Abdominal Abscess

• Barrigel™ rectal spacer provides high quality rectal spacing, enabling low dose to the rectum during prostate cancer radiation therapy, with an excellent toxicity and safety profile; and low incidence (0.32-1%) of rectal wall infiltration (RWI), which can be safely reversed using hyaluronidase4,5 • Data demonstrate safety and efficacy of Barrigel™ rectal spacer in stereotactic body radiation therapy (SBRT) for patients undergoing repeat therapy6 WAYNE, Pa., Oct. 17, 2024 (GLOBE NEWSWIRE) -- Teleflex Incorporated (NYSE: TFX), a leading global provider of medical technologies, today announced the presentation of data supporting the safety and efficacy of Barrigel™ rectal spacer, ​​the first and only sculptable hyaluronic acid​ rectal spacer. It is designed to significantly reduce radiation that reaches the rectum during prostate cancer radiation therapy.1-3 The data were presented in three abstracts5-7 at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting, which took place in Washington, DC, September 29 to October 2, 2024. Rectal spacers are used during prostate cancer radiation therapy to enable effective radiation dosing to the prostate while sparing healthy rectal tissue. This is especially important in hypofractionated treatment regimens, in which radiation is delivered at higher doses over a fewer number of treatment sessions. Unlike other rectal spacers made from different materials, which harden almost immediately after administration, the hyaluronic acid in Barrigel™ rectal spacer remains soft and pliable. This gives physicians time to sculpt, layer, and add more Barrigel™ rectal spacer as needed to optimize rectal protection.1,8-10 Additionally, Barrigel™ rectal spacer is highly visible in real time using transrectal ultrasound, which helps to ensure optimal spacing.1,8-10 Approximately 300,000 men will be diagnosed with prostate cancer this year in the U.S. alone. The incidence rate has increased by 3% per year overall over the past decade.11 “Building on the safety and efficacy of Barrigel™ rectal spacer previously proven in a randomized clinical trial,1 the data presented at ASTRO 2024 demonstrate that excellent outcomes can also be achieved in real-world settings and in patients undergoing repeat radiation therapy,” said Jacqueline Welch, Vice President of Global Clinical and Scientific Operations at Teleflex. “They also show that rare instances of unintended injection regions can be reversed with hyaluronidase, a naturally occurring enzyme. This is an important advantage over other rectal spacers, which cannot be reversed following the initial procedure and require time for biodegradation. Our ASTRO 2024 data underscore our ongoing commitment to advancing outcomes for patients with malignant and benign prostate conditions.” Presented Abstracts Impact of Hyaluronic Acid (HA) Rectal Spacer Quality Score (SQS) and Fischer-Valuck (FV) Spacer Symmetry Score on Rectal Dosimetry and Acute and Late Gastrointestinal (GI) Toxicity Outcomes – an Australian Experience (Abstract #3222)7 This abstract reports retrospective data from 100 men undergoing moderately fractionated EBRT (60Gy/62Gy in 20 fractions) for localized prostate cancer using Barrigel™ rectal spacer in Australia. Implants were assessed for quality (mSQS score), symmetry (FV score), and RWI (rectal wall infiltration), and acute and late gastrointestinal (GI) toxicity were also evaluated. Excellent implant quality (mSQS score=1) was reported for 74 patients; 24 patients had a score of 2 and only 2 patients had a 0 score. Symmetrical rectal spacing (FV score=1) was achieved in 97% of implants. Physicians deemed Barrigel™ rectal spacer very easy (98%) or easy (2%) to implant. No acute or late GI toxicity > Grade 2 was reported; 7 acute and 5 late Grade 1 toxicity events were reported. RWI occurred in 1 patient and was reversed with hyaluronidase with no subsequent adverse effects. Only 1 case of regional prostate cancer recurrence has been reported with median follow-up of 1.68 years. Rectal Wall Infiltration (RWI) with Hyaluronic Acid Based Rectal Spacer Reversal Protocol (Abstract #3185)5 This abstract reports data from a retrospective analysis of inadvertent RWI in 5,000 Australian men receiving Barrigel™ rectal spacer for prostate cancer radiation therapy. Results of magnetic resonance imaging (MRI) were used to identify RWI. Patients with RWI were followed for the remainder of their radiation therapy and for an additional 3 months following completion of radiation therapy. The study identified 16 patients (0.32%) with RWI after Barrigel™ rectal spacer insertion (Grade 1 by FV criteria n=5, Grade 2 n=6, Grade 3 n=5), with a median volume of misplaced Barrigel™ rectal spacer of 2.8 cc (total average Barrigel™ rectal spacer volume was 9.2 cc). No post-procedural GI symptoms or acute Grade 2+ GI toxicity were reported among these 16 men, and the rectal mucosa was intact in the 12 men who underwent sigmoidoscopy. Seven of the 16 men underwent Barrigel™ rectal spacer reversal procedures with hyaluronidase, all of which were successful, and no post-reversal complications were reported. The other 9 men were monitored. No severe adverse complications (mucosal ulceration, pelvic abscess, recto-prostatic fistula) have been reported among the 16 men with RWI. The presence of RWI resulted in delayed initiation of radiation therapy in 11 men (median delay = 3.2 months). “These real-world, retrospective analyses offer further evidence that Barrigel™ rectal spacer provides safe, effective, and high-quality spacing in routine clinical practice,” said Michael Chao, MD, a Radiation Oncologist at the Olivia Newton John Cancer Wellness & Research Centre in Victoria, Australia, and author on the two aforementioned abstracts.