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KOWA Pharmaceuticals America, Inc. Announces U.S. Commercial Launch and Availability of SEGLENTIS® (celecoxib 56-mg and tramadol 44-mg hydrochloride)

MONTGOMERY, AL, May 24, 2022 — Kowa Pharmaceuticals America, Inc. today announced the commercial availability of SEGLENTIS® (celecoxib 56-mg and tramadol hydrochloride 44-mg) C-IV.

SEGLENTIS, an oral medication with a unique co-crystal formulation of celecoxib (a nonsteroidal anti-inflammatory drug) and tramadol (a Schedule IV opioid analgesic), was approved by the United States Food and Drug Administration (FDA) on October 15, 2021, for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. 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.

“Millions of patients each year suffer from acute pain as a result of trauma, illness, or surgery. Acute pain can be complex to treat—it is not a one size fits all approach for every patient,” said Dr. Ira J. Gottlieb, SEGLENTIS clinical trial investigator and Medical Director, Chesapeake Research Group. “Healthcare professionals need new treatment options for patients with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. This novel co-crystal form of celecoxib and tramadol hydrochloride provides multimodal analgesia by acting on four complementary mechanisms of analgesia. Together the celecoxib and tramadol hydrochloride components of SEGLENTIS interact in a complementary manner at central and peripheral targets to address acute pain relief.”

“Patient safety is of the utmost importance to us, and we are committed to implementing measures in addition to a risk evaluation and mitigation strategy (REMS), to encourage safe and appropriate use of SEGLENTIS,” said Craig A. Sponseller, MD, Chief Medical Officer of Kowa Pharmaceuticals America, Inc. “As part of that commitment in a space that has historically been met with distrust, we will also be continuously listening to and securing feedback from healthcare professionals, patients and advocacy communities to understand how we can best support them and foster responsible use.”


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.
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]:

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-00178

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