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 profile similar 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 Profile and 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 profile of 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.
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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 Re
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