Zileuton

Brekiya® becomes the first and only DHE autoinjector that allows patients to self-administer the same medication used in hospitals in a ready-to-use form Product will be available for appropriate patients in the second half of 2025 BRIDGEWATER, N.J., May 15, 2025 (GLOBE NEWSWIRE) -- Amneal Pharmaceuticals, Inc. (Nasdaq: AMRX) (“Amneal” or the “Company”) today announced that the U.S. Food and Drug Administration (FDA) has approved Brekiya® (dihydroergotamine mesylate) injection, the first and only dihydroergotamine (DHE) autoinjector for the acute treatment of migraine with or without aura and the acute treatment of cluster headaches in adults.1,2 Brekiya autoinjector provides patients with the potential for sustained* pain relief† in a convenient, self-administered form.1,3,4 It contains the same medication (DHE) used in hospitals, now in a ready-to-use device.1,5 Brekiya autoinjector does not require refrigeration, assembly, or priming of the device.1 Patients can deliver one dose subcutaneously into the middle of the thigh.1 This may be beneficial for patients who respond inadequately to oral therapies due to lack of efficacy, experience nausea or vomiting during attacks, have gastroparesis, or delay dosing until too late into the attack.1,5,6 “We are thrilled to offer the first and only ready-to-use autoinjector for patients suffering from acute migraine and cluster headaches. Physicians are familiar with DHE, which is an effective and well-established therapy that provides sustained relief for headaches. Our single-dose autoinjector represents an innovative therapeutic option for patients that allows for quick self-administration of the medication during these painful attacks without visiting the emergency room,” said Joe Renda, Senior Vice President, Chief Commercial Officer – Specialty. DHE is commonly administered in emergency rooms, urgent care facilities, and headache clinics intravenously. DHE can be used at any point during a migraine attack, and may protect patients from headache recurrence.1,3,4 Approximately 39 million Americans are living with migraine7, and up to one million with cluster headache.8 Also, headache is the fourth most common reason for emergency department visits, and accounts for 3% of all emergency room visits in the United States.9 There are limited treatment options available for cluster headache, and Brekiya autoinjector represents a new treatment option for this underserved population.2 Do not take Brekiya autoinjector with strong CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics. See additional Important Safety Information below. IndicationBrekiya autoinjector is a prescription medicine used for the acute treatment of migraine with or without aura and acute cluster headaches in adults. Brekiya autoinjector is not used to prevent migraine or used to treat other types of headaches such as hemiplegic migraines (that make you unable to move on one side of your body) or basilar migraines (rare form of migraine with aura). It is not known if Brekiya autoinjector is safe and effective in children. IMPORTANT SAFETY INFORMATIONSerious or potentially life-threatening reductions in blood flow to the brain or extremities due to interactions between dihydroergotamine (the active ingredient in Brekiya autoinjector) with strong CYP3A4 inhibitors (such as protease inhibitors and macrolide antibiotics) have been reported rarely. As a result, these medications should not be taken together. Do not use Brekiya autoinjector if you: are taking medicines known as strong CYP3A4 inhibitors, such as: ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, ketoconazole, or itraconazole.have heart problems or a history of heart problems, or uncontrolled high blood pressure.have narrowing of blood vessels in your legs, arms, stomach, or kidneys (peripheral vascular disease).have sepsis, had vascular surgery, severe liver or kidney problems.are allergic to dihydroergotamine, ergot alkaloids, latex, or any of the ingredients in Brekiya autoinjector.have taken any of the following medicines in the last 24 hours: sumatriptan, frovatriptan, ergotamine or ergotamine-type medicines, almotriptan, naratriptan, zolmitriptan, eletriptan, or rizatriptanhave taken any medicines that constrict your blood vessels or raise your blood pressure. Before you take Brekiya autoinjector, tell your healthcare provider about all your medical conditions, including if you: have high blood pressure, liver problems, or kidney problems.have risk factors for heart disease, such as: high blood pressure, high cholesterol levels, smoke, are overweight, diabetes, family history of heart disease.are pregnant or plan to become pregnant. Brekiya autoinjector may cause preterm labor. Brekiya autoinjector should be avoided during pregnancy. Talk to your healthcare provider right away if you are pregnant or want to become pregnant.are breastfeeding or plan to breastfeed. Brekiya autoinjector may reduce breast milk supply and pass into your breast milk. Brekiya autoinjector may be harmful to your baby. Do not breastfeed your baby while taking Brekiya autoinjector and for 3 days after you use Brekiya autoinjector. Talk with your healthcare provider about the best way to feed your baby if you take Brekiya autoinjector. