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July 19, 2022 13:00 UTC Phase 3 clinical trial data in patients post-bunionectomy demonstrated SEGLENTIS as an efficacious and well-tolerated multimodal treatment option for appropriate adult patients with acute pain. MONTGOMERY, Ala.--(BUSINESS WIRE)-- Kowa Pharmaceuticals America, Inc. announced the publication of Phase 3 clinical trial results in Pain Practice reinforcing that SEGLENTIS® a unique co-crystal combination of celecoxib 56-mg and tramadol hydrochloride 44-mg, and oral treatment for appropriate patients with acute pain, provided superior analgesic efficacy than tramadol hydrochloride or celecoxib individually, and a safety pro to tramadol hydrochloride, while meeting its primary endpoint. As a multimodal agent, SEGLENTIS leverages 4 complimentary mechanisms of analgesia involving peripheral and central pathways. There are ongoing efforts to ensure multimodal analgesia is standard care for appropriate patients with moderate-to-severe acute pain. As such, SEGLENTIS was developed as a multimodal treatment option for the management of acute pain severe enough to require an opioid. Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, SEGLENTIS should be reserved for use in patients with acute pain severe enough to require an opioid and for whom alternative treatment options (e.g., non-opioid analgesics) have not been tolerated or are not expected to be tolerated and have not provided adequate analgesia or are not expected to provide adequate analgesia. Dr. Eugene R. Viscusi, Phase 3 trial clinical investigator and Vice Chair of Pain Management at Jefferson Thomas University said, “Now that multimodal analgesia has become the standard for acute pain treatment, we are excited that the results of this study demonstrate that SEGLENTIS is efficacious and safe in its unique co-crystal combination of tramadol hydrochloride and celecoxib. This novel multimodal form of analgesia may be an important alternative option for treating appropriate adults with certain types of acute pain.” Acute pain is characterized by a sudden sharp pain lasting less than 4 weeks, and chronic pain is characterized by pain which lasts more than 3 months.1,2 86% of the U.S. population undergoing surgery experiences acute postoperative pain3, with acute pain accounting for 42% of patients who experienced pain-related events in the U.S.4 “As a part of our continued efforts to ensure the safety and efficacy of our products, these results align with efforts and current guidance to offer physicians and their patients a treatment option that strives toward the lowest effective dose and shortest duration of therapy,” said Craig A. Sponseller Chief Medical Officer. “We are excited to publish the pivotal phase 3 data in adults post bunionectomy and osteotomy demonstrating that SEGLENTIS®, the first co-crystal, immediate-release, opioid combination agent with a unique dosage strength, had significantly better analgesia compared with each individual component at half the maximum daily doses for acute pain.” SEGLENTIS was approved as a Schedule IV controlled substance, which includes a Boxed Warning concerning addiction, abuse, and misuse. About the Pivotal Phase 3 Trial Study Design This randomized, double-blind, parallel-group, factorial, active- and placebo-controlled pivotal Phase 3 trial (NCT03108482), evaluated 637 adults, across 6 U.S.-based research centers, with moderate-to-severe acute pain (mean baseline NPRS score was 6.7) using an established model of acute surgical pain after bunionectomy and osteotomy. Trial participants (n=637) were randomized 2:2:2:1 to oral, 200 mg Q12H SEGLENTIS, 50 mg Q6H tramadol hydrochloride, 100 mg Q12H celecoxib, or Q6H placebo. Mean age of participants was 46 years, with most patients being female (86%) which is consistent with the clinical population seeking bunionectomy treatment. Rescue medication was allowed during the study, patients which required medical had a sequential offering of IV Acetaminophen 1 g every 4 to 6 hours, up to 4 g/24 hours, or oxycodone hydrochloride 5 mg immediate release tablet every 4 to 6 hours if needed, up to a total of 30 mg/24 hours. Primary and Secondary Endpoints The primary efficacy endpoint met and studied was summed pain intensity difference from 0 to 48 hours (SPID0-48). SEGLENTIS had a significantly greater effect on SPID0-48 (least-squares mean: −139.1 [95% confidence interval: −151.8, −126.5]) than tramadol (−109.1 [−121.7, −96.4]; P<0.001), celecoxib (−103.7 [−116.4, −91.0]; P<0.001) or placebo (−74.6 [−92.5, −56.6]; P<0.001). Secondary efficacy endpoints supported primary findings and included: SPID over 4, 6, 12 and 24 hours Total pain relief over 4, 6, 12, 24 and 48 hours Pain intensity and change from baseline in pain intensity at each time point Response rates Time to onset of analgesia Proportion of patients using rescue medication Time to first use of rescue medication Patients’ overall assessment of