Oligohydramnios

Offers health care providers a new multimodal approach to adult pain management LONDON, Feb. 5, 2024 /PRNewswire/ -- Hikma Pharmaceuticals PLC (Hikma), the multinational pharmaceutical company, announces the launch of COMBOGESIC® IV (acetaminophen and ibuprofen) injection in the US. COMBOGESIC® IV is an intravenous, opioid-free pain relief medicine that is a combination of 1,000 mg of acetaminophen and 300 mg of ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). It was approved by the US FDA in October 2023 for use in adults where an intravenous route of administration is considered clinically necessary for: (i) the relief of mild to moderate pain; and (ii) the management of moderate to severe pain as an adjunct to opioid analgesics.1 The American Society of Anesthesiology's (ASA) evidence-based recommendations emphasize the importance of a multimodal approach to pain management using multiple interventions with different mechanisms of action that may offer additive or synergistic effects to optimize pain relief.2 COMBOGESIC® IV offers health care providers a new, non-opioid approach to pain management by combining active drug substances with different mechanisms of action in a single formulation, providing: Shorter onset to analgesia3 Superior analgesia efficacy and comparable safety in common adverse events3 Sustained pain-management results3 In a Phase 3 clinical trial, COMBOGESIC® IV provided more than double the pain relief than that of acetaminophen IV and ibuprofen IV alone.3 Time to meaningful pain relief was shorter in the COMBOGESIC® IV group than that in the Ibuprofen IV or placebo groups.3 COMBOGESIC® IV also allows for superior analgesia efficacy.3 "The approval of COMBOGESIC® IV is an important step in providing hospitals and health care providers in the US with an alternative treatment option for managing patients' pain," said Dr. Bill Larkins, President of Injectables, Hikma. "This is another example of how we continue to expand our portfolio of critical medicines and we are pleased to make this important new treatment option available for patients, helping to put better health within reach, every day." In 2021, Hikma signed an exclusive license and distribution agreement with AFT Pharmaceuticals (AFT) for the commercialization of COMBOGESIC® IV in the US. Under the trade name of MAXIGESIC® IV outside of the United States, COMBOGESIC® IV is licensed in over 100 countries and marketed in over 20 countries. About COMBOGESIC® IV COMBOGESIC® IV is the only IV analgesic therapy formulated with 1,000 mg of acetaminophen and 300 mg of ibuprofen, utilizing the synergistic effect of both medicines for optimal pain relief.1 It offers health care providers a new approach to multimodal analgesia by combining active drug substances with different mechanisms of action that harness additive or synergistic effects to provide more effective pain relief compared with individual components used as single-modality interventions.1-3 COMBOGESIC® IV is supplied as a readily available solution with no mixing required for administration.1 It is administered as a 15-minute IV infusion, every 6 hours as needed, not to exceed the maximum total daily dose of 4,000 mg acetaminophen and 1,200 mg of ibuprofen in 24 hours.1 About Hikma (LSE: HIK) (NASDAQ Dubai: HIK) (OTC: HKMPY) (rated BBB-/stable S&P and BBB-/positive Fitch) Hikma helps put better health within reach every day for millions of people around the world. For more than 40 years, we've been creating high-quality medicines and making them accessible to the people who need them. Headquartered in the UK, we are a global company with a local presence across the North America, the Middle East and North Africa (MENA) and Europe, and we use our unique insight and expertise to transform cutting-edge science into innovative solutions that transform people's lives. We're committed to our customers, and the people they care for, and by thinking creatively and acting practically, we provide them with a broad range of branded and non-branded generic medicines. Together, our 8,800 colleagues are helping to shape a healthier world that enriches all our communities. We are a leading licensing partner, and through our venture capital arm, are helping bring innovative health technologies to people around the world. For more information, please visit: This product has been approved for marketing in the United States by the US FDA. This product approval does not confer the right on Hikma, or any other party, to market this product outside the United States. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS COMBOGESIC® IV is contraindicated in: Patients with previous demonstrated hypersensitivity to acetaminophen, ibuprofen, other NSAIDs or to any of the excipients/components of this product. Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients. The treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. Patients with severe hepatic impairment or severe active liver disease. WARNINGS & PRECAUTIONS Risk of Medication Errors. Take care when prescribing, preparing, and administering COMBOGESIC® IV in order to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that the dose in milligrams (mg) and milliliters (mL) is not confused, the dosing is based on weight for patients under 50 kg, infusion pumps are properly programmed, and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. Hepatotoxicity. (i) COMBOGESIC® IV contains acetaminophen which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. The use of COMBOGESIC® IV in patients with hepatic impairment is not recommended. (ii) COMBOGESIC® IV contains ibuprofen. Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs. Cardiovascular Thrombotic Events. Trials suggest that NSAIDs, taken for up to 3 years, elevate the risk of serious cardiovascular events like myocardial infarction and stroke. To minimize these risks, the lowest effective dose for the shortest duration possible should be used in these patients. Gastrointestinal Bleeding, Ulceration, and Perforation. NSAIDs cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small or large intestine, which can be fatal. These adverse events can occur at any time, with or without warning symptoms. Avoid use in patients at higher risk. In concomitant use with low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding. Serious Skin Reactions. Acetaminophen, or NSAIDs may cause serious skin reactions such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms and discontinue the use of the drug at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC® IV is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as COMBOGESIC® IV. Some of these events have been fatal or life-threatening. Hypersensitivity and Anaphylactic Reactions. There have been post marketing reports of hypersensitivity and anaphylaxis, including life-threatening anaphylaxis associated with the use of acetaminophen. Hypertension. NSAIDs can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Heart Failure and Edema. Studies have demonstrated an increase in hospitalizations for heart failure in NSAID-treated patients compared to placebo-treated patients. Additionally, in a study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions. Renal Toxicity and Hyperkalemia. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. No information is available regarding the use of COMBOGESIC® IV in patients with advanced renal disease. Exacerbation of Asthma Related to Aspirin Sensitivity. Patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe bronchospasm, which can be fatal and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, COMBOGESIC® IV is contraindicated in patients with this form of aspirin sensitivity. Fetal Toxicity: Premature Closure of Fetal Ductus Arteriosus. Avoid use of COMBOGESIC® IV in pregnant women at about 30 weeks gestation and later. COMBOGESIC® IV increases the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Fetal Toxicity: Oligohydramnios/Neonatal Renal Impairment. Use of COMBOGESIC® IV at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Hematologic Toxicity. Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect on erythropoiesis. NSAIDs included in COMBOGESIC® IV may increase the risk of bleeding events. Masking of Inflammation and Fever. Activity of COMBOGESIC® IV in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Ophthalmological Effects. If a patient develops ophthalmological complaints while receiving COMBOGESIC® IV, the drug should be discontinued, and the patient should have an ophthalmologic examination. Increased Risk of Hepatotoxicity with Concomitant Use of Other Acetaminophen-containing Products. COMBOGESIC® IV should not be used concomitantly with other acetaminophen containing products. Use with Alcohol. COMBOGESIC® IV should not be used concomitantly with alcoholic beverages. Laboratory Monitoring. Consider monitoring patients on NSAID treatment with a CBC and a chemistry profile as clinically indicated. ADVERSE REACTIONS The most common TEAEs (occurring in ≥ 3% of COMBOGESIC® IV -treated participants) were related to the infusion site (infusion site pain, infusion site extravasation), or affected the gastrointestinal (nausea, vomiting, constipation) or nervous (dizziness, headache, somnolence) systems. Other skin and subcutaneous-related TEAEs (pruritis, hyperhidrosis) also affected around 2 to 3% of the study population, as did procedural nausea and polyuria. DRUG INTERACTIONS A number of known or potential interactions between COMBOGESIC® IV and other drugs/drug classes exist. Please refer to the Drug Interactions in the Prescribing Information for further information. Drugs That Interfere with Hemostasis. Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Aspirin. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID increases the risk of serious gastrointestinal (GI) events. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers. NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or Beta-Blockers. Diuretics. NSAIDs can reduce the natriuretic effect of loop diuretics and thiazides in some patients. Lithium. NSAIDs produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. Monitor patients for signs of lithium toxicity. Methotrexate. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Monitor patients for methotrexate toxicity. USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential. Use of acetaminophen may cause reduced fertility in males and females of reproductive potential. It is not known whether these effects on fertility are reversible. The use of NSAIDs may delay or prevent rupture of ovarian follicles. Consider withdrawal of NSAID-containing products in women who have difficulties conceiving or who are undergoing investigation of infertility. Geriatric Use. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients (65 years and older) are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects. Hepatic Impairment. Use of COMBOGESIC® IV in patients with hepatic impairment is not recommended. Renal Impairment. The use of COMBOGESIC® IV in these patients is not recommended as it may hasten the progression of renal dysfunction in patients with pre-existing renal disease. INDICATIONS AND USAGE COMBOGESIC® IV is indicated in adults (over age 18) where an intravenous route of administration is considered clinically necessary for: The relief of mild to moderate pain. The management of moderate to severe pain as an adjunct to opioid analgesics. LIMITATIONS OF USE COMBOGESIC® IV is indicated for short-term use of five days or less. Patient counseling information should be shared with the patient prior to administration. For additional information, please refer to the Package Insert for full Prescribing Information, available on . To report an adverse event or product complaint, please contact us at [email protected] or call 1-877-845-0689 or 1-800-962-8364. Adverse events may also be reported to the FDA directly at 1-800-FDA-1088 or . Manufactured by: S.M. Farmaceutici SRL Zona Industriale, 85050 Tito (PZ), Italy Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 USA COMBOGESIC® is a registered trademark of AFT Pharmaceuticals Limited. © 2024 Hikma Pharmaceuticals USA Inc. All rights reserved. Document identification number: HK-2471-v3 1 COMBOGESIC® IV (acetaminophen 1000 mg and ibuprofen 300 mg) [package insert]. 