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- Approval Based on Positive Results from the Phase 3 HD21 Trial for StageIIb with Risk Factors/III/IV Hodgkin Lymphoma

- ADCETRIS-based Combination Demonstrated Superior Safety Profile and Efficacy Compared to eBEACOPP, a Standard of Care Regimen in Europe

- Second Approval in Frontline Hodgkin Lymphoma Broadens ADCETRIS’ Therapeutic Reach, Adding to Six Previously Approved, Distinct Indications for ADCETRIS in the European Union

Takeda (TSE:4502/NYSE:TAK) today announced that the European Commission (EC) approved ADCETRIS^® (brentuximab vedotin) in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (ECADD) – a chemotherapy regimen – in adult patients with newly diagnosed Stage IIb with risk factors/III/IV Hodgkin lymphoma. The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on April 25, 2025.

The approval for this ADCETRIS-based combination regimen, known as BrECADD, in frontline Hodgkin lymphoma is based on the results of the randomized Phase 3 HD21 trial. The study met its co-primary safety and efficacy endpoints, with BrECADD demonstrating significantly superior safety as assessed by treatment-related morbidity (TRMB) and non-inferior progression-free survival (PFS) in comparison to escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (eBEACOPP), a standard of care treatment in Europe¹.

“Today's approval represents a significant advancement for patients with Hodgkin lymphoma in the European Union,” said Teresa Bitetti, president of the Global Oncology Business Unit at Takeda. "This approval reinforces the role of ADCETRIS as a backbone in the treatment of specific lymphomas, offering healthcare professionals greater flexibility to tailor treatment plans according to individual patient needs. We’re proud to contribute another impactful option for those diagnosed with this challenging disease.”

ADCETRIS is an antibody-drug conjugate (ADC) directed at CD30, a defining marker of Hodgkin lymphoma, and has been previously approved as a therapy for adult patients in the European Union (EU) in six distinct indications. This decision marks the second approval for an ADCETRIS-based combination regimen for frontline Hodgkin lymphoma, broadening the spectrum of available treatments for patients who historically have had limited options.

“With BrECADD, patients now have a treatment option that not only offers greater curative potential^2* but also significantly reduces treatment-related morbidity compared to eBEACOPP,” said Peter Borchmann, MD, PhD, University Hospital of Cologne, Germany, and trial chairman of the HD21 study. “This new ADCETRIS-based combination therapy may offer a new standard of care for frontline treatment of adults with advanced stage Hodgkin lymphoma, contributing to improved long-term outcomes for patients.”

About the HD21 Trial
The HD21 study is a Phase 3, multi-country, prospective, open-label, randomized, multicenter trial conducted by the German Hodgkin Study Group (GHSG) with a PET-response adapted designed to assess the feasibility, efficacy, safety and tolerability of BrECADD, a novel, rationally designed, CD30-intensified frontline regimen for patients with advanced Hodgkin lymphoma.

Enrolled patients with newly diagnosed, Stage IIb with large mediastinal mass and/or extranodal lesions, Stage III or IV Hodgkin lymphoma were randomized to receive two cycles of either escalated BEACOPP or BrECADD, respectively, followed by interim PET staging. A decision is then made if patients received a further two or four cycles of escalated BEACOPP or BrECADD.

The HD21 trial aims to evaluate a new treatment regimen to minimize side effects, while maintaining similar responses to treatment. The study has co-primary endpoints: safety is assessed by treatment-related morbidity (TRMB) (superiority), a novel endpoint focused on clinically relevant, acute toxicities of primary chemotherapy, and efficacy is assessed by PFS (non-inferiority). Secondary endpoints are tumor response (complete response [CR] rate), overall survival (OS), infertility rate at one year, second malignancies, frequency of adverse events, therapy adherence and quality of life.

About ADCETRIS® (brentuximab vedotin)
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 Pfizer’s 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 eight indications:

• Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine (2018)
• Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022)
• Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015)
• Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (2011)
• Adult patients with 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 (2018)
• Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen (2011)
• Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017)
• Adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy who are not eligible for auto-HSCT or CAR T-cell therapy, in combination with lenalidomide and a rituximab product (2025)

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, for previously untreated Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012, and the specific obligations of the conditional marketing authorization were fulfilled in May 2022. The approved indications in the European Union are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage III or IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) 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, (4) for the treatment of adult patients with relapsed or refractory sALCL, (5) for the treatment of adult patients with previously untreated sALCL in combination with CHP, (6) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy and (7) for the treatment of adult patients with previously untreated CD30+ Stage IIB with risk factors, Stage III or Stage IV HL in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD).

ADCETRIS has received marketing authorization by regulatory authorities in 80 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.

Pfizer and Takeda fund 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. Combined use of bleomycin and ADCETRIS causes pulmonary toxicity.

Special Warnings and Precautions
Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death can occur in ADCETRIS-treated patients. PML has been reported in patients who received this treatment 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.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. ADCETRIS should be held for any suspected case 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. ADCETRIS dosing should be permanently discontinued if a diagnosis of PML is confirmed.

The physician should be particularly alert to symptoms suggestive of PML 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.

Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding ADCETRIS 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, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS.

Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered.

If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. Premedication may include paracetamol, an antihistamine and a corticosteroid.

IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumour and high tumour burden are at risk of tumour lysis syndrome. These patients should be monitored closely and managed according to best medical practice. Management of TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care.

Peripheral neuropathy (PN): ADCETRIS may cause peripheral neuropathy, both sensory and motor. ADCETRIS-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases. In clinical trials, the majority of patients had resolution or improvement of their symptoms. Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a dose reduction of ADCETRIS or discontinuation of treatment.