† “They also show that the incidence of RWI with Barrigel™ rectal spacer is quite rare—only 0.32%—and that these rare cases can be reversed effectively with hyaluronidase. Reversal is not feasible when RWI occurs with other spacers because the inorganic materials of which they are made cannot safely be dissolved in the body and must be absorbed over time. This is another important benefit of Barrigel™ rectal spacer that should be considered when selecting a rectal spacer for men undergoing prostate cancer radiation therapy.” Hyaluronic Acid Rectal Spacer in Locally Recurrent Prostate Cancer with Prior Radiation Receiving SBRT: on Feasibility, Safety, and Toxicity (Abstract #3236)6 This abstract reports Barrigel™ rectal spacer safety, rectal separation, ease of spacer placement, and treatment toxicity in 17 men undergoing repeat local radiation therapy for prostate cancer using SRBT. There was a 100% success rate for Barrigel™ rectal spacer placement, with no use of saline dissection and no adverse events reported. Mean minimum separation between gross tumor volume (GTV) and rectal tissue was 8.7 (± 5.6) mm, and adequate separation was achieved in 86.4% of cases. No >Grade 1 GI toxicity or acute Grade 3+ urinary toxicity were reported, and there was 1 case of Grade 3 hemorrhagic cystitis (which the patient also experienced during initial EBRT). Maximum point dose (Dmax) for radiation was 22.7 Gy (± 6.8), and the dose received by 30% (D30) and 60% (D60) of the prostate was 6.8 Gy (±3.0), and 3.0 Gy (± 2.2), respectively. “Patients with local recurrence of prostate cancer treated initially with EBRT (external beam radiation therapy) are often not considered for repeat radiation therapy,” said LaToya McLean, MD, a resident member at Thomas Jefferson University in Philadelphia, Pennsylvania and lead author on the abstract. “A key reason for this is concern about safely and effectively placing a rectal spacer in tissue that has been previously irradiated, as this tissue may be scarred or have adhesions that make it difficult to separate. In this study, we show that Barrigel™ rectal spacer can be used safely and effectively to achieve meaningful rectal separation that allows patients with local prostate cancer recurrence to receive radiation therapy while meeting dosimetric constraints. I hope these findings will help reduce the barriers to radiation therapy that these patients face.” About Barrigel™ Rectal Spacer Barrigel™ rectal spacer is the first and only hyaluronic acid rectal spacer that separates the prostate from the rectum to protect the rectum during radiation therapy treatment for prostate cancer.1 Barrigel is made from Non-Animal Stabilized Hyaluronic Acid (NASHA).12 Hyaluronic acid is a substance naturally present in the human body and is highly compatible and fully absorbable. NASHA has a proven history of safety and efficacy in a wide variety of medical applications in men, women and children worldwide.8,13 Barrigel™ rectal spacer has been proven to significantly reduce unwanted side effects from prostate cancer radiation therapy and is approved for rectal spacing in the United States, Australia, and Europe. Barrigel™ rectal spacer is indicated for prostate cancer patients with T1-T3b disease. For more information about Barrigel™ rectal spacer, please visit https://barrigel.com/hcp/barrigel-control-matters. Barrigel™ Rectal Spacer Important Safety InformationBarrigel is intended to temporarily position the anterior rectal wall away from the prostate during radiotherapy for prostate cancer and, in creating this space, it is the intent of Barrigel to reduce the radiation dose delivered to the anterior rectum. Barrigel is composed of biodegradable material and maintains space for the entire course of prostate radiotherapy treatment and is intended to be absorbed by the patient’s body over time. Barrigel should only be administered by qualified and properly trained physicians with experience in ultrasound guidance and injection techniques in the urogenital/pelvic area. As with any medical treatment, there are some risks involved with the use of Barrigel. Potential complications associated with the use of Barrigel include, but are not limited to: pain associated with Barrigel injection; needle penetration of the bladder, prostate, rectal wall, rectum, or urethra; injection of Barrigel into the bladder, prostate, rectal wall, rectum, urethra, or intravascularly; local inflammatory reactions; infection; urinary retention; rectal mucosal damage, ulcers, necrosis; bleeding; constipation; and rectal urgency. More information on indications, contraindications, warnings and instructions for use can be found in the Instructions For Use at www.barrigel.com. Caution: Federal (USA) law restricts this device to sale by or on the order of a physician. † Michael Chao is a paid consultant of Teleflex About Teleflex IncorporatedAs a global provider of medical technologies, Teleflex is driven by our purpose to improve the health and quality of people’s lives. Through our vision to become the most trusted partner in healthcare, we offer a diverse portfolio with solutions in the therapy areas of anesthesia, emergency medicine, interventional cardiology and radiology, surgical, vascular access, and urology. We believe that the potential of great people, purpose driven innovation, and world-class products can shape the future direction of healthcare. Teleflex is the home of Arrow™, Barrigel™, Deknatel™, LMA™, Pilling™, QuikClot™ Rüsch™, UroLift™ and Weck™ – trusted brands united by a common sense of purpose. At Teleflex, we are empowering the future of healthcare. For more information, please visit