart disease. Arterial obstruction events increased with age and in patients with ischemia, hypertension, diabetes or hyperlipidemia.
Venous thromboembolism: Venous thromboembolic events occurred in 6 percent (25/449) of ICLUSIG-treated patients. Incidence rates were 5 percent (13/270 CP-CML), 4 percent (3/85 AP-CML), 10 percent (6/62 BP-CML), and 9 percent (3/32 Ph + ALL). Events included deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. In patients who develop severe venous thromboembolism, dose adjustment or discontinuation of ICLUSIG should be considered.
Heart failure: 6% of ICLUSIG-treated patients (29/449) had fatal and severe cardiac insufficiency or left ventricular dysfunction. 9 percent of patients (39/449) had heart failure or left ventricular dysfunction of any grade. The most frequently reported cardiac insufficiency events were congestive heart failure and reduced ejection fraction (14 patients, 3% each). Patients should be monitored for signs and symptoms of heart failure and treated as clinically indicated, including discontinuation of ICLUSIG therapy. If severe heart failure develops, discontinuation of Iclusig should be considered
hepatotoxicity:ICLUSIG can cause liver toxicity, liver failure and death. Fulminant liver failure with fatal outcome occurred in one patient within one week of initiation of ICLUSIG treatment. Two more deaths from acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph + ALL. Heavy liver toxicity was observed in all disease cohorts, with 11 percent (50/449) showing grade 3 or 4 liver toxicity. The most common form of liver toxicity was elevations of AST or ALT (54% all grade, 8% grade 3 or 4, 5% not normalized at last follow-up), bilirubin and alkaline phosphatase. Hepatotoxic events were observed in 29 percent of patients. The median time to onset of the hepatic toxicity event was 3 months. Laboratory monitoring of liver function should be performed at baseline and then at least once a month or after clinical indication. Treatment with ICLUSIG should be discontinued, reduced or discontinued depending on the clinical judgment.
Arterial hypertension:Treatment-related increases in systolic or diastolic blood pressure (RR) occurred in 68 percent (306/449) of ICLUSIG-treated patients. 53 patients (12%) developed severe symptomatic blood pressure elevation, including hypertensive crisis, as serious adverse reactions. Patients whose blood pressure is associated with confusion, headache, chest pain or shortness of breath may require emergency clinical intervention. In patients with systolic RR <140 mm Hg and diastolic RR <90 mm Hg at baseline, 80% (229/285) had treatment-related hypertension, where 44 percent (124/285) developed stage 1 and 37 percent stage 2 hypertension. Of the 132 patients with stage 1 onset hypertension, 67 percent (88/132) developed stage 2 hypertension. During therapy with ICLUSIG, patients should be monitored for blood pressure elevations and, if necessary, treated until normalization of blood pressure is achieved. If hypertension can not be stopped by medication, treatment with ICLUSIG should be discontinued, reduced in dose or discontinued. In the event of marked deterioration and unstable or refractory hypertension, treatment should be discontinued and consideration given to the presence of renal artery stenosis should be considered.
pancreatitis:Pancreatitis occurred in 7% (31/449, 6% severe or grade 3/4) of ICLUSIG-treated patients. The incidence of treatment-related lipase elevations was 42 percent (16% at least grade 3). Because of pancreatitis, 6 percent of patients (26/449) discontinued or discontinued therapy. The median time to onset of pancreatitis was 14 days. In 23 of the 31 cases of pancreatitis, it receded within 2 weeks of discontinuation or dose reduction. Serum lipase should be monitored every two weeks for the first 2 months and then monthly or as clinically indicated. In patients with a history of pancreatitis or alcoholism, additional controls of serum lipase levels should be considered. Interruption of treatment or dose reduction may be required. In cases where lipase elevations are associated with abdominal symptoms, treatment with ICLUSIG should be discontinued and the patient should be screened for the presence of pancreatitis. Recovery of ICLUSIG treatment should not be considered until all symptoms have resolved and lipase levels have dropped to less than 1.5 times the upper limit of normal. If lipase elevations are associated with abdominal symptoms, discontinue treatment with ICLUSIG and examine the patient for the presence of pancreatitis. Recovery of ICLUSIG treatment should not be considered until all symptoms have resolved and lipase levels have dropped to less than 1.5 times the upper limit of normal. If lipase elevations are associated with abdominal symptoms, discontinue treatment with ICLUSIG and examine the patient for the presence of pancreatitis. Recovery of ICLUSIG treatment should not be considered until all symptoms have resolved and lipase levels have dropped to less than 1.5 times the upper limit of normal.