Hematological toxicities: Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥ 1 week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 10⁹/L, fever ≥ 38.5 ⁰C; ref CTCAE v3) has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

In combination therapy with AVD or CHP, advanced age was a risk factor for febrile neutropenia. When ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patients regardless of age. In combination therapy with AVD or CHP, advanced age was a risk factor for febrile neutropenia.

Severe cutaneous adverse reactions (SCARs): Cases of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with ADCETRIS. Fatal outcomes have been reported for SJS and TEN. If SJS, TEN or DRESS occur, ADCETRIS should be discontinued, and appropriate medical therapy should be administered.

Gastrointestinal (GI) Complications: GI complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with ADCETRIS. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Hepatotoxicity: Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has 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. Liver function should be tested before initiating the treatment and routinely monitored in patients receiving ADCETRIS. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.

Infusion site extravasation: Extravasation during intravenous infusion has occurred. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration.

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. Nevertheless, ADCETRIS should be used with caution in other CD30+ CTCL patients after careful consideration of the potential benefit-risk on an individual basis.

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.

Polysorbate content in excipients: This medicinal product contains 2 mg of polysorbate 80 per vial, equivalent to 0.2 mg/ml. Polysorbates may cause allergic reactions.

Interactions
Interaction with medicinal products metabolised through CYP3A4 route (CYP3A4 inhibitors/inducers)
Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Tables 1 and 2 for dosing recommendations for neutropenia.

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin. Though PK data are limited, co-administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed.

Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure to medicines that are metabolized by CYP3A4 enzymes.

Etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD regimen)
The pharmacokinetics of ADC and MMAE have not been characterized in the setting of BrECADD. Exposures of brentuximab vedotin and concurrent chemotherapy are not expected to be affected in the BrECADD regimen.

Fertility, pregnancy and lactation
Women of childbearing potential: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment.

Pregnancy: There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the fetus.

Breast-feeding: There is no data as to whether brentuximab vedotin or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman.

Fertility: In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have anagenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines (e.g. dizziness).

Undesirable Effects
Monotherapy: The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnea, 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 studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL and 223 patients with previously untreated CD30+ PTCL, the most common adverse reactions (≥ 10%) were: infections, neutropenia, peripheral sensory neuropathy, nausea, constipation, vomiting, diarrhea, fatigue, pyrexia, alopecia, anemia, weight decreased, stomatitis, febrile neutropenia, abdominal pain, decreased appetite, insomnia, bone pain, rash, cough, dyspnea, arthralgia, myalgia, back pain, peripheral motor neuropathy, upper respiratory tract infection, and dizziness. In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (15%), pyrexia (5%), and neutropenia (3%). Adverse events led to treatment discontinuation in 10% of patients.

In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (15%), pyrexia (5%), and neutropenia (3%). Adverse events led to treatment discontinuation in 10% of patients.

Adverse events led to treatment discontinuation in 10% of patients. Adverse events that led to treatment discontinuation in ≥ 2% of patients included peripheral sensory neuropathy, and peripheral neuropathy.

Combination Therapy (BrECADD regimen): In the HD21 study, 747 patients received BrECADD, and 741 patients received eBEACOPP. The safety profile of ADCETRIS in patients receiving BrECADD remained consistent with other combination therapy (AVD/CHP).

Serious adverse reactions occurred in 39.4% patients receiving BrECADD treatment, and 36.4% in patients who received eBEACOPP. The most common serious adverse reactions in patients who received BrECADD (> 3%) were febrile neutropenia (19.3%), pyrexia (3.9%), and neutropenia (3.2%).

Serious cardiac adverse reactions occurred in 2.7% of patients receiving BrECADD and 1.1% of patients receiving eBEACOPP. The most common serious cardiac adverse reaction in patients who received BrECADD (>0.5%) was tachycardia (0.9%).

Serious adverse events led to treatment discontinuation in 2% of patients in both BrECADD and eBEACOPP arms. The most common serious adverse events that led to discontinuation in the BrECADD arm were febrile neutropenia (0.3%) and cardiac failure (0.3%).

ADCETRIS^® (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

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

CONTRAINDICATION
Contraindicated with concomitant 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. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

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 adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

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 infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

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. 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. 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 pre-existing 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.

Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.

ADVERSE REACTIONS
The most common adverse reactions (≥20%) in adult patients are peripheral neuropathy, nausea, fatigue, musculoskeletal pain, constipation, diarrhea, vomiting, pyrexia, upper respiratory tract infection, mucositis, abdominal pain, and rash. The most common laboratory abnormalities (≥20%) in adult patients are decreased neutrophils, increased creatinine, decreased hemoglobin, decreased lymphocytes, increased glucose, increased ALT, and increased AST.

The most common Grade ≥3 adverse reactions (≥5%) in combination with AVEPC in pediatric patients were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.

DRUG INTERACTIONS
Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

Lactation: Breastfeeding is not recommended during ADCETRIS treatment.

Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.

About Takeda
Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

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Medical Information
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Footnotes:

*While late relapse is rare, PFS status after 5 years does not guarantee cure. Patients should be monitored and encouraged to report any return of symptoms as appropriate.

References:

1. Borchmann P, Ferdinandus J, Schneider G, et al. Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial [published correction appears in Lancet. 2024 Nov 30;404(10468):2164. doi: 10.1016/S0140-6736(24)02571-6.]. Lancet. 2024;404(10450):341-352.
2. Bröckelmann PJ, Goergen H, Kohnhorst C, von Tresckow B, Moccia A, Markova J, Meissner J, Kerkhoff A, Ludwig WD, Fuchs M, Borchmann P, Engert A. Late Relapse of Classical Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group HD7 to HD12 Trials. J Clin Oncol. 2017 May 1;35(13):1444-1450. doi: 10.1200/JCO.2016.71.3289. Epub 2017 Feb 27. PMID: 28240973.

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