teleflex.com. Forward-Looking StatementsAny statements contained in this press release that do not describe historical facts may constitute forward-looking statements. Any forward-looking statements contained herein are based on our management's current beliefs and expectations, but are subject to a number of risks, uncertainties and changes in circumstances, which may cause actual results or company actions to differ materially from what is expressed or implied by these statements. These risks and uncertainties are identified and described in more detail in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K. Teleflex, the Teleflex logo, Arrow, Barrigel, Deknatel, LMA, Pilling, QuikClot, Rüsch, Titan SGS, UroLift and Weck are trademarks or registered trademarks of Teleflex Incorporated or its affiliates, in the U.S. and/or other countries. All other trademarks are the property of their respective owners. © 2024 Teleflex Incorporated. All rights reserved. References: Mariados NF, Orio PF III, King MT et al. Hyaluronic acid spacer for hypofractionated prostate radiation therapy: A randomized clinical trial. JAMA Oncol. 2023:e1-e8.*King MT, Svatos M, Orio PF III et al. Evaluating the Quality-of-Life Effect of Apical Spacing with Hyaluronic Acid Prior to Hypofractionated Prostate Radiation Therapy: A Secondary Analysis, Pract Radiat Oncol. 2023;e1-e6.*Data on File. As of 06/01/2024.Hong A, Ischia J, Chao M. Case report: Reversal of hyaluronic acid rectal wall infiltration with hyaluronidase. Front Oncol. 2022;12:870388.Hong A, Bolton D, Ramani S et al. Rectal wall infiltration with hyaluronic acid based rectal spacer reversal protocol. Abstract #3185. Presented at ASTRO 2024 October 1, 2024.McLean L, et al. Hyaluronic Acid Rectal Spacer in Locally Recurrent Prostate Cancer with Prior Radiation Receiving SBRT: on Feasibility, Safety, and Toxicity. Abstract #3236. Presented at ASTRO 2024 October 1, 2024.Lin YH, et al. Impact of Hyaluronic Acid (HA) Rectal Spacer Quality Score (SQS) and Fischer-Valuck (FV) Spacer Symmetry Score on Rectal Dosimetry and Acute and Late Gastrointestinal (GI) Toxicity Outcomes – an Australian Experience. Abstract #3222. Presented at ASTRO 2024 October 1, 2024.Svatos M, Chell E, Low DA, et al. Symmetry, separation, and stability: Physical properties for effective dosimetric space with a stabilized hyaluronic acid spacer. Med Phys. 2024; 1-15. https://doi-org.libproxy1.nus.edu.sg/10.1002/mp.17292*Gejerman G, Goldstein MM, Chao M et al. Barrigel spacer injection technique. Pract Radiat Oncol. 2023:e1-e5. (Drs Gejerman, Chao, Lederer, and Orio are paid consultants of Palette Life Sciences, now part of Teleflex).Williams J, Mc Millan K, Chao M et al. Hyaluronic acid rectal spacer in EBRT: Usability, safety and symmetry related to user experience. J Med Imag Radiat Sci (2022).American Cancer Society. Key Statistics for Prostate Cancer. www.cancer.org. 2023. Accessed: Jan 26, 2023. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.Barrigel Injectable Gel Instructions for Use (2022).Restylane® celebrates 25 years of natural-looking results with its signature line of hyaluronic acid fillers. 2021. Available at: https://www.prnewswire.com/news-releases/restylane-celebrates-25-years-of-natural-looking-results-with-its-signature-line-of-hyaluronic-acid-fillers-301388779.html. Accessed Sept 30, 2021. *Study sponsored by Palette Life Sciences, now part of Teleflex. Contacts:TeleflexLawrence KeuschVice President, Investor Relations and Strategy Developmentinvestor.relations@teleflex.com610-948-2836 Media Contact:Glenn SilverPartner National Media Relations Specialistglenn.silver@finnpartners.com646-871-8485 APM943A

- Pivotal trial found the enfortumab vedotin plus pembrolizumab combination significantly extended overall and progression-free survival vs platinum-containing chemotherapy- - If approved, enfortumab vedotin with KEYTRUDA would be the first combination in China to offer an alternative to chemotherapy, the current standard of care in first-line locally advanced or metastatic urothelial cancer- TOKYO, March 28, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") today announced that on March 27, 2024 the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the supplemental Biologics License Application (sBLA) for enfortumab vedotin with KEYTRUDA® (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). If approved, enfortumab vedotin with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC. Urothelial cancer (UC) encompasses cancers of both the lower urinary tract (bladder and urethra) and upper tract (ureter and renal pelvis), with disease that originates in the lower tract accounting for 90% to 95% of all UC cases.i,ii Globally, approximately 614,000 new cases of bladder cancer and approximately 220,000 deaths are reported annually.iii It is estimated that approximately 93,000 people in China were diagnosed with bladder cancer and approximately 41,000 deaths were reported in 2022.iv Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas "Locally advanced or metastatic urothelial cancer is a life-threatening condition in China with nearly half of those diagnosed succumbing to the disease. The CDE's acceptance of our sBLA for enfortumab vedotin and pembrolizumab brings us one step closer to delivering a much-needed, innovative new treatment option for this patient population." Professor Guo Jun, lead PI in China for the EV-302 trial, director of the Department of Melanoma and Urological Oncology at Beijing Cancer Hospital, executive board member of the Chinese Society Of Clinical Oncology (CSCO) "In China, the recommended first-line treatment for advanced urothelial cancer is platinum-based chemotherapy, and there are