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Takeda to Highlight Expanded Portfolio of Products Across Oncology and Hematology at 61st American Society of Hematology (ASH) Annual Meeting

November 6, 2019, 12:00 am
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CAMBRIDGE, Mass. & OSAKA, Japan

Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE:TAK) today announced that it will present a total of 29 company-sponsored abstracts at the 61st American Society of Hematology (ASH) Annual Meeting on December 7-10, 2019 in Orlando, FL, highlighting the company’s commitment to advancing the treatment of hematologic cancers and bleeding disorders.

Pursuing Breakthrough, Patient-Centric Innovation in Oncology and Bleeding Disorders

Takeda will present 29 scientific updates on the company’s investigational and early-stage therapies, which demonstrates its investment in new compounds to address patient needs, as well as data from Phase 3 trials and real-world evidence findings, in disease states including multiple myeloma, lymphoma and leukemia.

“We are presenting notable data on several clinical programs at ASH, highlighting our deep oncology pipeline and our commitment to developing innovative therapies that may address unmet needs for blood cancer patients,” said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. “In particular we look forward to sharing data from the Phase 3 clinical trial of ixazomib in amyloidosis patients, data from the US MM-6 study, which evaluates an in-class transition from parenteral bortezomib to oral ixazomib in multiple myeloma, further analyses from the Phase 3 ECHELON-2 trial of ADCETRIS in peripheral T-cell lymphoma, as well as early stage data from several of our pipeline programs.”

In hematology, Takeda will present real-world evidence from studies of its portfolio of treatments across bleeding disorders, including hemophilia A, hemophilia B and von Willebrand disease. The company will also present scientific updates related to its hemophilia A and hemophilia B gene therapy programs and adeno-associated virus (AAV) gene therapy platform.

“Understanding real-world evidence is critical as Takeda continues to provide patients with innovative therapies for hemophilia A and hemophilia B while broadening our research and development efforts in von Willebrand disease and other bleeding disorders,” said Daniel Curran, M.D., Head, Rare Diseases Therapeutic Area Unit, Takeda. “Also at ASH, we look forward to providing an update on our gene therapy programs in hemophilia and the optimization of Takeda’s AAV gene therapy platform, particularly for patients with pre-existing immunity to AAV serotypes.”

Accepted oncology abstracts include:

Note: all times listed are in Eastern Standard Time

NINLARO™ (ixazomib) and Multiple Myeloma

ADCETRIS® (brentuximab vedotin) and Lymphoma

ICLUSIG® (ponatinib)

Pipeline (multiple myeloma, lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia)

Accepted hematology abstracts include:

Note: all times listed are in Eastern Standard Time

ADYNOVATE® (Antihemophilic Factor (Recombinant), PEGylated) and Hemophilia A

FEIBA® (Anti-Inhibitor Coagulant Complex)

von Willebrand Disease

Pipeline (hemophilia A, hemophilia B and gene therapies)

About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression in 2017, adults with pcALCL or CD30-expressing MF who have had prior systemic therapy in 2018, and for previously untreated Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) for the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy and (5) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD.

ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) Important Safety Information (European Union)
Please refer to Summary of Product Characteristics (SmPC) before prescribing.

CONTRAINDICATIONS

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

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.

Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed.

Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms (e.g., cough, dyspnoea) appropriately. Consider holding dosing during evaluation and until symptomatic improvement.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Carefully monitor patients during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and manage according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically an effect of cumulative exposure to ADCETRIS and is reversible in most cases. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.

When ADCETRIS is administered in combination with AVD, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs and administer appropriate medical therapy.

Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported with ADCETRIS. Promptly evaluate and treat patients if new or worsening GI symptoms occur.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Test liver function prior to treatment initiation and routinely monitor during treatment. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.

Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.

CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use with caution in other CD30+ CTCL patient types.

Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

INTERACTIONS
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia. If neutropenia develops, refer to dosing recommendations for neutropenia (see SmPC section 4.2). Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus.

LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Advise men being treated with ADCETRIS not to father a child during treatment and for up to 6 months following the last dose.

Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS

Monotherapy: The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain. Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%. Adverse events led to treatment discontinuation in 24% of patients.

Combination Therapy: In the study of ADCETRIS as combination therapy with AVD in 662 patients with previously untreated advanced HL, the most common adverse reactions (≥ 10%) were: neutropenia, nausea, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhoea, pyrexia, alopecia, peripheral motor neuropathy, decreased weight, abdominal pain, anaemia, stomatitis, febrile neutropenia, bone pain, insomnia, decreased appetite, cough, headache, arthralgia, back pain, dyspnoea, myalgia, upper respiratory tract infection, alanine aminotransferase increased. Serious adverse reactions occurred in 36% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (17%), pyrexia (6%), and neutropenia (3%). Adverse events led to treatment discontinuation in 13% of patients.

ADCETRIS (brentuximab vedotin) Important Safety Information (U.S.)

BOXED WARNING
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

  • Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
  • Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
  • Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.

    Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

    Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

  • Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
  • Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
  • Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
  • Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
  • Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
  • PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
  • Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
  • Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
  • Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
  • Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Most Common (≥20% in any study) Adverse Reactions
Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including BOXED WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or http://www.ADCETRIS.com.