study drug. Safety Pro Total Emergent Adverse Events The overall rates of treatment emergent adverse events (TEAEs) were similar in the SEGLENTIS (63.4%) and tramadol (63.4%) groups, and lower in both the celecoxib (52.2%) and placebo (57.3%) groups. The most common AEs reported were nausea (30%), dizziness (17%), vomiting (16%), headache (12%) and somnolence (8%). There were no serious TEAEs or death. TEAEs leading to study medication discontinuation were experienced by 6 patients, 3 in the SEGLENTIS group (nausea, n=2; pruritus and rash, n=1) and 3 in the tramadol group (vomiting, n=2; supraventricular tachycardia, n=1). Overall, the safety pro SEGLENTIS was similar to that of tramadol hydrochloride and no additional safety concerns were observed during the study period. About SEGLENTIS Approved by the U.S. Food and Drug Administration in October 2021, SEGLENTIS is a co-crystal formulation of two commonly prescribed analgesics, celecoxib and tramadol hydrochloride. SEGLENTIS provides celecoxib and tramadol hydrochloride as a lower maximum daily dose than each of the individual agent at maximum doses for acute pain (224-mg and 176-mg in SEGLENTIS vs ≥400-mg and 400-mg for celecoxib and tramadol, respectively). SEGLENTIS was developed by Esteve Pharmaceuticals and is commercialized and available from Kowa Pharmaceuticals America, Inc. within the U.S. Indication SEGLENTIS contains tramadol hydrochloride, an opioid agonist, and celecoxib, a nonsteroidal anti-inflammatory drug, and is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve SEGLENTIS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated, or are not expected to be tolerated. Have not provided adequate analgesia, or are not expected to provide adequate analgesia. Important Safety Information, including Boxed Warning WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; CARDIOVASCULAR (CV) THROMBOTIC EVENTS; GASTROINTESTINAL (GI) BLEEDING, ULCERATION, AND PERFORATION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS Addiction, Abuse, and Misuse SEGLENTIS exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing SEGLENTIS and monitor all patients regularly for the development of these behaviors and conditions. Opioid Analgesic REMS To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of SEGLENTIS. Monitor for respiratory depression, especially during initiation of SEGLENTIS. Accidental Ingestion Accidental ingestion of even one dose of SEGLENTIS, especially by children, can be fatal. CV Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious CV thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. GI Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events. Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of SEGLENTIS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SEGLENTIS requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of SEGLENTIS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit treatment to the minimum duration. Follow patients for signs and symptoms of respiratory depression and sedation. Contraindications Children younger than 12 years of age. Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Significant respiratory depression. In the setting of CABG surgery. Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. Known or suspected GI obstruction, including paralytic ileus. Hypersensitivity to tramadol, celecoxib, any other component of this product, or sulfonamides, or opioids. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Warnings and Precautions Addiction, Abuse, and Misuse: Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SEGLENTIS. Addiction can occur at recommended dosages and if the drug is misused or abused. Life-threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of SEGLENTIS, the risk is greatest during the initiation of therapy. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with SEGLENTIS. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. CV Thrombotic Events: To minimize the potential risk for an adverse CV event in NSAID-treated patients, use SEGLENTIS for the shortest duration possible. Avoid the use of SEGLENTIS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SEGLENTIS is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. GI Bleeding, Ulceration, and Perforation: Use the approved dosage for the shortest possible duration. Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children: Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use SEGLENTIS. Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants: Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SEGLENTIS with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. Serotonin Syndrome Risk: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, a component of SEGLENTIS, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue SEGLENTIS if serotonin syndrome is suspected. Increased Risk of Seizure: Can occur at the recommended dose of tramadol. Concomitant use of SEGLENTIS increases the seizure risk in patients taking: SSRIs and SNRIs, antidepressants or anorectics, TCAs, and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), other opioids, MAOIs, neuroleptics, or other drugs that reduce the seizure threshold. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures. Suicide Risk: Prescribe SEGLENTIS with caution for patients with a history of misuse and/or who are currently taking CNS-active drugs including tranquilizers, or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression. Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Life-threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: SEGLENTIS-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, are at increased risk of decreased respiratory drive including apnea, even at the recommended dosage of SEGLENTIS. Elderly, Cachectic, or Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, or altered clearance, compared to younger, healthier patients. Monitor such patients closely, particularly when initiating SEGLENTIS and when SEGLENTIS is given concomitantly with other drugs that depress respiration. Severe Hypotension: Tramadol, a component of SEGLENTIS, may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating dosage of SEGLENTIS. In patients with circulatory shock, tramadol may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SEGLENTIS in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SEGLENTIS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SEGLENTIS. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SEGLENTIS in patients with impaired consciousness or coma. Risk of Use in Patients with GI Conditions: The tramadol in SEGLENTIS may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. Hepatotoxicity: As tramadol and celecoxib are both extensively metabolized by the liver, the use of SEGLENTIS in patients with moderate and severe hepatic impairment is not recommended. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SEGLENTIS immediately, and perform a clinical evaluation of the patient. Inform patients of warning signs and symptoms of hepatotoxicity. Hypertension: NSAIDs, including celecoxib, a component in SEGLENTIS, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema: Avoid the use of SEGLENTIS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If SEGLENTIS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, or liver dysfunction; those taking diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs); and the elderly. Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. Exacerbation of Asthma Related to Aspirin Sensitivity: SEGLENTIS is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). Serious Skin Reactions: Serious skin reactions have occurred following treatment with celecoxib, a component of SEGLENTIS, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These serious events may occur without warning and can be fatal. Discontinue SEGLENTIS at first appearance of skin rash or other signs of hypersensitivity. DRESS: Discontinue and evaluate clinically. Fetal Toxicity: Limit use of NSAIDs, including SEGLENTIS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. Hematologic Toxicity: Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with SEGLENTIS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including SEGLENTIS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs may increase this risk. Monitor these patients for signs of bleeding. Withdrawal: Do not abruptly discontinue SEGLENTIS in a patient physically dependent on opioids. When discontinuing SEGLENTIS in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including SEGLENTIS. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. Driving and Operating Machinery: SEGLENTIS may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SEGLENTIS and know how they will react to the medication. Masking of Inflammation and Fever: The pharmacological activity of SEGLENTIS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Hyponatremia: Hyponatremia (serum sodium <135 mmol/L) has been reported with the use of tramadol, a component of SEGLENTIS, and many cases are severe (sodium level <120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion. Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation) during treatment with SEGLENTIS, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue SEGLENTIS. Hypoglycemia: Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g., diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate. Adverse Reactions Most common adverse reactions (incidence >5% and > placebo) for SEGLENTIS are nausea (30%), vomiting (16%), dizziness (17%), headache (12%), and somnolence (8%). Select Drug Interactions Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with SEGLENTIS because they may reduce analgesic effect of SEGLENTIS or precipitate withdrawal symptoms. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking SEGLENTIS with drugs that interfere with hemostasis. Concomitant use of SEGLENTIS and analgesic doses of aspirin is not generally recommended. ACE Inhibitors, ARBs, or Beta Blockers: Concomitant use with SEGLENTIS may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs: Concomitant use with SEGLENTIS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function. Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. Digoxin: Concomitant use with SEGLENTIS can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. Drug Abuse and Dependence SEGLENTIS contains tramadol, a Schedule IV controlled substance with a high potential for abuse similar to other opioids and can be abused and is subject to misuse, addiction, and criminal diversion. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Overdosage SEGLENTIS is a combination drug composed of tramadol and celecoxib. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, celecoxib toxicity, or both. Tramadol: Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, seizures, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Deaths due to overdose have been reported with abuse and misuse of tramadol. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. Celecoxib: Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. GI bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. For more information on appropriate treatment of overdose with SEGLENTIS, see the full Prescribing Information. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics, including SEGLENTIS, outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS continuing education, call 1-800-503-0784, or log on to . To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc. at 1-888-SEGLENTIS or the FDA at 1-800-FDA-1088 or . For additional information please see full Prescribing Information, including Boxed Warning, and Medication Guide, for SEGLENTIS. Intended for healthcare professionals of the United States of America only. SEGLENTIS is a registered trademark of Esteve Pharmaceuticals, S.A., and is used under license. © Kowa Pharmaceuticals America, Inc. (2022) References: Dowell D. Draft Updated CDC Guidelines for Prescribing Opioids: Background, Overview, and Progress. . Published July 16, 2021. Accessed January 25, 2022 DHHS Pain Management Best Practices Inter-Agency Task Report, May 2019. . Accessed November 17, 2021 Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2014;30:149-160. Aggregated claims data deliverable from Symphony’s APLD offering.

EMERYVILLE, Calif.--(BUSINESS WIRE)-- Adamas Pharmaceuticals, Inc. (Nasdaq: ADMS), a company dedicated to developing and delivering medicines that make a meaningful difference to people affected by neurological diseases, today announced the publication of an article entitled “Amantadine ER (Gocovri®) significantly increases ON time without any dyskinesia: Pooled analyses from pivotal studies in Parkinson’s disease” in the peer-reviewed journal Frontiers in Neurology. GOCOVRI® (amantadine) extended release capsules is the first and only medicine approved as a treatment both for dyskinesia in patients with Parkinson’s disease (PD) receiving levodopa-based therapy and as an adjunctive treatment to levodopa/carbidopa in patients with PD experiencing OFF episodes. The publication examined data from two pivotal, placebo-controlled Phase 3 clinical studies evaluating a total of 196 patients. The results demonstrated that treatment with GOCOVRI more than doubled the daily time patients spent ON without any dyskinesia (whether troublesome or non-troublesome), from 3.9 hours a day at baseline to 8.4 hours at Week 12. Compared to placebo, those treated with GOCOVRI experienced an additional 2.9 hours ON time without dyskinesia, an increase driven by a reduction in both OFF time and dyskinesia. Typically, PD clinical trials for the treatment of motor complications differentiate dyskinesia into ‘troublesome’ and ‘non- troublesome’ categories. This analysis is unique in evaluating treatment impact by measuring the increase in ON time without any dyskinesia. GOCOVRI-related adverse events were consistent with the known safety pro amantadine. “Patients prefer to experience ON time without any dyskinesia, so balancing the need for levodopa-based treatment to reduce OFF time that comes with a risk of increased dyskinesia is a challenge for patient care in Parkinson’s disease,” said Robert A. Hauser, M.D., MBA, Professor of Neurology and Director of the Parkinson’s Disease and Movement Disorders Center at the University of South Florida. “These results expand the knowledge of GOCOVRI’s efficacy as an adjunctive treatment to levodopa to address both motor complications.” “This publication highlights GOCOVRI’s ability to improve ON time with no dyskinesia – which can make a significant impact on better movement control for someone living with PD motor complications,” said Adrian Quartel, M.D., Chief Medical Officer, Adamas. “As the only treatment that addresses both ends of the spectrum in PD motor complications, we are proud to publish data that continue to support GOCOVRI as a treatment