Increased toxicity of newly diagnosed CML in the chronic phase:In a prospective randomized clinical trial for first-line treatment of patients with newly diagnosed CML in the chronic phase (CP CML), monotherapy with ICLUSIG 45 mg once daily doubled the risk of serious adverse reactions compared to monotherapy with imatinib 400 mg once daily. Median exposure to treatment was less than 6 months. The study was stopped in October 2013 for safety reasons. Arterial and venous thrombosis and occlusion were at least twice as common in the ICLUSIG arm than in the imatinib arm. Compared with imatinib-treated patients, ICLUSIG-treated patients had a higher incidence of myelosuppression, pancreatitis, Liver toxicity, heart failure, hypertension and diseases of the skin and subcutaneous tissue. Treatment with ICLUSIG is not recommended and recommended for patients with newly diagnosed CP-CML.
neuropathy:Neuropathies of the peripheral nerves and cranial nerves were observed in patients treated with ICLUSIG. Overall, 20 percent (90/449) of ICLUSIG-treated patients had peripheral grade neuropathy (2%, grade 3/4). The most common reported peripheral neuropathies were paraesthesia (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). Two percent (10/449) of ICLUSIG-treated patients (<1%, 3/449 – grade 3/4) developed cranial nerve neuropathy. Among the patients who developed neuropathy, this occurred in 26 percent (23/90) of cases in the first month of treatment. Patients should be monitored for the appearance of symptoms of neuropathy such as hypoaesthesia, hyperesthesia, paraesthesia, discomforting and burning sensations, neuropathic pain or weakness. If neuropathy is suspected, interruption of ICLUSIG treatment and clarification of symptoms should be considered.
Toxicity to the eye:Patients treated with ICLUSIG have been reported to have severe eye toxic effects leading to blindness or blurred vision. Retinal toxicity, including macular edema, retinal venous occlusion and retinal haemorrhage, was found in 2 percent of ICLUSIG-treated patients. Conjunctival irritation, corneal erosion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14 percent of patients. Blurred vision was reported by 6 percent of patients. Other toxic effects on the eye included cataract, periorbital edema, blepharitis, glaucoma, eyelid edema, iritis, iridocyclitis, and ulcerative keratitis.
Bleeding: 6 percent (28/449) of ICLUSIG-treated patients experienced major bleeding events, including fatal cases. Bleeding occurred in 28 percent (124/449) of the patients. Patients with AP-CML, BP-CML, and Ph + ALL had a higher incidence of major bleeding events. Gastrointestinal haemorrhage and subdural hematomas were the most frequently reported major bleeding events, occurring at 1 percent (4/449), respectively. Most, but not all, bleeding events occurred in patients with Grade 4 thrombocytopenia. Treatment with ICLUSIG should be discontinued in case of serious or severe bleeding and the cause of bleeding should be clarified.
Fluid retention: 4 percent (18/449) of the patients treated with ICLUSIG experienced severe fluid retention. A case of brain edema was deadly. Regarding fluid retention events, which occurred in> 2 percent of patients (treatment-related), including severe cases, pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and peripheral edema (2/449, <1%).
Overall, fluid retention occurred in 31 percent of patients. The most common forms of fluid retention were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%), and peripheral swelling (3%).
Patients should be monitored for storage of fluid and treated as clinically indicated. Treatment with ICLUSIG should be discontinued, reduced or discontinued according to the clinical situation.
Cardiac arrhythmias: Arrhythmias occurred in 19 percent (86/449) of ICLUSIG-treated patients, with 7 percent (33/449) at least third-degree. Ventricular arrhythmias accounted for 3 percent (3/86) of all cardiac arrhythmias, with a grade of at least third grade. Symptomatic bradyarrhythmias leading to pacemaker implantation occurred in 1 percent (3/449) of ICLUSIG-treated patients.
Atrial fibrillation was the most common cardiac arrhythmia and occurred in 7 percent (31/449) of the patients, with about half of the third or. 4th degree were. Other third or fourth degree arrhythmia events included syncope (9 patients, 2.0%), tachycardia and bradycardia (2 patients, 0.4% each), and ECG QT prolongation, atrial flutter, supraventricular tachycardia, ventricular Tachycardia, atrial tachycardia, complete AV block, respiratory circulatory arrest, unconsciousness and sinus node dysfunction (1 patient each, 0.2%). 27 patients were hospitalized for the event.
In patients with symptoms of slow (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), ICLUSIG treatment should be discontinued and symptoms clarified.