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: sumatriptan, ergot-type medicine, saquinavir, nefazodone, fluconazole, grapefruit juice, zileuton, nicotine, propranolol or other medicines that can lower your heart rate, any medicines that can increase your blood pressure, selective serotonin reuptake inhibitors. These are not all of the medicines that could affect how Brekiya autoinjector works. Your healthcare provider can tell you if it is safe to take Brekiya autoinjector with other medicines. How should I use Brekiya autoinjector? Certain people should take their first dose of Brekiya autoinjector in their healthcare provider’s office or in another medical setting.Brekiya autoinjector is for injection under the skin (subcutaneous) only.Use Brekiya autoinjector exactly as your healthcare provider tells you to use it.Each autoinjector contains one dose (1 mg).If your headache comes back after the first complete dose, you may give yourself up to 2 more doses as needed. Wait at least one hour between doses.Do not inject more than 3 doses (3 mg) of Brekiya autoinjector in a 24-hour period or 6 doses (6 mg) in a 1-week (7 day) period. What are the possible side effects of Brekiya autoinjector?Brekiya autoinjector can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking Brekiya autoinjector and get emergency medical help right away if you have any symptoms of a heart attack, such as: numbness or tingling in your fingers and toes, muscle pain or cramps in your arms and legs, weakness in your legs, temporary speeding or slowing of your heart rate, or swelling or itching. Brekiya autoinjector is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. Stroke. Stop using Brekiya autoinjector and get emergency medical help right away if you have any of the symptoms of a stroke.Changes in color or sensation in your fingers and toes (Raynaud’s syndrome).Stomach and intestinal problems.Increased blood pressure.Medicine overuse headache. Some people who use too much Brekiya autoinjector may make their headaches worse. If your headaches get worse, your healthcare provider may decide to stop your treatment with Brekiya autoinjector.Preterm labor.Tissue changes (fibrotic complications). Inflammation and fiber-like tissue that is not normal (fibrosis) can occur around the lungs and stomach. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Brekiya autoinjector. Call your healthcare provider for medical advice about side effects. How should I store Brekiya autoinjector? Store at room temperature between 68°F to 77°F (20°C to 25°C). Do not refrigerate or freeze.Protect Brekiya autoinjector from light.Keep Brekiya autoinjector in the original pack until ready to use. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Specialty, a division of Amneal Pharmaceuticals LLC at 1-877-835-5472, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see full Prescribing Information, including Boxed Warning, Medication Guide, and Instructions for Use at Brekiya.com. *Sustained represents a duration of approximately 24-72 hours2,3†Cluster headache results reported using IV administration.4 References: Brekiya [package insert]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2025.Data on File. Amneal Pharmaceuticals LLC.Winner P, Ricalde O, Le Force B, Saper J, Margul B. Arch Neurol. 1996;53(2):180-184.Mather PJ, Silberstein SD, Schulman EA, Hopkins MM. Headache. 1991;31(8):525-532.Silberstein SD, Shrewsbury SB, Hoekman J. Headache. 2020;60(1):40-57. doi:10.1111/head.13700Aurora SK, Papapetropoulos S, Kori SH, Kedar A, Abell TL. Cephalalgia. 2013;33(6):408-415.https://migraineresearchfoundation.org/about-migraine/migraine-facts/https://americanmigrainefoundation.org/resource-library/cluster-headache-2/Phelan, M, Thompson NR, Zubair A et al. Emergency department utilization among patients who receive outpatient specialty care for headache: A retrospective cohort study analysis. Headache. 