October 18, 2021 — Esteve Pharmaceuticals has received approval from the U.S. Food and Drug Administration (FDA) for SEGLENTIS^® (celecoxib and tramadol hydrochloride) for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

As part of an agreement with Esteve Pharmaceuticals, Kowa Pharmaceuticals America will commercialize SEGLENTIS in the United States, with a launch currently planned for early 2022.

SEGLENTIS is a prescription, oral medication with a unique co-crystal formulation of celecoxib (a nonsteroidal anti-inflammatory drug) and tramadol (a Schedule IV opioid analgesic).

“The unique co-crystal formulation of SEGLENTIS provides effective pain relief via a multimodal approach,” said Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America. “SEGLENTIS uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate. To support the responsible commercialization of SEGLENTIS and as part of our commitment to patients and healthcare providers, Kowa is implementing multiple measures, including a risk evaluation and mitigation strategy (REMS), to encourage safe and appropriate use of SEGLENTIS.”

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, SEGLENTIS should be reserved for use in patients for whom alternative treatment options (e.g., nonopioid 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.

Important Safety Information, including Boxed Warning

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.

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 gastrointestinal 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

• Serotonin Syndrome: May be life-threatening. Can occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol.
• Risk of Seizure: Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase seizure risk. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures.
• Risk of Suicide: Do not prescribe for suicidal or addiction-prone patients.
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid.
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
• Severe Hypotension with Tramadol: Monitor during dosage initiation. Avoid use of SEGLENTIS in patients with circulatory shock.
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of SEGLENTIS in patients with impaired consciousness or coma.
• Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.
• Hepatotoxicity: 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: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.
• Heart Failure and Edema: Avoid use of SEGLENTIS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.
• Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of SEGLENTIS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.
• 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: Discontinue SEGLENTIS at first appearance of skin rash or other signs of hypersensitivity.
• Drug Reaction with Eosinophilia and Systemic Symptoms (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: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia.

Adverse Reactions

Most common adverse reactions (incidence > 5% and > placebo) for SEGLENTIS are nausea, vomiting, dizziness, headache, somnolence.

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, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [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.

Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), 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.

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. Gastrointestinal 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.

ISI-SEG-US-00001 10/2021

SEGLENTIS^® is a registered trademark of Esteve Pharmaceuticals, S.A. and is used under license.

© Kowa Pharmaceuticals America, Inc. (2021)

SEG-US-00011