2 Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of post operative pain: a clinical practice guideline from the American pain society, the American society of regional anesthesia and pain medicine, and the American society of anesthesiologists' committee on regional anesthesia, executive committee, and administrative council. J Pain. 2016;17:131-157. 3 Daniels SE, Playne R, Stanescu I, Zhang J, Gottlieb IJ, Atkinson HC. Efficacy and safety of an intravenous acetaminophen/ibuprofen fixed-dose combination after bunionectomy: A randomized, double-blind, factorial, placebo-controlled trial. Clinical Therapeutics. 2019;41(10). SOURCE Hikma Pharmaceuticals USA Inc.

STOUGHTON, Mass., Aug. 30, 2022 (GLOBE NEWSWIRE) -- Collegium Pharmaceutical, Inc. (Nasdaq: COLL), a leading, diversified specialty pharmaceutical company, today announced that 11 poster presentations highlighting data regarding its product portfolio will be presented at the Annual PAINWeek National Conference, taking place September 6-9, 2022 in Las Vegas, NV. “Collegium is excited to support 11 posters regarding our meaningfully differentiated product portfolio that will be presented at PAINWeek 2022 National Conference,” said Thomas Smith, MD, EVP and Chief Medical Officer of Collegium. “We welcome opportunities to share clinical and real-world data with the medical community as part of our commitment to make a positive difference in the lives of people living with serious medical conditions.” Poster Presentations: Poster Title:Budget Impact Analysis of Xtampza® ER (oxycodone extended-release) for the Treatment of Chronic Pain from a Managed Care PerspectiveAuthors:Alan G. White, Todd Kunkel, Mancia Ko, Hongjue Wang Poster Title:Treatment Effects of Celecoxib Oral Solution in Migraine with Aura and Without Aura: Post-HOC Analysis of Results from Two Randomized, Double-Blind Placebo-Controlled TrialsAuthors:Stewart Tepper, Daniel Serrano, Mancia Ko, Todd Kunkel, Richard B. Lipton Poster Title:Consistency of Response to Liquid Celecoxib in Adults with Migraine: Post HOC Analysis of Results from Two Randomized, Placebo-Controlled StudiesAuthors:Daniel Serrano, Stewart Pepper, Mancia Ko, Todd Kunkel, Richard B. Lipton Poster Title:Efficacy of Celecoxib Oral Solution in Adults with and Without Baseline Nausea: Post-HOC Analysis of Results from Two Randomized, Double-Blind Placebo-Controlled Trials in the Acute Treatment of MigraineAuthors:Richard B. Lipton, Daniel Serrano, Mancia Ko, Todd Kunkel, Stewart Pepper Poster Title:Celecoxib Oral Solution in the Acute Treatment of Migraine: Pooled Efficacy and Safety Results From 2 Randomized Placebo-controlled TrialsAuthors:Stewart Pepper, Harvey Kushner, Mancia Ko, Todd Kunkel, Richard B. Lipton Poster Title:Impact of Celecoxib Oral Solution on Symptomatic Improvements in the Acute Treatment of MigraineAuthors:Stewart Pepper, Harvey Kushner, Mancia Ko, Todd Kunkel Poster Title:Prescription Opioid Nonmedical Use via Oral Manipulation: An Under-Recognized RiskAuthors:Jody L. Green, Taryn Dailey-Govoni, Suzanna K. Vosburg Poster Title:Association between per capita prescribing and abuse of tapentadol and other opioids among individuals entering treatment for opioid use disordersAuthors:Stevan Geoffrey Severtson, Annika M. Czizik, Matthew Ellis, Joshua C. Black, Janetta Iwanicki, Richard C. Dart Poster Title:Non-Medical Use of XTAMPZA ER: Motivation, Methods, and Perceptions of TamperingAuthors:Joshua C. Black, Karilynn M. Rockhill, S. Geoff Severtson, Richard C. Dart Poster Title:Cross-sectional Study of Tampering in an Abuse-Deterrent Formulation of an Extended-Release Opioid in a Treatment Center PopulationAuthors:Jennifer Jewell, Joshua Black, Matthew Ellis, Heather Olsen, Janetta Iwanicki, Richard Dart Poster Title:Differences in the severity of medical outcomes of exposures reported to poison centers involving XTAMPZA® ER and other opioid analgesicsAuthors:Stevan Geoffrey Severtson, Joshua C. Black, Janetta Iwanicki, Richard C. Dart For more information on PAINWeek 2022, visit: https://www.painweek.org/ Xtampza ER (oxycodone) extended-release capsules, CII, Nucynta® ER (tapentadol) extended-release tablets, CII, and Nucynta® (tapentadol) tablets, CII, can be abused or misused, and carry a risk of addiction. These products are intended for use only in appropriate pain patients and only when other treatment alternatives are inadequate. Use of Xtampza® ER, Nucynta® ER and Nucynta® can result in serious, life-threatening or fatal respiratory depression, even when used exactly as prescribed. See Important Safety Information including Boxed Warning on addiction, abuse, and misuse and other serious risks regarding each of these three products at the end of this press release. Nonsteroidal anti-inflammatory drugs (NSAIDs), including ELYXYB (celocoxib) oral solution, cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. See Important Safety Information including Boxed Warning at the end of this press release. About Collegium Pharmaceutical, Inc. Collegium is a diversified, specialty pharmaceutical company committed to improving the lives of people living with serious medical conditions. Collegium’s headquarters are located in Stoughton, Massachusetts. For more information, please visit the Company’s website at www.collegiumpharma.com. Xtampza ER (oxycodone) INDICATIONS AND USAGEXtampza® ER (oxycodone) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Xtampza ER for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of painXtampza ER is not indicated as an as-needed (prn) analgesic IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTSAddiction, Abuse, and