Amebiasis

— 12 Weeks of Treatment with EOHILIA May Address Significant Unmet Needs of Patients 11 Years of Age and Older — EoE Is a Chronic Disease That Can Significantly Impact Patients, with Esophageal Inflammation and Intermittent Symptoms of Choking and Difficult or Painful Swallowing OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Takeda (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has approved EOHILIA (budesonide oral suspension), the first and only FDA-approved oral therapy for people 11 years and older with eosinophilic esophagitis (EoE).1 It will be available in 2 mg/10 mL convenient, single-dose stick packs by the end of February. EOHILIA is a corticosteroid indicated for 12 weeks of treatment in patients 11 years and older with EoE.1 Developed specifically for EoE, EOHILIA’s novel formulation of budesonide confers thixotropic properties – flowing more freely when shaken and returning to a more viscous state when swallowed.1,2 “Various formulations of corticosteroids have been used in the past to manage EoE, but in an off-label capacity and using multiple delivery options. With EOHILIA, it’s gratifying to now have an FDA-approved treatment specifically formulated for a consistent dose delivery with demonstrated ability to address esophageal inflammation and EoE dysphagia symptoms,” said Ikuo Hirano, MD, professor of medicine and director of the Kenneth C. Griffin Esophageal Center in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine. “As the treatment needs and goals of patients with EoE can vary, I welcome the flexibility that EOHILIA offers as an oral medication.” The FDA approval of EOHILIA 2 mg twice daily is based on efficacy and safety data from two multicenter, randomized, double-blind, parallel-group, placebo-controlled 12-week studies (Study 1 and Study 2) in patients (ages 11 to 56 and 11 to 42, respectively) with EoE.1 In both studies, patients received at least one dose of either EOHILIA 2 mg twice daily or placebo orally twice daily. Efficacy endpoints included histologic remission (peak eosinophil count of ≤6 per high-powered field across all available esophageal levels) and the absolute change from baseline in patient-reported Dysphagia Symptom Questionnaire (DSQ) combined score after 12 weeks of treatment. The DSQ measures how often a patient with EoE has trouble swallowing and the behavioral adaptations they subsequently use, as reported directly by patients.3 Significantly more patients receiving EOHILIA achieved histologic remission vs. placebo in Study 1 (53.1% vs. 1%).1 In Study 2, 38% of EOHILIA patients achieved histologic remission vs. 2.4% of those in the placebo group. Absolute change from baseline in DSQ combined score in the EOHILIA vs. placebo groups in Study 1 was -10.2 (1.5) vs. -6.5 (1.8) and in Study 2, -14.5 (1.8) vs. -5.9 (2.1). During the last two weeks of each study, more patients receiving EOHILIA experienced no dysphagia or only experienced dysphagia that “got better or cleared up on its own” as compared to placebo, as measured by the DSQ. EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. The most common adverse reactions (≥2% of patients receiving EOHILIA and at a rate greater than placebo) in Study 1 included: respiratory tract infection (13%), gastrointestinal mucosal candidiasis (8%), headache (5%), gastroenteritis (3%), throat irritation (3%), adrenal suppression (2%) and erosive esophagitis (2%). The safety pro EOHILIA in Study 2 was generally similar to Study 1.1 “For most of us, eating is a simple experience. But for people living with eosinophilic esophagitis, sitting down for a meal can include painful and difficult swallowing, chest pain and a choking sensation,” said Brandon Monk, senior vice president and head, U.S. Gastroenterology Business Unit, Takeda. “With EOHILIA, patients and their physicians now have the first and only FDA-approved oral treatment option for EoE that was shown during two 12-week clinical studies to reduce esophageal inflammation and improve the ability to swallow.” EoE is a chronic, immune-mediated, inflammatory disease localized in the esophagus.4 Although the exact cause is unknown, it is believed to be triggered by a variety of stimuli including certain foods and environmental allergens.5,6 The chronic inflammation of EoE can lead to a range of symptoms, which can vary by person and age, and include difficulty swallowing, vomiting and pain.7 Identifying EoE can be complex and delayed diagnosis is common among patients. If left untreated, the inflammation of EoE can worsen and narrow the esophagus, which can lead to food impaction (when food becomes stuck in the esophagus).8,9 In fact, EoE is the leading cause of emergency room visits for food impaction.10 Takeda is assessing the financial impacts of the approval, including a reversal of impairment loss for intangible assets, on the fiscal year ending on March 31, 2024 (FY2023), but does not anticipate the impact to be material. Indication and Limitations of Use EOHILIA is indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE). EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS EOHILIA is contraindicated in patients with hypersensitivity to budesonide. Serious hypersensitivity reactions, including anaphylaxis, have occurred with oral budesonide products. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression Systemic effects such as hypercorticism and adrenal axis suppression may occur. Monitor patients for signs and symptoms and consider reducing the dosage of EOHILIA. Use is not recommended in patients with severe hepatic impairment (Child‑Pugh Class C) and monitoring for signs and/or symptoms of hypercorticism is recommended in patients with moderate hepatic impairment (Child‑Pugh Class B). Corticosteroids, including EOHILIA, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to trauma, surgery, infection, or other stress situations, supplementation with a systemic corticosteroid is recommended. Immunosuppression and Increased Risk of Infection Corticosteroids, including EOHILIA, suppress the immune system and increase the risk of infection with any pathogen. Corticosteroid-associated infections can be mild, severe, and at times fatal. Monitor patients and consider discontinuation of EOHILIA if the patient develops an infection. Tuberculosis reactivation may occur. Closely monitor patients with latent tuberculosis or tuberculin reactivity while receiving EOHILIA. Varicella Zoster and Measles can be serious or fatal in non-immune patients taking corticosteroids. Avoid exposure. If a patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. If a patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation can occur. Prior to starting EOHILIA for patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Amebiasis: It is recommended that latent or active amebiasis be ruled out before starting EOHILIA in patients who have spent time in the tropics or have unexplained diarrhea. Avoid EOHILIA in patients with: systemic fungal infections, known or suspected Strongyloides (threadworm) infection, cerebral malaria, and active ocular herpes simplex. Localized Infections: In clinical trials, some patients developed Candida albicans infections in the mouth, throat, and esophagus. Instruct patients: do not eat or drink for 30 minutes after taking EOHILIA; after 30 minutes rinse mouth with water and spit without swallowing. If oropharyngeal or esophageal candidiasis develops, treat with appropriate antifungal therapy and consider discontinuing EOHILIA. Erosive Esophagitis Erosive esophagitis occurred in subjects who received EOHILIA in a 12-week clinical trial. None of the subjects had erosions at baseline esophagogastroduodenoscopy (EGD), and most were receiving concomitant therapy with a proton pump inhibitor (PPI). Advise patients or caregivers to report new onset or worsening signs or symptoms of erosive esophagitis to their healthcare provider. Consider endoscopic evaluation as appropriate. Effect on Growth Use of corticosteroids may cause a reduction of growth velocity in pediatric patients. Monitor the growth of pediatric patients on EOHILIA. The maximum recommended duration of treatment with EOHILIA is 12 weeks. Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids Monitor patients who are transferred from corticosteroids with high systemic effects to corticosteroids with lower systemic availability, such as EOHILIA, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic corticosteroids with EOHILIA may unmask allergies (e.g., rhinitis and eczema) previously controlled by the systemic drug. Other Corticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, or cataracts, or with family history of diabetes, glaucoma, or with other conditions where corticosteroids may have unwanted effects. Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. The maximum recommended duration of treatment with EOHILIA is 12 weeks. ADVERSE REACTIONS Most common adverse reactions (≥2%) are: respiratory tract infection, gastrointestinal mucosal candidiasis, headache, gastroenteritis, throat irritation, adrenal suppression, and erosive esophagitis. DRUG INTERACTIONS Budesonide is a substrate for CYP3A4. Avoid concomitant use with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice), which can increase systemic budesonide concentrations. USE IN SPECIFIC POPULATIONS Pregnancy: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism and managed accordingly. Lactation: Lactation studies have not been conducted with EOHILIA. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EOHILIA and any potential adverse effects on the breastfed infant from EOHILIA, or from the underlying maternal condition. Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), monitor for signs and/or symptoms of hypercorticism. Please click here for full Prescribing Information. Takeda’s Commitment to Gastroenterology With this latest milestone, Takeda continues to demonstrate a commitment to meeting the very real needs of those living with gastrointestinal (GI) diseases. We believe that GI and liver diseases are life-disrupting conditions. Beyond a fundamental need for effective treatment options, we understand that improving patients’ lives also depends on their needs being recognized. With more than 35 years of experience in gastroenterology, Takeda has made significant strides in addressing patient needs with treatments for inflammatory bowel disease (IBD), acid-related diseases, short bowel syndrome (SBS) and motility disorders. We are making significant strides toward closing the gap on new areas of unmet need. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI. 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 . Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question-and-answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. 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These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: or at . Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Medical Information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. References 1 EOHILIA (budesonide oral suspension) Prescribing Information. Takeda Pharmaceuticals U.S.A., Inc. 2 Mewis J, Wagner NJ. Advances in Colloid and Interface Science. 2009; 214–227. 3 Hudgens S, Evans C, Phillips E, et al. J Patient Rep Outcomes. 2017;1(1):3. 4 Furuta GT, Katzka DA. N Engl J Med. 2015;373(17):1640-1648. 5 Clayton F, Peterson K. Gastrointest Endosc Clin N Am. 2018;28(1):1-14. 6 O’Shea KM, Aceves SS, Dellon ES, et al. Gastroenterology. 2018;154(2):333-345. 7 Muir AB, Brown-Whitehorn T, Gowin B, et al. Clin Exp Gastroenterol. 2019;12:391-399. 8 Shaheen NJ, Mukkada V, Eichinger CS, et al. Dis Esophagus. 2018;31(8):1-14. 9 Hirano I, Furuta GT. Gastroenterology. 2020;158(4):840-851. 10 Dellon ES, Hirano I. Gastroenterology. 2018;154(2):319-332.e3. US-BOS-0537v1.0 02/24

LIKMEZ™ (metronidazole) Oral Suspension, the First and Only FDA-Approved Liquid Option for Patients with Adherence Hurdles such as Dysphagia, Difficulty Swallowing Kesin Pharma Launches Novel Formulation of Mainstay Anti-Infective, Metronidazole Kesin Pharma: Solutions for Better Health™ OLDSMAR, Fla.--(BUSINESS WIRE)-- Kesin Pharma Corporation, a pharmaceutical company focused on innovative Specialty brands and Unit Dose formulations, announced today that the U.S. Food and Drug Administration (FDA) has approved LIKMEZ™ (metronidazole) oral suspension, 500 mg/5 mL. Available now, LIKMEZ™ is the first and only FDA-approved ready-to-use oral liquid metronidazole in the U.S. market. LIKMEZ™ is a novel presentation of a mainstay antibiotic drug, reinvented to address common adherence issues. Kesin is the exclusive U.S. commercialization partner for LIKMEZ™ through its collaboration with Saptalis Pharmaceuticals, LLC, the developer and NDA holder of the product. LIKMEZ™ is a novel proprietary liquid formulation of metronidazole for patients who may struggle with dysphagia, difficulty swallowing, or high taste sensitivities. These potential compliance and persistency obstacles can lead to treatment discontinuation and inefficient treatment outcomes, including rebound infection. LIKMEZ™ is approved for the treatment of trichomoniasis and anaerobic bacterial infections in adults and amebiasis in adults and pediatric patients. LIKMEZ™ comes in a 200 mL bottle as a strawberry peppermint flavored suspension, with a 24-month shelf life and does not require refrigeration. Metronidazole has been shown to be carcinogenic in mice and rats, and the most common adverse reactions to metronidazole include nausea, headache, anorexia, vomiting, diarrhea, abdominal cramping, epigastric distress, and constipation. LIKMEZ™ addresses inherent risks associated with crushing tablets for those patients needing a liquid formulation and eliminates the potential inconsistences associated with extemporaneously compounding metronidazole prescriptions. Additionally, compounding can amplify the pronounced bitter, metallic taste of metronidazole tablets, which can also negatively influence patients’ adherence to therapy. “LIKMEZ™ is for patients and providers who need a liquid option for those faced with adherence obstacles due to taste sensitivities or difficulty swallowing. An increasing number of patients can benefit from a safe and efficacious product that can support medication adherence. We are very excited with our first brand launch which is part of our upcoming pipeline of novel products, designed to