currently no other treatments approved in the first-line setting. Given the efficacy brought by chemotherapy, alternate treatment options are extremely needed to extend survival benefits and potentially improve the prognosis of those patients. The results of the EV-302 study demonstrated that enfortumab vedotin in combination with pembrolizumab, as the first non-platinum first-line treatment, can achieve a clinically meaningful improvement in response rate, nearly double the median progression-free survival, and significantly improve the overall survival benefit of patients with locally advanced or metastatic urothelial cancer compared to chemotherapy." The sBLA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found that the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified. The NMPA is also reviewing enfortumab vedotin as a treatment for patients with locally advanced or metastatic urothelial cancer (la/mUC) who received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is reviewing the enfortumab vedotin in combination with pembrolizumab therapy, as well as Japan's Ministry of Health, Labour and Welfare (MHLW). The U.S. Food and Drug Administration approved the combination therapy in December 2023. About EV-302 The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety. The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) Congress 2023 in October 2023. About Bladder and Urothelial Cancer Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.v If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.vi Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.iii Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.vii Ongoing Investigational Trials The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC). Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective. The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma. The EV-203 trial (NCT04995419) is a Phase 2, multicenter, single-arm bridging study in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the study. About Enfortumab Vedotin Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.viii Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).ix PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information BOXED WARNING: SERIOUS SKIN REACTIONS PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later. Closely monitor patients for skin reactions. Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Indication PADCEV®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who: have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV. Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months). In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months). Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD. Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months). PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients. Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN. Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders. Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions. Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose. ADVERSE REACTIONS Most common adverse reactions, including laboratory abnormalities  (≥20%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets. Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin. EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).  Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The  most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The  most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The  most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%). EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%).  Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%).  Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%).  Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%).  Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%). EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%).  Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each).  Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%).  Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%).  Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each). EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%). DRUG INTERACTIONS Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors) Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors. SPECIFIC POPULATIONS Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose. Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment. For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . About the Astellas, Pfizer and Merck Collaboration Astellas and Pfizer have a clinical collaboration agreement with Merck to evaluate the combination of Astellas' and Pfizer's PADCEV™ (enfortumab vedotin) and Merck's KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada). Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. i Leow JJ, Liu Z, Tan TW, Lee YM, Yeo EK, Chong YL. Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives. Onco Targets Ther. 2020;13:1-15. ii Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1794-8. iii International Agency for Research on Cancer. Cancer Today: Bladder Globocan 2022 fact sheet (01-2024). 30-bladder-fact-sheet.pdf (who.int) iv International Agency for Research on Cancer (IARC). Bladder Fact Sheet. Lyon, France. 2022 (02-2024). Available at: 160-china-fact-sheet.pdf (who.int) v National Cancer Institute. What is bladder cancer? . vi American Society of Clinical Oncology. Bladder cancer: introduction (12-2021). . viiNational Cancer Institute. Cancer stat facts: bladder cancer. . viii Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13. ix PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc. SOURCE ASTELLAS PHARMA INC.