Myelosuppression: Myelosuppression has been reported as an adverse reaction in 59 percent (266/449) of ICLUSIG-treated patients, with grade 3 or 4 myelosuppression observed in 50 percent (226/449) of patients. The incidence of these events was higher in patients with AP-CML, BP-CML, and Ph + ALL than in patients with CP-CML. Severe myelosuppression (Grade 3 or 4) was observed at the early stages of treatment, with a median beginning of 1 month (range <1-40 months). In the first 3 months every 2 weeks, then monthly or as clinically indicated, create a large blood count and adjust the dose as recommended.
Tumor lysis syndrome: Two of the ICLUSIG-treated patients (<1%, one with AP-CML and one with BP-CML) developed a serious tumor lysis syndrome. Hyperuricemia was found in 7 percent (31/449) of the patients. Since tumor lysis syndrome may be present in patients with advanced disease, adequate hydration and treatment with elevated uric acid levels should be considered prior to initiation of ICLUSIG therapy.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Cases of reversible posterior leukoencephalopathy syndrome (RPLS – also known as posterior reversible encephalopathy syndrome (PRES)) have been reported in the post-marketing surveillance study in ICLUSIG-treated patients. RPLS is a neurological disorder characterized by symptoms such as seizure, headache, decreased attention, altered mental functions, vision loss, and other neurological and visual disturbances. Often there is hypertension and the diagnosis is made with supportive brain magnetic resonance imaging (MRI) findings. If the RPLS diagnosis is made, treatment with ICLUSIG should be discontinued. Therapy should only be restarted
Impairment of wound healing and gastrointestinal perforation: Since ICLUSIG may interfere with wound healing, treatment with ICLUSIG should be discontinued at least one week prior to major surgery. In one patient, 38 days after cholecystectomy, a severe gastrointestinal perforation (fistula) occurred.
Embryo-fetal toxicity: The mechanism of action and observations in animals suggest that ICLUSIG may induce fetal harm when used in pregnancy. In animal reproduction studies, oral administration of ponatinib to pregnant rats during the organogenesis phase caused adverse developmental effects at exposure lower than human exposure at the human recommended dose. Pregnant women should be made aware of the potential risk to the unborn child. Women of childbearing potential should use effective contraception during treatment with ICLUSIG and during the 3 weeks following the last dose.
INACCURATE RESPONSES
Most common adverse reactions: Overall, the most common non-hematological adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, fever, arthralgia, nausea, diarrhea, lipase elevation, vomiting, muscle pain and pain in one limb. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia and leukopenia.
To report POSSIBLE REACTIONS, 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 OTHER MEDICINES
Strong CYP3A inhibitors: Avoid concomitant use or reduce the dose of ICLUSIG if co-administration can not be avoided.
Strong CYP3A inducers: avoid concomitant use.
Use in special groups of patients
Women of childbearing potential and fertile men: Use of ICLUSIG during pregnancy may cause damage to the unborn child. Women are advised to use effective contraception during treatment with ICLUSIG and in the 3 weeks following the last dose. Ponatinib may affect fertility in women, and it is not known if these effects are reversible. In women of childbearing potential, pregnancy status should be checked before initiating therapy with ICLUSIG.
Breast-feeding: Women are advised not to breastfeed during ICLUSIG therapy and six days after the last dose.
The US prescribing information can be found at: View Source
About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is an oral proteasome inhibitor that is also being studied in the multiple myeloma therapy continuum and in systemic light chain amyloidosis (AL). It was the first oral proteasome inhibitor studied in Phase 3 clinical trials and received approval. NINLARO was approved by the US Food and Drug Administration in November 2015 following a Priority Review and by the European Commission in November 2016. In the US and Europe, NINLARO in combination with lenalidomide and dexamethasone is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO has received regulatory approval from regulators in more than 55 countries.
Ixazomib has been granted orphan drug status in multiple myeloma in the United States and Europe in 2011 and in AL and amyloidosis in 2012 in the United States and Europe. Ixazomib was awarded FDA Breakthrough Therapy status in 2014 for relapsed or refractory systemic light chain amyloidosis (AL), a related extremely rare disease. The Japanese Ministry of Health, Labor and Social Affairs granted Ixazomib orphan drug status in 2016.
TOURMALINE, the comprehensive Ixazomib clinical development program, includes a total of six ongoing regulatory trials – five investigating all major groups of multiple myeloma patients and one dealing with light chain amyloidosis:
TOURMALINE-MM1 for testing ixazomib over placebo in combination with lenalidomide and dexamethasone in relapsed and / or refractory multiple myeloma.