MisuseXtampza ER 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 Xtampza ER and monitor all patients regularly for the development of these behaviors or conditions.Opioid Analgesic Risk Evaluation and Mitigation Strategy (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 DepressionSerious, life-threatening, or fatal respiratory depression may occur with use of Xtampza ER. Monitor for respiratory depression, especially during initiation of Xtampza ER or following a dose increase.Accidental IngestionAccidental ingestion of even one dose of Xtampza ER, especially by children, can result in a fatal overdose of oxycodone.Neonatal Opioid Withdrawal SyndromeProlonged use of Xtampza ER 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.Cytochrome P450 3A4 InteractionThe concomitant use of Xtampza ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving Xtampza ER and any CYP3A4 inhibitor or inducer.Risks From Concomitant Use With Benzodiazepines or Other CNS DepressantsConcomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Xtampza ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.Limit dosages and durations to the minimum required.Follow patients for signs and symptoms of respiratory depression and sedation. CONTRAINDICATIONS: Xtampza ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, and hypersensitivity (eg, anaphylaxis) to oxycodone WARNINGS AND PRECAUTIONS:Addiction, Abuse, and MisuseXtampza ER contains oxycodone, a Schedule II controlled substance. As an opioid, Xtampza ER exposes users to the risks of addiction, abuse, and misuse. As extended-release products such as Xtampza ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present. Opioid Analgesic Risk Evaluation and Mitigation Strategy (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 Risk Evaluation and Mitigation Strategy (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 do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with PainDiscuss with patients and/or their caregivers, with every prescription, the safe use, serious risks, and proper storage and disposal of these products. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCGEmphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacistConsider other tools to improve patient, household, and community safety such as patient-prescriber agreements that reinforce patient-prescriber responsibilities For further information on the REMS and a list of accredited REMS CME/CE, call 1-800-503-0784, or visit www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 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 opioidsEducate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdoseOpioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Xtampza ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administeredConsider 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. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone Neonatal Opioid Withdrawal Syndrome Prolonged use of Xtampza ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome, and ensure that appropriate treatment will be available Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Xtampza ER with a CYP3A4 inhibitor, such as macrolide antibiotics (eg, erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (eg, ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Xtampza ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Xtampza ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Xtampza ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Xtampza ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Xtampza ER until stable drug effects are achievedConcomitant use of Xtampza ER with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Xtampza ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Xtampza ER with benzodiazepines or other CNS depressants (eg, 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 inadequateObservational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose Risk of Life-Threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Xtampza ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated Patients with Chronic Pulmonary Disease: Xtampza ER-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 recommended dosages of Xtampza ER Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients Monitor such patients closely, particularly when initiating and titrating Xtampza ER and when Xtampza ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of Xtampza ER less than 9 mg 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 Severe Hypotension Xtampza ER may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an 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 (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Xtampza ER. In patients with circulatory shock, Xtampza ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Xtampza ER 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 (eg, those with evidence of increased intracranial pressure or brain tumors), Xtampza ER 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 Xtampza EROpioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Xtampza ER in patients with impaired consciousness or coma Risks of Use in Patients with Gastrointestinal Conditions Xtampza ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileusThe oxycodone in Xtampza ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms Risk of Use in Patients with Seizure Disorders The oxycodone in Xtampza ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Xtampza ER therapy Withdrawal Do not abruptly discontinue Xtampza ER in a patient physically dependent on opioids. When discontinuing Xtampza ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of painAdditionally, avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including Xtampza ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms Risks of Driving and Operating Machinery Xtampza ER 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 Xtampza ER and know how they will react to the medication Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative.” Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results ADMINISTRATION WITH FOOD: Instruct patients to always take Xtampza ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, Xtampza ER can also be taken as a sprinkle on soft foods or sprinkled into a cup and administered directly into the mouth, or through a nasogastric or gastric feeding tube ADVERSE REACTIONS: The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing Xtampza ER with placebo were nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness See full Prescribing Information, including Boxed Warning on Addiction, Abuse and Misuse and other serious risks, accompanying this piece or at XtampzaER.com/PI. NUCYNTA® ER (tapentadol) INDICATIONS AND USAGENUCYNTA ER (tapentadol) is indicated for the management of: Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequateNeuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long- term opioid treatment and for which alternative treatment options are inadequate Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA ER for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of painNUCYNTA ER is not indicated as an as-needed (prn) analgesic WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTSAddiction, Abuse, and MisuseNUCYNTA ER 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 NUCYNTA ER, and monitor all patients regularly for the development of these behaviors and conditions.Opioid Analgesic Risk Evaluation and Mitigation Strategy (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, andconsider other tools to improve patient, household, and community safety. Life-Threatening Respiratory DepressionSerious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA ER. Monitor for respiratory depression, especially during initiation of NUCYNTA ER or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole; crushing, chewing, or dissolving NUCYNTA ER tablets can cause rapid release and absorption of a potentially fatal dose of tapentadol.Accidental IngestionAccidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in a fatal overdose of tapentadol.Neonatal Opioid Withdrawal SyndromeProlonged use of NUCYNTA ER 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.Interaction With AlcoholInstruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking NUCYNTA ER. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol.Risks From Concomitant Use With Benzodiazepines or Other CNS DepressantsConcomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.Limit dosages and durations to the minimum required.Follow patients for signs and symptoms of respiratory depression and sedation. CONTRAINDICATIONS:NUCYNTA ER is contraindicated in patients with: Significant respiratory depressionAcute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipmentKnown or suspected gastrointestinal obstruction, including paralytic ileusHypersensitivity (eg, anaphylaxis, angioedema) to tapentadol or to any other ingredients of the productConcurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS:Addiction, Abuse, and MisuseNUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Opioid Analgesic Risk Evaluation and Mitigation Strategy (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 Risk Evaluation and Mitigation Strategy (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 do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with PainDiscuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCGEmphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to themConsider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. Life-Threatening Respiratory DepressionSerious, 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 NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with NUCYNTA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. 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. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. Neonatal Opioid Withdrawal SyndromeProlonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risk From Concomitant Use With Benzodiazepines or Other CNS DepressantsPatients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (eg, 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. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics. 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. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs. Risk of Life-Threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated PatientsThe use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA ER-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 recommended dosages of NUCYNTA ER. 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. Alternatively, consider the use of non-opioid analgesics in these patients. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration. Serotonin Syndrome With Concomitant Use of Serotonergic DrugsCases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, tramadol), certain muscle relaxants (ie, cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, 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. Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Adrenal InsufficiencyCases 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. Severe HypotensionNUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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 (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock. Risks of Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired ConsciousnessIn patients who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER 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 NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients With Gastrointestinal ConditionsNUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER 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. Increased Risk of Seizures in Patients With Seizure DisordersThe tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy. WithdrawalDo not abruptly discontinue NUCYNTA ER in a patient physically dependent on opioids. When discontinuing NUCYNTA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of tapentadol 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 (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Risks of Driving and Operating MachineryNUCYNTA ER 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 NUCYNTA ER and know how they will react to the medication. Risk of Toxicity in Patients With Hepatic ImpairmentA study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients With Renal ImpairmentUse of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ADVERSE REACTIONS:In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence. See full Prescribing Information, including Boxed Warning on Addiction, Abuse and Misuse and other serious risks, accompanying this piece or at Nucynta.com/ERpi. NUCYNTA® (tapentadol) INDICATIONS AND USAGE NUCYNTA (tapentadol) tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults. Limitations of UseBecause of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve NUCYNTA tablets for use in patients for whom alternative treatment options (eg, non-opioid analgesics or opioid combination products): Have not been tolerated, or are not expected to be toleratedHave not provided adequate analgesia, or are not expected to provide adequate analgesia IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTSAddiction, Abuse, and MisuseNUCYNTA tablets expose 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 NUCYNTA tablets, and monitor all patients regularly for the development of these behaviors and conditions.Opioid Analgesic Risk Evaluation and Mitigation Strategy (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 stronglyencouraged 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, andconsider other tools to improve patient, household, and community safety. Life-Threatening Respiratory DepressionSerious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA tablets. Monitor for respiratory depression, especially during initiation of NUCYNTA tablets or following a dose increase.Accidental IngestionAccidental ingestion of even one dose of NUCYNTA tablets, especially by children, can result in a fatal overdose of tapentadol.Neonatal Opioid Withdrawal SyndromeProlonged use of NUCYNTA tablets 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.Risks From Concomitant Use With Benzodiazepines or Other CNS DepressantsConcomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of NUCYNTA tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.Limit dosages and durations to the minimum required.Follow patients for signs and symptoms of respiratory depression and sedation. CONTRAINDICATIONS:NUCYNTA tablets are contraindicated in patients with: Significant respiratory depressionAcute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipmentKnown or suspected gastrointestinal obstruction, including suspected paralytic ileusHypersensitivity to tapentadol (eg, anaphylaxis, angioedema) or to any other ingredients of the productConcurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS:Addiction, Abuse, and MisuseNUCYNTA tablets contain tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA tablets expose users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA tablets and monitor all patients receiving NUCYNTA tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA tablets, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Opioid Analgesic Risk Evaluation and Mitigation Strategy (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 Risk Evaluation and Mitigation Strategy (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 do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with PainDiscuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCGEmphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to themConsider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient- prescriber responsibilities To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. Life-Threatening Respiratory DepressionSerious, 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 NUCYNTA tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA tablets. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA tablets are essential. Overestimating the NUCYNTA tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA tablets, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with NUCYNTA tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered 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. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. Neonatal Opioid Withdrawal SyndromeProlonged use of NUCYNTA tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risks From Concomitant Use With Benzodiazepines or Other CNS DepressantsProfound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA tablets with benzodiazepines or other CNS depressants (eg, 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. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics. 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. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs. Life-Threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated PatientsThe use of NUCYNTA tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA tablets-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 recommended dosages of NUCYNTA tablets. 