option that may help people with Parkinson’s increase good movement throughout the day.” This publication analyzed self-reported diary data from pivotal trials, where participants recorded their predominant motor state every 30 minutes for two days prior to each clinic visit. These diary recordings may not be reflective of their typical daily or weekly experience. About Parkinson’s disease, OFF, and dyskinesia Parkinson’s disease (PD) is a progressive, neurodegenerative disorder caused by the gradual loss of brain cells that produce the neurotransmitter dopamine and affects approximately one million people in the United States. Dopamine decline in the brain results in a wide range of motor (movement-related) and non-motor symptoms. As the disease progresses, people taking levodopa-based therapy are likely to experience reemergence or sudden return of stiffness, rigidity, and tremors between medication doses referred to as OFF episodes, which may be unpredictable. The primary treatment for PD is with levodopa; however, over time levodopa may lead to involuntary, uncontrolled movements known as dyskinesia. The abrupt and unpredictable transitions between episodes of dyskinesia, normal movement, and OFF lead to a considerable impact on patients’ lives. About GOCOVRI GOCOVRI® (amantadine) extended-release capsules is the first and only FDA-approved medicine indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications, and as an adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing OFF episodes. Taken once daily at bedtime, GOCOVRI provides an initial lag (delayed release) and a slow rise in amantadine concentration during the night, resulting in a high concentration from the morning and throughout the waking day (extended release). Additionally, in the clinical trials, the adjunctive use of GOCOVRI did not require dose changes to dopaminergic therapies. The most commonly observed adverse reactions with GOCOVRI were hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. For more information about GOCOVRI, please visit . IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS GOCOVRI® is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities. Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases. Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications. ADVERSE REACTIONS The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and, orthostatic hypotension. Please see full Prescribing Information for additional important safety information at . About Adamas At Adamas our vision is clear – to deliver innovative medicines that reduce the burden of neurological diseases on patients, caregivers and, society. We are a fully-integrated company focused on growing a portfolio of therapies to address a range of neurological diseases. For more information, please visit . Source: Adamas Pharmaceuticals, Inc.

LEBANON, N.J., Jan. 26, 2021 /PRNewswire/ -- Recordati Rare Diseases Inc. today announced the U.S. Food and Drug Administration (FDA) has approved a new indication for CARBAGLU® (carglumic acid) tablets 200mg as adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA) in pediatric and adult patients. CARBAGLU is the first and only FDA approved medication for the treatment of acute hyperammonemia due to PA and MMA. CARBAGLU was initially approved by the FDA for N-acetylglutamate synthase (NAGS) deficiency, another rare metabolic disorder, as adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to NAGS deficiency, and maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency. PA and MMA are rare inherited metabolic disorders that result in the dysfunction of a specific step of amino acid catabolism, or breaking down of certain fatty acids, due to deficient enzyme activity. As a result, toxic metabolites accumulate, which can cause hyperammonemia, a potentially life-threatening condition. CARBAGLU acts as a replacement for N-acetylglutamate (NAG) in NAGS deficiency, PA, and MMA patients by activating carbamoyl phosphate synthetase (CPS 1), improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production. "There are few approved drugs that treat hyperammonemia, and none that are indicated for the treatment of acute hyperammonemia in PA and MMA patients," said Mendel Tuchman, MD, Medical Geneticist and Professor Emeritus of Pediatrics at The George Washington University School of Medicine and Health Science. "Carbaglu has the potential to impact these patients by reducing high plasma ammonia levels during critical situations." FDA approval of the new indication was supported by a randomized, double-blind, placebo-controlled, multicenter clinical trial comparing the effectiveness of CARBAGLU to placebo in the treatment of hyperammonemic episodes in patients with PA or MMA. The efficacy evaluation, based on 90 hyperammonemic episodes occurring in 24 patients, showed that patients receiving CARBAGLU demonstrated a quicker reduction of ammonia compared to patients receiving placebo. The primary endpoint was