address unmet patient needs and bring value to the healthcare system,” said Narasimhan Mani, President & CEO of Kesin Pharma Corporation. “We are pleased with our partnership with Saptalis Pharmaceuticals, the NDA holder and manufacturer of LIKMEZ™. The timely approval of this NDA505(b)(2) presents a significant opportunity for Kesin Pharma to bring a value-added product to the market,” said Narasimhan Mani. LIKMEZ™ will be available through most full-line wholesalers and retail pharmacies. To learn more and view Full Prescribing Information, including complete BOXED WARNING and additional Safety Information see . About Kesin Pharma Kesin Pharma Corporation, based in Oldsmar, FL, is a specialty pharmaceutical company with deep experience and strong capabilities in commercial sales & marketing, distribution, and market access. Kesin’s mission is to provide unique healthcare solutions to patients through our portfolio of strategic, value-driven brand and unit-dose products. Kesin Pharma works closely with patients, payers, and provider partners to bring to market innovative pharmaceutical products to better address unfulfilled needs and enhance patient adherence and accessibility. For more information, visit . About Saptalis Pharmaceuticals, LLC Saptalis Pharmaceuticals, LLC is a rapidly growing pharmaceutical company specialized in development, manufacturing, and commercialization of generic and innovative products in liquid and semi-solid dosage forms. Located in the Hauppauge Industrial Park on Long Island, NY, USA, Saptalis has fully equipped Research & Development Laboratories and state of the art commercial scale manufacturing facility designed to meet FDA cGMP requirements. For more information, visit . Important Safety Information INDICATIONS AND USAGE LIKMEZ™ (metronidazole) is a nitroimidazole antimicrobial indicated for: Trichomoniasis in adults Amebiasis in adults and pediatric patients Anaerobic Bacterial Infections in adults To reduce the development of drug-resistant bacteria and maintain the effectiveness of LIKMEZ™ and other antibacterial drugs, LIKMEZ™ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. WARNING: POTENTIAL FOR CARCINOGENICITY Metronidazole has been shown to be carcinogenic in mice and rats. Avoid unnecessary use of LIKMEZ™. Reserve LIKMEZ™ for use in the following indications: trichomoniasis, amebiasis, and anaerobic bacterial infections. See full prescribing information for complete BOXED WARNING. CONTRAINDICATIONS Hypersensitivity Reactions: LIKMEZ is contraindicated in patients with known hypersensitivity to metronidazole or other nitroimidazole derivatives. Psychotic Reactions with Disulfiram: LIKMEZ is contraindicated in patients who have used disulfiram within the last two weeks. Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Interaction with Alcohol: LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least three days after LIKMEZ therapy. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Cockayne Syndrome: LIKMEZ is contraindicated in patients with Cockayne syndrome. WARNINGS AND PRECAUTIONS Potential for Carcinogenicity: Metronidazole has been shown to be carcinogenic in mice and rats. Reserve LIKMEZ for use in the following indications: trichomoniasis, amebiasis, and anaerobic bacterial infections. Central and Peripheral Nervous System Effects: Encephalopathy, aseptic meningitis, peripheral neuropathy (including optic neuropathy) and convulsive seizures have been reported with metronidazole. The appearance of abnormal neurological signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy. Fungal Superinfections: Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with LIKMEZ and requires treatment with an antifungal agent. Blood Dyscrasias: LIKMEZ is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. Total and differential leukocyte counts are recommended before and after therapy. Drug-Resistant Bacteria: Prescribing LIKMEZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Adverse Reactions The most serious adverse reactions in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole. In addition, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia have been reported. The most common adverse reactions reported: Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic: Erythematous rash and pruritus. Hematopoietic: Reversible neutropenia (leukopenia); reversible thrombocytopenia. Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T‑wave may be seen in electrocardiographic tracings. Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness”. Cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause-and-effect relationship has not been established. Crohn’s disease is not an approved indication for LIKMEZ. DRUG INTERACTIONS Disulfiram: Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. LIKMEZ is contraindicated in patients who have taken disulfiram within the last two weeks. Alcoholic Beverages: LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least 3 days after therapy with LIKMEZ. Use of LIKMEZ with alcohol or other products containing propylene glycol is associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) Warfarin and other Oral Anticoagulants: Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When LIKMEZ is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. Lithium: In patients stabilized on relatively high doses of lithium, short-term use of LIKMEZ has been associated with elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations for several days after beginning treatment with LIKMEZ to detect any increase that may precede clinical symptoms of lithium toxicity. Busulfan: Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer LIKMEZ concomitantly with busulfan unless the benefit outweighs the risk. Inhibitors of CYP450 Liver Enzymes: The simultaneous administration of LIKMEZ and drugs that decrease microsomal liver enzymes, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Inducers of CYP450 Liver Enzymes: The simultaneous administration of LIKMEZ and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported. Drugs that Prolong the QT Interval: QT prolongation has been reported. Drug/Laboratory Test Interactions: Metronidazole may interfere with certain types of determinations of serum chemistry values. Values of zero may be observed. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary: Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Lactation Risk Summary: There are no data on the effects of metronidazole on milk production. Pediatric Use: The safety and effectiveness of LIKMEZ for the treatment of amebiasis have been established in pediatric patients. The safety and effectiveness of LIKMEZ for the treatment of trichomoniasis and anaerobic bacterial infections have not been established in pediatric patients. Geriatric Use: In elderly geriatric patients, monitoring for LIKMEZ associated adverse events is recommended. Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage. Renal Impairment: Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for LIKMEZ associated adverse events is recommended. Hepatic Impairment: Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment, reduce the dose of LIKMEZ by 50%. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for LIKMEZ associated adverse reactions. OVERDOSAGE There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy. In case of an overdose, patients should contact a physician, poison control center, or emergency room. Please see full Prescribing Information, including BOXED WARNING at LIKMEZ™ and the stylized LIKMEZ™ logo are registered trademarks of Saptalis Pharmaceuticals, LLC. LIKMEZ™ is marketed by Kesin Pharma Corporation. © 2023 Kesin Pharma Corporation. All rights reserved.

A drug candidate has been found to be highly effective in treating a rare sight-threatening eye infection in a new international clinical trial. A drug candidate, based on pioneering UCL and Moorfields Eye Hospital research and currently under development by SIFI S.p.A., has been found to be highly effective in treating a rare sight-threatening eye infection in a new international clinical trial. The findings, published in Ophthalmology, describe the efficacy and safety of the first drug candidate for the treatment of Acanthamoeba keratitis (AK), applying a novel and evidence-based treatment protocol. AK is one type of microbial keratitis (corneal infection) -- a condition that results in inflammation of the cornea (the eye's clear protective outer layer). AK can cause extreme levels of pain as well as light sensitivity. AK is relatively uncommon, affecting about one in 37,000 contact lens wearers per year in the UK, but it is responsible for about half the cases of sight loss in this group. Contact lens wearers face an increased risk of the disease; a UCL and Moorfields team recently found that people who wear reusable contact lenses face nearly four times the risk of those wearing daily disposables, while showering with lenses in and wearing lenses overnight also each raised the risk by more than threefold.