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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue levomilnacipran and serotonergic agents and initiate supportive treatment ( 5.2 ). Elevated Blood Pressure and Heart Rate: Control hypertension before initiating therapy with levomilnacipran. Monitor blood pressure regularly during treatment ( 5.3 , 5.4 ). Increased Risk of Bleeding: Concomitant use of NSAIDs, aspirin, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.5 ). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.6 ). Urinary Hesitation or Retention: Can occur. If such symptoms occur, discontinue levomilnacipran or consider other appropriate medical intervention ( 5.7 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder. Caution patients about risk of activation of mania/hypomania ( 5.8 ). Seizures: Can occur. Use with caution in patients with a seizure disorder ( 5.9 ). Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms ( 5.10 ). Hyponatremia: Can occur in association with SIADH ( 5.11 ). Sexual Dysfunction: Levomilnacipran may cause symptoms of sexual dysfunction ( 5.12 ). 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 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric * and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥ 65 years old 6 fewer patients *Levomilnacipran 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 antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication 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 levomilnacipran, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including levomilnacipran, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e. MAOIs [see Contraindications (4) , Drug Interactions (7.1) ]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of levomilnacipran with MAOIs is contraindicated. In addition, do not initiate levomilnacipran in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking levomilnacipran, discontinue levomilnacipran before initiating treatment with the MAOI [see Dosage and Administration (2.5 , 2.6) and Contraindications (4) , Drug Interactions (7.1) ] . Monitor all patients taking levomilnacipran for the emergence of serotonin syndrome. Discontinue treatment with levomilnacipran and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of levomilnacipran with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure SNRIs, including levomilnacipran, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing hypertension should be controlled before initiating treatment with levomilnacipran. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience a sustained increase in blood pressure while receiving levomilnacipran, discontinuation or other appropriate medical intervention should be considered. Table 2 shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in levomilnacipran-treated adult patients in the short-term placebo-controlled studies. Table 2: Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive Status with Levomilnacipran (in Adults) Placebo Levomilnacipran 40 to 120 mg/day Mean change from baseline to end of treatment, mm Hg Systolic blood pressure (SBP) -0.4 3.0 Diastolic blood pressure (DBP) -0.0 3.2 Sustained Hypertension, % of patients Broad Criteria: SBP ≥ 140 mm Hg and an increase ≥ 15 mm Hg OR DBP ≥ 90 mm Hg and an increase ≥ 10 mm Hg for at least 3 consecutive visits 1.2 1.8 Strict Criteria: SBP ≥ 140 mm Hg and an increase ≥ 15 mm Hg AND DBP ≥ 90 mm Hg and an increase ≥ 10 mm Hg for at least 3 consecutive visits 0.1 0.3 Upward Shifts in Hypertensive Status a , % of patients Normal/ Pre-hypertensive → Stage I/ Stage II 7.1 10.4 a Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm Hg Pre-hypertension: SBP ≥ 120 mm Hg and ≤ 139 mm Hg or DBP ≥ 80 mm Hg and ≤ 89 mm Hg Stage I hypertension: SBP ≥ 140 mm Hg and ≤ 159 mm Hg or DBP ≥ 90 mm Hg and ≤ 99 mm Hg Stage II hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg In the short-term, placebo-controlled MDD studies in adults, the mean increase from initiation of treatment in systolic BP was 3 mm Hg and diastolic BP was 3.2 mm Hg, as compared to no change in the placebo group. There were no dose-related changes in systolic and diastolic blood pressure observed. In adult patients exposed to one-year, open-label treatment of levomilnacipran (doses range from 40 mg to 120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg. In short-term, placebo- and active-controlled MDD studies in pediatric patients 7 years to less than 18 years of age, treatment with levomilnacipran was associated with the occurrence of new-onset hypertension (two systolic and/or diastolic BP measurements in the stage I hypertension range and/or one measurement in the stage II range) in 36.2% of treated patients compared with 20.7% of patients randomized to placebo. Elevations in either systolic or diastolic BP leading to measures at or above the stage II hypertension threshold occurred in 12.1% of pediatric patients treated with levomilnacipran and 7.5% of patients randomized to placebo. Sustained hypertension (three or more consecutive systolic or diastolic BP measurements at or above the stage I hypertension threshold) occurred in 15% of pediatric patients treated with levomilnacipran and 4% of patients randomized to placebo. The safety and effectiveness of levomilnacipran have not been established in pediatric patients for the treatment of MDD. In the short-term, placebo-controlled studies in adults, 11.6% of patients met orthostatic hypotension criteria (SBP or DBP) in the levomilnacipran group compared to 9.7% in the placebo group. Orthostatic reductions of blood pressure ≥ 10 mm Hg in DBP occurred in 5.8%, 6.1% and 9.8% of levomilnacipran-treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients. Concomitant use of levomilnacipran with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of levomilnacipran on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Levomilnacipran should be used with caution in these patients. 5.4 Elevated Heart Rate SNRIs, including levomilnacipran, have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with levomilnacipran. For patients who experience a sustained increase in heart rate while receiving levomilnacipran, discontinuation or other appropriate medical intervention should be considered. In short-term clinical studies, levomilnacipran treatment was associated with a mean increase in heart rate of 7.4 beats per minute (bpm) compared to a mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in levomilnacipran-treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm. Levomilnacipran has not been systematically evaluated in patients with a cardiac rhythm disorder. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake, including levomilnacipran, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1) ] . Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of levomilnacipran and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1) ] . 5.6 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including levomilnacipran may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including levomilnacipran, in patients with anatomically narrow angles. 5.7 Urinary Hesitation or Retention The noradrenergic effect of SNRIs including levomilnacipran, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of levomilnacipran-treated patients receiving doses of 40, 80 and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of levomilnacipran in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with levomilnacipran, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered. 5.8 Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in 0.2% of levomilnacipran-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. Prior to initiating treatment with levomilnacipran, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.9 Seizures One case of seizure has been reported in pre-marketing clinical studies with levomilnacipran. Levomilnacipran has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Levomilnacipran should be prescribed with caution in patients with a seizure disorder. 5.10 Discontinuation Syndrome There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor patients for these symptoms when discontinuing levomilnacipran. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see Dosage and Administration (2.4) ] . 5.11 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including levomilnacipran. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Levomilnacipran should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.12 Sexual Dysfunction Use of SNRIs, including levomilnacipran, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of levomilnacipran and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.