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warnings and cautions
5 WARNINGS AND PRECAUTIONS QT Interval Prolongation: EXXUA prolongs the QTc. Correct electrolyte abnormalities. Perform ECGs prior to initiation, during dose titration, and periodically during treatment with EXXUA. Monitor ECGs more frequently when EXXUA is used concomitantly with drugs known to prolong the QT interval, in patients who develop QTc ≥ 450 msec during treatment or are at significant risk of developing torsade de pointes. Do not escalate dosage if QTc > 450 msec ( 2.1 , 5.2 , 7 ). Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents. If serotonin syndrome occurs, discontinue EXXUA and initiate supportive measures ( 5.3 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 5.4 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . Table 1 Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥ 65 years old 6 fewer patients *EXXUA is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing EXXUA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 QT Prolongation EXXUA prolongs the QTc interval [see Clinical Pharmacology (12.2)] . EXXUA is contraindicated in patients with congenital long QT syndrome and in patients with severe hepatic impairment or in patients receiving concomitant strong CYP3A4 inhibitors as they increase EXXUA plasma concentrations [see Contraindications (4) , Drug Interactions (7) , and Use in Specific Populations (8.7) ]. Do not initiate EXXUA if QTc is > 450 msec at baseline [see Dosage and Administration (2.1) and Contraindications (4) ] . Correct electrolyte abnormalities prior to EXXUA initiation. In patients with electrolyte abnormalities, who are receiving diuretics or glucocorticoids, or have a history or hypokalemia or hypomagnesemia, also monitor electrolytes during dose titration and periodically during treatment with EXXUA. Perform an ECG prior to EXXUA initiation, during dosage titration, and periodically during treatment. Monitor patients with ECGs more frequently. If EXXUA is used concomitantly with drugs known to prolong the QT interval [see Drug Interactions (7)] . In patients who develop QTc ≥ 450 msec during treatment with EXXUA. Do not escalate the EXXUA dosage if QTcF is > 450 msec [see Dosage and Administration (2.1)] . In patients with a significant risk of developing torsade de pointes, including those with uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Reduce the EXXUA dosage when used concomitantly with moderate CYP3A4 inhibitors, as they may increase EXXUA concentrations [see Dosage and Administration (2.7) and Drug Interactions (7) ] . 5.3 Serotonin Syndrome Concomitant use of EXXUA with SSRIs or tricyclic antidepressants may cause serotonin syndrome, a potentially life-threatening condition with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7)] . The concomitant use of EXXUA with MAOIs is contraindicated. In addition, do not initiate EXXUA in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking EXXUA discontinue EXXUA before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7) ]. If concomitant use of EXXUA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. Discontinue EXXUA and/or concomitant serotonergic drug immediately if the above symptoms occur and initiate supportive symptomatic treatment. 5.4 Activation of Mania/Hypomania Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating treatment with EXXUA, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression) [see Dosage and Administration (2.1)] . EXXUA is not approved for use in treating bipolar depression.