2023;63:472–483. Brekiya is a registered trademark of Amneal Pharmaceuticals LLC. About AmnealAmneal Pharmaceuticals, Inc. (Nasdaq: AMRX), headquartered in Bridgewater, NJ, is a global biopharmaceutical company. We make healthy possible through the development, manufacturing, and distribution of a diverse portfolio of over 280 pharmaceuticals, primarily within the United States. In its Affordable Medicines segment, the Company is expanding across a broad range of complex product categories and therapeutic areas, including injectables and biosimilars. In its Specialty segment, Amneal has a growing portfolio of branded pharmaceuticals focused primarily on central nervous system and endocrine disorders. Through its AvKARE segment, the Company is a distributor of pharmaceuticals and other products for the U.S. federal government, retail, and institutional markets. For more information, please visit www.amneal.com and follow us on LinkedIn. Cautionary Statement on Forward-Looking StatementsCertain statements contained herein, regarding matters that are not historical facts, may be forward-looking statements (as defined in the U.S. Private Securities Litigation Reform Act of 1995). Such forward-looking statements include statements regarding management’s intentions, plans, beliefs, expectations, financial results, or forecasts for the future, including among other things: discussions of future operations; expected or estimated operating results and financial performance; and statements regarding our positioning, including our ability to drive sustainable long-term growth, and other non-historical statements. Words such as “plans,” “expects,” “will,” “anticipates,” “estimates,” and similar words, or the negatives thereof, are intended to identify estimates and forward-looking statements. The forward-looking statements contained herein are also subject generally to other risks and uncertainties that are described from time to time in the Company’s filings with the Securities and Exchange Commission, including under Item 1A, “Risk Factors” in the Company’s most recent Annual Report on Form 10-K and in its subsequent reports on Forms 10-Q and 8-K. Forward-looking statements included herein speak only as of the date hereof and we undertake no obligation to revise or update such statements to reflect the occurrence of events or circumstances after the date hereof. Investor Contact Anthony DiMeoVP, Investor Relations anthony.dimeo@amneal.comMedia ContactBrandon SkopSr. Director, Corporate CommunicationsBrandon.skop@amneal.com PP-PRS-DHE-US-0001 05/2025

Leukotrienes are a group of inflammatory mediators produced by the metabolism of arachidonic acid (AA) through the 5-lipoxygenase (5-LO) pathway, featuring a conjugated triene structure of a 20-carbon unsaturated acid. They are classified into six types - A, B, C, D, E, F, based on their substituents. Among these, LTC4, LTD4, and LTE4 all contain cysteinyl at C-6, collectively referred to as cysteinyl leukotrienes (CysLTs). Leukotrienes can be produced by cells after various immunological or non-immunological stimuli, through autocrine or paracrine mechanisms. These stimuli include antigens, immune complexes, complements, cytokines, osmotic pressure, and environmental pollutants. Once leukotrienes bind with specific G-protein coupled receptors (GPCRs) on the cell surface, they activate Gq proteins leading to an increase in intracellular calcium concentrations, and activating Gi proteins causing a decrease in cAMP, both of which can trigger a cascade of kinase protein signal transduction, inducing intracellular transcription responses and cell movement, thereby widely participating in the body's immune response. Currently, anti-leukotriene drugs are primarily divided into two categories: the first are leukotriene receptor antagonists, which inhibit tissue responses to leukotrienes by blocking leukotriene receptors, including Montelukast, Zafirlukast, and Pranlukast; the second one are leukotriene synthesis inhibitors, which inhibit the activity of the key enzyme 5-LO in the leukotriene synthesis pathway, thereby inhibiting the synthesis of cysteinyl leukotrienes and LTB4. Leukotriene Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 18 Sep 2023, there are a total of 142 5-LOX drugs worldwide, from 105 organizations, covering 60 indications, and conducting 52 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. 