IMPORTANT SAFETY INFORMATION

Contraindications

• FETZIMA is contraindicated in patients with a hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation.
• The use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated due to an increased risk of serotonin syndrome. The use of FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
  Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated due to an increased risk of serotonin syndrome.

Warnings and Precautions

• Suicidal Thoughts and Behavior: All patients being treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when increasing or decreasing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need to monitor patients daily. Prescriptions for FETZIMA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
• Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms. If symptoms of serotonin syndrome occur, discontinue FETZIMA immediately and initiate supportive treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
• Increased Blood Pressure: SNRIs, including FETZIMA, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing hypertension should be controlled before initiating treatment with FETZIMA. Use with caution in patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Concomitant use of FETZIMA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure, discontinuation or other appropriate medical intervention should be considered.
• Increased Heart Rate: SNRIs, including FETZIMA, have been associated with an increase in heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate, discontinuation or other appropriate medical intervention should be considered.
• Increased Risk of Bleeding: SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events, some serious. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to this risk.
• Angle-closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. The pupillary dilation that occurs following use of many antidepressant drugs including FETZIMA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
• Urinary Hesitation or Retention: FETZIMA can affect urethral resistance. In clinical studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA-treated patients receiving doses of 40, 80, and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised when using FETZIMA in patients prone to obstructive urinary disorders.
• Activation of Mania/Hypomania: Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. As with all antidepressants, FETZIMA should be used cautiously in patients with a history or family history of bipolar disorder, mania or hypomania. Prior to initiating treatment with FETZIMA, patients should be adequately screened to determine if they are at risk for bipolar disorder. FETZIMA is not approved for use in treating bipolar depression.
• Seizures: FETZIMA should be prescribed with caution in patients with a seizure disorder.
• Discontinuation Syndrome: Discontinuation symptoms, some serious, have been reported with discontinuation of serotonergic antidepressants such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients when discontinuing FETZIMA. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate.
• Hyponatremia: Advise patients that if they are treated with diuretics or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking FETZIMA. Although no cases of hyponatremia resulting from FETZIMA treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Adverse Reactions

The most commonly observed adverse reactions in MDD patients treated with FETZIMA in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: nausea (17% vs 6%), constipation (9% vs 3%), hyperhidrosis (9% vs 2%), heart rate increased (6% vs 1%), erectile dysfunction (6% vs 1%), tachycardia (6% vs 2%), vomiting (5% vs 1%), and palpitations (5% vs 1%).

Please also see the full Prescribing Information, including Boxed Warning.