- Priority review designation is based on results from the Phase 3 EV-302 trial, which found enfortumab vedotin plus pembrolizumab significantly extended overall survival and progression free survival compared to platinum-containing chemotherapy- TOKYO, Feb. 15, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") today announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has granted priority review for the company's Supplemental New Drug Application (sNDA) for PADCEV™ (enfortumab vedotin (genetical recombination)) with KEYTRUDA® (pembrolizumab (genetical recombination)) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). The sNDA was submitted in January 2024. If approved, PADCEV with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC. Priority reviews are granted by MHLW for applications based on their clinical usefulness and the seriousness of the diseases for which they are indicated.i The sNDA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified. Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas "The MHLW's priority review for our application for PADCEV in combination with pembrolizumab reflects the significance of the EV-302 trial findings and the urgent need for innovative new treatment options. We are pleased by this review designation and hope to quickly bring this treatment option to those who need it most." The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is also reviewing the combination therapy. The U.S. Food and Drug Administration approved the combination therapy in December 2023. Globally, approximately 614,000 new cases of bladder cancer and approximately 220,000 deaths are reported annually.ii It is estimated that approximately 25,000 people in Japan are diagnosed with bladder cancer each year and approximately 10,000 deaths were reported in 2022.iii About EV-302 The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety. The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) Congress 2023 in October 2023. About Bladder and Urothelial Cancer Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.iv If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.v Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.iii Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.vi Ongoing Investigational Trials The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and patients with muscle-invasive bladder cancer (MIBC). Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective. The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma. About PADCEV ™ (enfortumab vedotin (genetical recombination)) PADCEV (enfortumab vedotin (genetical recombination)) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.vi Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which results in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).vii PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information BOXED WARNING: SERIOUS SKIN REACTIONS PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occur predominantly during the first cycle of treatment but may occur later. Closely monitor patients for skin reactions. Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Indication PADCEV®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who: have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Hyperglycemia  and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV. Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months). In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months). Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD. Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months). PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients. Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN. Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders. Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions. Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose. ADVERSE REACTIONS Most common adverse reactions, including laboratory abnormalities  (≥20%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets. Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin. EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).  Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The  most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The  most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The  most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%). EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%).  Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%).  Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%).  Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%).  Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%). EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%).  Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each).  Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%).  Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%).  Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each). EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%). DRUG INTERACTIONS Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors) Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors. SPECIFIC POPULATIONS Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose. Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment. For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . About the Astellas, Pfizer and Merck Collaboration Astellas and Pfizer have a clinical collaboration agreement with Merck to evaluate the combination of Astellas' and Pfizer's PADCEV™ (enfortumab vedotin) and Merck's KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada). Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. i Pharmaceuticals and Medical Devices Agency. Drug Reviews. . Accessed February 1, 2024 ii International Agency for Research on Cancer. Cancer Today: bladder globocan 2022 fact sheet (01-2024). 30-bladder-fact-sheet.pdf (who.int) iii Cancer Information Service, Cancer Statistics in Japan. Published 2022. iv National Cancer Institute. What is bladder cancer? . v American Society of Clinical Oncology. Bladder cancer: introduction (12-2021). . vi National Cancer Institute. Cancer stat facts: bladder cancer. . SOURCE ASTELLAS PHARMA INC.