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Kowa Pharmaceuticals America, Inc. Announces Publication of Phase 3 Data Supporting FDA Approval of SEGLENTIS® (celecoxib 56-mg and tramadol hydrochloride 44-mg) CI-V as an Efficacious Alternative for Moderate-to-Severe Acute Pain in Appropriate Patients

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, AL, July 19, 2022 — 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 complementary 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 Thomas Jefferson 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 that lasts more than 3 months.1,2 86% of the US population undergoing surgery experience acute postoperative pain,3 with acute pain accounting for 42% of patients who experienced pain-related events in the US.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 US-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 who 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:

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 US 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 US.

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]:

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
Warnings and Precautions
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 www.opioidanalgesicrems.com.

To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc. at 1-888-SEGLENTIS or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)

SEG-US-00226


References:

  1. Dowell D. Draft Updated CDC Guidelines for Prescribing Opioids: Background, Overview, and Progress. https://www.cdc.gov/injury/pdfs/bsc/BSC_Background_Overview_Progress-GL-Update_6_28_cleared_final_D_Dowell-508-fx.pdf. Published July 16, 2021. Accessed January 25, 2022
  2. DHHS Pain Management Best Practices Inter-Agency Task Report, May 2019. https://www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf. Accessed November 17, 2021
  3. 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.
  4. Aggregated claims data deliverable from Symphony’s APLD offering.

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