* The treatment being studied, low concentration polihexanide (PHMB 0.02%), was first compounded and used in the 1990s to treat AK, introduced by a team co-led by this latest study's lead author, Professor John Dart, and is widely recommended as a treatment for AK, but it is not a licensed drug, and treatment outcomes have been variable. Professor John Dart (UCL Institute of Ophthalmology and Moorfields Eye Hospital NHS Foundation Trust) said: "Acanthamoeba keratitis in contact lens users can be prevented by following safe use advice: do use daily disposables if possible, wash and dry hands before handling lenses, maintain good lens and lens case hygiene, and don'tuse them when bathing swimming or showering, or use goggles and renew the lens after use, don't wear them overnight, and don't use them every day. "Unfortunately, when the disease does develop the course is prolonged and, in the recent past, one third of patients have had poor visual outcomes with one quarter requiring surgery at some stage. "PHMB 0.02% is an effective and widely recommended unlicensed therapy, but many clinicians have trouble accessing it, mistakes in formulation can sometimes lead to poor results, and the lack of a proven treatment protocol has resulted in wide variations in how the drug is used and in treatment outcomes. We hope that our new robust findings with polihexanide 0.08% will be a game changer for AK treatment, by improving access and the consistency of treatment, addressing currently unmet patient needs." The Phase 3 randomised controlled double blind clinical trial followed a Phase 1 trial in healthy volunteers which showed that a significantly higher concentration (0.08%) of polihexanide was safe to use. The Phase 3 trial was run in accordance with European Medicines Agency scientific advice and compared the efficacy and safety of a high concentration of polihexanide (0.08%) as a monotherapy to a widely used dual therapy, combining a lower dose of PHMB (0.02%) with propamidine. All trials were sponsored and funded by Italian pharmaceutical company SIFI, with partial co-funding by the European Commission. The study involved the analysis of 127 people being treated for AK at six hospitals across Europe (in England, Italy and Poland). The researchers found both formulations to be highly effective when used with the detailed drug delivery protocol, with medical cure rates of 110/127 (87%) overall and for each treatment individually, meaning 87% of people were cured of AK without needing surgery, one of the highest ever reported for AK. The treatment failure rate was 17/127 (13.4%), nearly half of whom required therapeutic corneal transplant surgery. The overall transplant surgery rate of 8/127 (6.3%) is one of the lowest reported in any case series of AK. The researchers say that the widely recommended dual therapy was more effective than usual in this trial because clinicians were strictly following a set treatment protocol. In addition, the new monotherapy has advantages over dual therapy, as the simplicity reduces the risk of errors in practice. Dr Vincenzo Papa (Head of Scientific Affairs at SIFI) and co-author of the study said: "This publication in Ophthalmology, the leading peer-reviewed journal in our field, further encourages our continued efforts to make polihexanide 0.08% (Akantior®) available to patients with AK, as the first approved orphan medicinal product. Given the extreme burden of the disease and the high unmet medical need, we are proud of the high efficacy outcomes in the robust setting that the trial created, especially when compared with the efficacy rates of 60% reported with the current best treatment." Based on the comprehensive quality, preclinical and clinical data package generated over 15 years of research, SIFI is now seeking regulatory approvals for polihexanide 0.08% in Europe, the UK and the US. Juliette Vila Sinclair Spence, Rare Disease Patient Advocate & Chairwoman, Acanthamoeba Keratitis Eye Foundation, commented: "Exciting news! AK Warriors (aka patients) are now one step closer to receiving the first-ever product with a standardised protocol for Acanthamoeba keratitis. This is starting to bring light to the end of the tunnel." More about Acanthamoeba keratitis AK causes the front surface of the eye, the cornea, to become painful and inflamed, due to infection by Acanthamoeba, a cyst-forming microorganism. The most severely affected patients (a quarter of the total) end up with less than 25% of vision or become blind following the disease and face prolonged treatment. Overall, 25% of people affected require corneal transplants to treat the disease or restore vision.** Contact lens use is now the leading cause of microbial keratitis in patients with otherwise healthy eyes in countries in the global north. Sight loss resulting from microbial keratitis is uncommon but Acanthamoeba, although a rare cause, is one of the most severe and is responsible for about half of those contact lens users who develop sight loss after keratitis. 90% of AK cases are associated with avoidable risks. In recent years a UCL and Moorfields team found AK to be on the rise in South-East England.*** Furthermore, AK is also increasing in prevalence in some part of the global south, including parts of India, where the leading risk factor is agriculture associated corneal trauma. The findings reported here are also relevant to these populations.