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 and titrating NUCYNTA tablets and when NUCYNTA tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients. Serotonin Syndrome With Concomitant Use of Serotonergic DrugsCases of serotonin syndrome, a potentially life-threatening condition, have been reported during concurrent use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, tramadol), certain muscle relaxants (ie, cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, 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. Serotonin syndrome symptoms may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/orgastrointestinal symptoms (eg, nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA tablets if serotonin syndrome is suspected. Adrenal InsufficiencyCases 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. Severe HypotensionNUCYNTA tablets 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 (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA tablets. In patients with circulatory shock, NUCYNTA tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA tablets in patients with circulatory shock. Risks of Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired ConsciousnessIn patients who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), NUCYNTA tablets 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 NUCYNTA tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA tablets in patients with impaired consciousness or coma. Risks of Use in Patients With Gastrointestinal ConditionsNUCYNTA tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA tablets 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. Increased Risk of Seizures in Patients With Seizure DisordersThe tapentadol in NUCYNTA tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA tablets therapy. WithdrawalDo not abruptly discontinue NUCYNTA tablets in a patient physically dependent on opioids. When discontinuing NUCYNTA tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of tapentadol 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 (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including NUCYNTA tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. Risks of Driving and Operating MachineryNUCYNTA tablets 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 NUCYNTA tablets and know how they will react to the medication. Interactions With Alcohol, Other Opioids, and Drugs of AbuseDue to its mu-opioid agonist activity, NUCYNTA tablets may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA tablets therapy. Risk of Toxicity in Patients With Hepatic ImpairmentA study with NUCYNTA tablets in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA tablets in patients with severe hepatic impairment. Reduce the dose of NUCYNTA tablets in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA tablets. Risk of Toxicity in Patients With Renal ImpairmentUse of NUCYNTA tablets in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ADVERSE REACTIONS:In clinical studies, the most common (≥10%) adverse reactions were nausea, dizziness, vomiting, and somnolence. See full Prescribing Information, including Boxed Warning on Addiction, Abuse and Misuse and other serious risks, accompanying this piece or at Nucynta.com/IRpi. ELYXYB™ (celecoxib) oral solution INDICATIONELYXYB™ (celecoxib) oral solution is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the acute treatment of migraine with or without aura in adults. Limitations of UseELYXYB is not indicated for the preventive treatment of migraine. IMPORTANT SAFETY INFORMATION about ELYXYB™ WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTSCardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use.ELYXYB is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (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. CONTRAINDICATIONSELYXYB is contraindicated in the following patients: Known hypersensitivity to celecoxib or any components of the drug product or sulfonamides.History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs.In the setting of coronary artery bypass graft (CABG) surgery. WARNINGS AND PRECAUTIONSPost-MI Patients: Avoid the use of ELYXYB in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ELYXYB is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hepatotoxicity: Elevations of ALT or AST have been reported in patients with NSAIDs. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported. Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. Hypertension: NSAIDs, including ELYXYB, 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 some antihypertension medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. Heart Failure and Edema: Avoid the use of ELYXYB in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ELYXYB is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury and may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ELYXYB in patients with severe renal impairment unless benefits are expected to outweigh the risk of worsening renal function. If ELYXYB is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia: Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions: Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin-sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Exacerbation of Asthma Related to Aspirin Sensitivity: ELYXYB is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without known aspirin sensitivity). Serious Skin Reactions: Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal. Discontinue ELYXYB at the first appearance of skin rash or any other sign of hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Eosinophilia is often present. If such signs or symptoms are present, discontinue ELYXYB and evaluate the patient immediately. Medication Overuse Headache: Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, NSAIDs, or combination of these drugs for 10 or more days per month), including ELYXYB, may lead to exacerbation of headache (medication overuse headache). Detoxification of patients, including withdrawal of the overused drugs and treatment of withdrawal symptoms may be necessary. Premature Closure of Fetal Ductus Arteriosus: ELYXYB may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including ELYXYB, in pregnant women starting at about 30 weeks gestation and later. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including ELYXYB, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ELYXYB use to the lowest effective dose and shortest duration possible. Discontinue ELYXYB if oligohydramnios occurs. Hematological Toxicity: Anemia has occurred in NSAID-treated patients. Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia or blood loss. NSAIDs, including ELYXYB, may increase the risk of bleeding events. Monitor patients for signs of bleeding. Masking of Inflammation and Fever: The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring: Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID, including ELYXYB, treatment with a CBC and a chemistry profile periodically. Disseminated Intravascular Coagulation (DIC): ELYXYB is not indicated in pediatric patients or for the treatment of juvenile rheumatoid arthritis (JRA). Disseminated intravascular coagulation has occurred with use of celecoxib capsules in pediatric patients with systemic-onset JRA, which required monitoring for signs and symptoms of abnormal clotting or bleeding. DRUG INTERACTIONSDrugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ELYXYB with drugs that interfere with hemostasis. Concomitant use of ELYXYB and oral corticosteroids, antiplatelet drugs (e.g., aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs), is not recommended. ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with ELYXYB may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs: Concomitant use with ELYXYB in the 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 ELYXYB can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. USE IN SPECIFIC POPULATIONSPregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation. Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ELYXYB in women who have difficulties conceiving. ADVERSE REACTIONSMost common adverse reaction (at least 3% and greater than placebo) reported by patients treated with ELYXYB in the clinical trials was dysgeusia. Please see full Prescribing Information, including Boxed Warning and Medication Guide for ELYXYB. To report SUSPECTED ADVERSE REACTIONS, contact BioDelivery Sciences International, Inc. at 1-800-469-0261 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch. Intended for healthcare professionals of the United States of America only. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. We may, in some cases, use terms such as "predicts," "forecasts," "believes," "potential," "proposed," "continue," "estimates," "anticipates," "expects," "plans," "intends," "may," "could," "might," "should" or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Examples of forward-looking statements contained in this press release include, among others, statements related to our full-year 2022 financial guidance, including total projected product revenue, adjusted operating expenses and adjusted EBITDA, current and future market opportunities for our products and our assumptions related thereto, expectations (financial or otherwise) and intentions, and other statements that are not historical facts. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results, performance, or achievements to differ materially from the company's current expectations. Actual results may differ materially from management’s expectations and such forward-looking statements in this press release could be affected as a result of various important factors, including risks relating to, among others: risks related to the ability to realize the anticipated benefits of our acquisition of BDSI, including the possibility that the expected benefits from the BDSI acquisition will not be realized or will not be realized within the expected time period; the risk that BDSI’s business will not be integrated successfully; unknown liabilities; risks related to future opportunities and plans for the products acquired with BDSI, including uncertainty of the expected financial performance of such products; the impact of the COVID-19 pandemic on our ability to conduct our business, reach our customers, and supply the market with our products; our ability to commercialize and grow sales of our products; our ability to manage our relationships with licensors; the success of competing products that are or become available; our ability to obtain and maintain regulatory approval of our products and any product candidates, and any related restrictions, limitations, and/or warnings in the label of an approved product; the size of the markets for our products and product candidates, and our ability to service those markets; our ability to obtain reimbursement and third-party payor contracts for our products; the rate and degree of market acceptance of our products and product candidates; the costs of commercialization activities, including marketing, sales and distribution; changing market conditions for our products; the outcome of any patent infringement, opioid-related or other litigation that may be brought by or against us, including litigation with Purdue Pharma, L.P.; the outcome of any governmental investigation related to our business; our ability to secure adequate supplies of active pharmaceutical ingredient for each of our products and manufacture adequate supplies of commercially saleable inventory; our ability to obtain funding for our operations and business development; regulatory developments in the U.S.; our expectations regarding our ability to obtain and maintain sufficient intellectual property protection for our products; our ability to comply with stringent U.S. and foreign government regulation in the manufacture of pharmaceutical products, including U.S. Drug Enforcement Agency, or DEA, compliance; our customer concentration; and the accuracy of our estimates regarding expenses, revenue, capital requirements and need for additional financing. These and other risks are described under the heading "Risk Factors" in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other filings with the SEC. Any forward-looking statements that we make in this press release speak only as of the date of this press release. We assume no obligation to update our forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. Contact: Alex Dasalla Head of Investor Relations adasalla@collegiumpharma.com

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.