5-LOX, or 5-lipoxygenase, is an enzyme that plays a crucial role in the human body's inflammatory response. It is responsible for the conversion of arachidonic acid into leukotrienes, which are potent mediators of inflammation. These leukotrienes are involved in various physiological processes, including immune response, allergic reactions, and the development of certain diseases such as asthma and arthritis. Due to its involvement in inflammation, 5-LOX has become an attractive target for pharmaceutical research, with the aim of developing drugs that can modulate its activity and potentially alleviate inflammatory conditions. Drugs under this target have been approved for indications such as asthma. Small molecule drugs are progressing most rapidly, with one approved and six in preclinical development. The United States is the leading country in terms of drug development for target 5-LOX, followed by Australia, Israel, and the European Union. China has made progress in preclinical development for this target. The current competitive landscape for target 5-LOX is characterized by a diverse range of companies and drug types. The presence of biosimilars indicates intense competition around the innovative drugs. Further research and development are needed to explore the potential of target 5-LOX in various indications and to expand its market presence globally. Leukotriene Pathway Inhibitor: ZileutonZileuton is a Leukotriene pathway inhibitor, classified as a 5-lipoxygenase inhibitor, used for the treatment of asthma and allergic rhinitis. Zileuton is associated with rare drug-induced liver disease and is considered contraindicated in patients with active liver disease. The 5- lipoxygenase is responsible for the conversion of arachidonic acid into leukotriene A4, leukotriene A4 is an effective mediator of the inflammatory cascade reaction, playing a pivotal role in asthma and allergic rhinitis. Zileuton has been shown to improve the symptoms of asthma and allergic rhinitis and was approved for use in the United States in 1996. Current indications include the prophylaxis and chronic treatment of asthma in adults and children aged 12 and above. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. Given its approval for asthma, Zileuton is expected to have a positive impact on patients suffering from this condition. By targeting 5-LOX, the drug helps to reduce the production of leukotrienes, which are known to contribute to airway inflammation and bronchoconstriction in asthma patients. By inhibiting this pathway, Zileuton can potentially alleviate symptoms and improve lung function in individuals with asthma. In summary, Zileuton is a small molecule drug developed by Abbott Laboratories that targets 5-LOX and is indicated for the treatment of asthma. Its approval in 1996 in the United States signifies its efficacy and safety in managing this respiratory condition. As a therapeutic option, Zileuton has the potential to provide relief to asthma patients by reducing airway inflammation and constriction. Targeted 5-LOX Small Molecule Drugs:A-72694The drug A-72694 is a small molecule drug that targets 5-LOX, which stands for 5-lipoxygenase. It is primarily developed for the treatment of asthma, a respiratory disease that affects the immune system. The drug is currently in the preclinical phase, indicating that it is still undergoing laboratory testing and has not yet progressed to human clinical trials. A-72694 is being developed by Abbott Laboratories, a well-known pharmaceutical company with expertise in the field of biomedicine. The therapeutic areas of A-72694 include immune system diseases and respiratory diseases, with asthma being the active indication. This indicates that the drug is specifically designed to target and treat asthma, a chronic condition characterized by inflammation and narrowing of the airways. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. As a small molecule drug, A-72694 is likely to have a low molecular weight and can be easily synthesized in a laboratory setting. Small molecule drugs are typically orally administered and can easily penetrate cell membranes, allowing them to interact with specific targets within the body. Although the drug is still in the preclinical phase, it shows promise for the treatment of asthma by targeting 5-LOX. 5-LOX is an enzyme involved in the production of leukotrienes, which are inflammatory molecules that play a role in asthma pathogenesis. By inhibiting 5-LOX, A-72694 may help reduce inflammation and improve respiratory symptoms in asthma patients. In summary, A-72694 is a small molecule drug developed by Abbott Laboratories that targets 5-LOX for the treatment of asthma. It is currently in the preclinical phase, and further research and development are needed to determine its safety and efficacy in human clinical trials.