Serious And Life-Threatening Risks From Use Of Seglentis

Addiction, Abuse, and Misuse

• Because the use of 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

• Serious, life-threatening, or fatal respiratory depression may occur with use of SEGLENTIS, especially during initiation. To reduce the risk of respiratory depression, proper dosing of SEGLENTIS is essential [see Warnings and Precautions (5.2)].

Accidental Ingestion

• Accidental ingestion of even one dose of SEGLENTIS, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2)].

Risks From Concomitant Use With Benzodiazepines or Other Cns Depressants

• Concomitant 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 SEGLENTIS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) and Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

• If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

• Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)].

Cardiovascular 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 [see Warnings and Precautions (5.6)].
• SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

Ultra-Rapid Metabolism Of Tramadol and Other Risk Factors For Lifethreatening 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 [see Warnings and Precautions (5.8)]. 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 [see Contraindications (4)]. 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 [see Warnings and Precautions (5.8)].

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