the time from the first dose to the earlier of blood ammonia level below 50 micromol/L or hospital discharge. Throughout the first three days of treatment, a higher proportion of CARBAGLU-treated episodes reached the primary endpoint compared to placebo-treated episodes. In the clinical trial, at least 1 adverse reaction was reported in 42.2% of the 90 hyperammonemic episodes that occurred. The most common adverse events were (≥5%) neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. "People living with these conditions face potentially serious complications from hyperammonemia that, without treatment, can lead to coma or even death," said Andrea Recordati, CEO of Recordati S.p.A.. "We are pleased to receive this new indication for Carbaglu which will enable Recordati to address an unmet medical need in these patients." About Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare inherited metabolic disorders. PA results from a deficiency of the enzyme propionyl-CoA carboxylase. Most PA patients present with symptoms in the first few days of life. MMA results from different types of enzyme deficiencies or defects. The most common cause is a deficiency of the enzyme methylmalonyl-CoA mutase. In both disorders, complete lack of enzyme or very limited enzyme causes more severe symptoms. Hyperammonemia is one of the most severe and life-threatening events that can occur in patients with PA or MMA. Hyperammonemia is a medical emergency that if left untreated, can progress to irreversible brain damage, coma, or death. Please click here for Full Prescribing Information and Instructions for Use. Important Safety Information Contraindications: None. NAGS deficiency: Most common adverse reactions (≥13%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. PA and MMA: Most common adverse reactions (≥5%) are: neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or If CARBAGLU is administered during pregnancy to women with NAGS deficiency, health care providers should report CARBAGLU exposure to the pregnancy pharmacovigilance program by calling 1-888-575-8344. About Recordati Rare Diseases Inc. Recordati Rare Diseases Inc. is a biopharmaceutical company committed to providing often-overlooked orphan therapies to the underserved rare disease communities of the United States. Recordati Rare Diseases is part of the Recordati Group, a public international pharmaceutical company committed to the research and development of new specialties with a focus on treatments for rare diseases. Recordati Rare Diseases' mission is to reduce the impact of extremely rare and devastating diseases by providing urgently needed therapies. We work side-by-side with rare disease communities to increase awareness, improve diagnosis and expand availability of treatments for people with rare diseases. The company's U.S. corporate headquarters is located in Lebanon, NJ, with global headquarter offices located in Milan, Italy. For a full list of products please click here: . For additional information, please visit our website: . Recordati, established in 1926, is an international pharmaceutical group, listed on the Italian Stock Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271), with a total staff of more than 4,300, dedicated to the research, development, manufacturing and marketing of pharmaceuticals. Headquartered in Milan, Italy, Recordati has operations throughout the whole of Europe, including Russia, Turkey, North Africa, the United States of America, Canada, Mexico, some South American countries, Japan and Australia. An efficient field force of medical representatives promotes a wide range of innovative pharmaceuticals, both proprietary and under license, in several therapeutic areas including a specialized business dedicated to treatments for rare diseases. Recordati is a partner of choice for new product licenses for its territories. Recordati is committed to the research and development of new specialties with a focus on treatments for rare diseases. Consolidated revenue for 2019 was € 1,481.8 million, operating income was € 465.3 million and net income was € 368.9 million. Forward Looking Statement Statements contained in this release, other than historical facts, are "forward-looking statements" (as such term is defined in the Private Securities Litigation Reform Act of 1995). These statements are based on currently available information, on current best estimates, and on assumptions believed to be reasonable. This information, these estimates and assumptions may prove to be incomplete or erroneous, and involve numerous risks and uncertainties, beyond the Company's control. Hence, actual results may differ materially from those expressed or implied by such forward-looking statements. All mentions and descriptions of Recordati products are intended solely as information on the general nature of the company's activities and are not intended to indicate the advisability of administering any product in any particular instance.