ADYNOVATE Professional Important Information

ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] Important Information

Indications and Limitation of Use
ADYNOVATE is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management
  • Routine prophylaxis to reduce the frequency of bleeding episodes

ADYNOVATE is not indicated for the treatment of von Willebrand disease.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS
Prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE [Antihemophilic Factor (Recombinant)]), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

WARNINGS & PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

ADVERSE REACTIONS
The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea.

Click here for Full Prescribing Information
https://www.shirecontent.com/PI/PDFs/ADYNOVATE_USA_ENG.pdf

FEIBA [Anti-Inhibitor Coagulant Complex] Indications and Detailed Important Risk Information

Indications for FEIBA

FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for:

  • Control and prevention of bleeding episodes
  • Perioperative management
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.

Detailed Important Risk Information for FEIBA

 

WARNING: EMBOLIC AND THROMBOTIC EVENTS

 

  • Thromboembolic events have been reported during post-marketing surveillance following infusion of FEIBA, particularly following the administration of high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors.
  • Monitor patients receiving FEIBA for signs and symptoms of thromboembolic events.

CONTRAINDICATIONS

FEIBA is contraindicated in patients with:

  • History of anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components, including factors of the kinin generating system
  • Disseminated intravascular coagulation (DIC)
  • Acute thrombosis or embolism (including myocardial infarction)

WARNINGS AND PRECAUTIONS

Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) can occur, particularly following the administration of high doses (>200 units/kg/day) and/or in patients with thrombotic risk factors.

Patients with DIC, advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with recombinant factor VIIa have an increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy. Potential benefit of treatment should be weighed against potential risk of these thromboembolic events.

Infusion should not exceed a single dose of 100 units/kg and daily doses of 200 units/kg. Maximum injection or infusion rate must not exceed 2 units/kg/minute. Monitor patients receiving >100 units/kg for the development of DIC, acute coronary ischemia and signs and symptoms of other thromboembolic events. If clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain, discontinue FEIBA and initiate appropriate diagnostic and therapeutic measures.

Safety and efficacy of FEIBA for breakthrough bleeding in patients receiving emicizumab has not been established. Cases of thrombotic microangiopathy (TMA) were reported in a clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding following emicizumab treatment. Consider the benefits and risks with FEIBA if considered required for patients receiving emicizumab prophylaxis. If treatment with FEIBA is required for patients receiving emicizumab, the hemophilia treating physician should closely monitor for signs and symptoms of TMA. In FEIBA clinical studies TMA has not been reported.

Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can occur. Symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. Reactions can be severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been reported. If signs and symptoms of severe allergic reactions occur, immediately discontinue FEIBA and provide appropriate supportive care.

Because FEIBA is made from human plasma it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

FEIBA contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D, may interfere with some serological tests for red cell antibodies, such as antiglobulin test (Coombs test).

ADVERSE REACTIONS

Most frequently reported adverse reactions observed in >5% of subjects in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting.

Serious adverse reactions seen are hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.

DRUG INTERACTIONS

Consider possibility of thrombotic events when systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used with FEIBA. No adequate and well-controlled studies of combined or sequential use of FEIBA and recombinant factor VIIa, antifibrinolytics, or emicizumab, have been conducted. Use of antifibrinolytics within approximately 6 to 12 hours after FEIBA is not recommended.

Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab.

Please see FEIBA full Prescribing Information, including BOXED
WARNING on Embolic and Thrombotic Events

About ICLUSIG® (ponatinib) tablets

ICLUSIG is a kinase inhibitor primarily targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG targets native BCR-ABL1, as well as BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG which received full approval from the FDA in November 2016, is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.

In the U.S., ICLUSIG is indicated for:

  • Treatment of adult patients with chronic-phase, accelerated-phase or blast-phase CML (CP-CML, AP-CML or BP-CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
  • Treatment for adult patients with T315I-positive CML (CP, AP or BP) or T315I-positive Ph+ ALL.

Limitations of Use: ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

ICLUSIG (ponatinib) IMPORTANT SAFETY INFORMATION (U.S.)
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

  • Arterial occlusion has occurred in at least 35% of ICLUSIG® (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
  • Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
  • Heart Failure, including fatalities occurred in 9% of ICLUSIG treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
  • Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.

WARNINGS AND PRECAUTIONS
Arterial Occlusions: Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of ICLUSIG-treated patients from the phase 1 and phase 2 trials. In the phase 2 trial, 33% (150/449) of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193, 526, and 478 days, respectively. Patients with and without cardiovascular risk factors, some age 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing arterial occlusive events, interrupt or stop ICLUSIG.

Venous Thromboembolism: Venous thromboembolic events occurred in 6% (25/449) of ICLUSIG-treated patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.

Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of ICLUSIG-treated patients (29/449). Nine percent of patients (39/449) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (14 patients each; 3%). Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in a patient within one week of starting ICLUSIG. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.

Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of ICLUSIG-treated patients. Fifty-three patients (12%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during ICLUSIG use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled.

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