TOURMALINE-MM2 for the testing of ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.
TOURMALINE-MM3 for testing ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem cell transplantation (ASCT)
TOURMALINE-MM4 for testing ixazomib over placebo as maintenance treatment in patients with newly diagnosed multiple myeloma who have not undergone ASCT. Patients are currently enrolled in this study.
TOURMALINE-MM5 for the testing of ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and / or refractory multiple myeloma who have become resistant to lenalidomide.
TOURMALINE-AL1 for the testing of ixazomib plus dexamethasone for a physician on the basis of a selection of therapies in patients with relapsed or refractory AL amyloidosis. Patients are currently enrolled in this study.
For more information on actively recruiting Phase 3 studies, visit View Source
In addition to the TOURMALINE study program, Ixazomib is currently being evaluated in several therapeutic combinations in various patient populations worldwide through investigator-initiated studies (IIT).
NINLARO (Ixazomib) Capsules: Important Safety Information Worldwide
SPECIAL WARNING (S) AND PRECAUTIONS
Thrombocytopenia been reported with NINLARO (28% vs 14% with the NINLARO or placebo regimen). Platelets reached their lowest point between the 14th and 21st day of the 28-day treatment cycle and recovered to baseline by the start of the next cycle. This did not lead to increased bleeding events or platelet transfusions. During treatment with NINLARO, the platelet count should be monitored at least monthly and more frequent monitoring should be considered during the first three cycles. Thrombocytopenia should be treated with dose adjustment and platelet transfusions in accordance with the recommendations of the standard guidelines.
Gastrointestinal toxicities were reported in the NINLARO and placebo regimens, for example, diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs 11%). These occasionally required the use of medication for vomiting and diarrhea, as well as supportive therapy.
Peripheral neuropathy has been reported in NINLARO (28% vs. 21% with the NINLARO or placebo regimen). The most commonly reported adverse reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO or placebo regimen). Peripheral motor neuropathy has not been reported in any of the two regimens (<1%). Patients should be monitored for signs of peripheral neuropathy and dosing adjusted if necessary.
Peripheral edema has been reported in NINLARO (25% vs. 18% with the NINLARO or placebo regimen). The underlying causes should be clarified. If necessary, patients should receive supportive care. Dose adjustment should be made with dexamethasone according to the SPC or with NINLARO if severe symptoms occur.
Skin reactions occurred in 19 percent of patients with the NINLARO regimen compared to 11 percent of patients on the placebo regimen. The most common form of rash on both schemes was a maculopapular and macular rash. Rashes should be treated with supportive therapy, dose adjustment or discontinuation of the drug
Hepatotoxicity, drug-induced liver damage, hepatocellular damage, fatty liver, and cholestatic hepatitis have not been reported frequently in NINLARO-treated patients. Liver values should be monitored regularly and dose adjustments should be made for symptoms of Grade 3 and 4.
Pregnancy – NINLARO can lead to harm to unborn life. For fertile men and women of childbearing potential, contraceptive methods should be used during treatment and for a further 90 days after the last dose of NINLARO. Due to the possible risk to the unborn child, women of childbearing age should be prevented from taking pregnancy while being treated with NINLARO. Women using hormonal contraceptives should also use a barrier prevention method.
Breastfeeding – It is not known whether NINLARO or its breakdown products are excreted in breast milk. Due to possible adverse events in breast-fed infants, NINLARO-treated patients should abstain.
SPECIAL PATIENT POPULATIONS
Hepatic impairment: The starting dose of NINLARO should be reduced to 3 mg in patients with moderate or severe hepatic impairment.
Renal impairment: In patients with severe renal insufficiency or patients with end-stage renal disease (ESRD) requiring dialysis, the starting dose of NINLARO should be reduced to 3 mg. NINLARO is not dialyzable and can therefore be administered independently of the dialysis schedule.
INTERACTIONS WITH OTHER MEDICINES
The simultaneous use of NINLARO and potent CYP3A inducers is foreseeable.
UNWANTED REACTIONS
The most common adverse reactions seen in at least 20% of patients treated with the NINLARO regimen or more frequently than placebo regimens 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%). The severe adverse reactions that occurred in at least 2 percent of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1 percent of patients in the NINLARO regimen.
The EU Prescribing Information can be found at View Source
The US prescribing information can be found at https: //www.ninlarohcp .com / pdf / prescribing-information.pdf
You can find the Canadian product monograph at View Source