FETZIMA^® is a serotonin and norepinephrine reuptake inhibitor

The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of reuptake at serotonin and norepinephrine transporters¹
Nonclinical studies have shown that levomilnacipran is a potent and selective SNRI¹

Pharmacodynamic profile

Levomilnacipran potently inhibits serotonin (5-HT) and norepinephrine reuptake (IC₅₀=16-19 nM and 11 nM, respectively)*¹
- Greater reuptake inhibition of norepinephrine over serotonin was shown in vitro¹
- The clinical significance is unknown
Levomilnacipran lacks significant affinity for any other receptors, ion channels, or transporters tested in vitro, including serotonergic (5HT_1-7), α- and β- adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+, or Cl- channels¹

IC₅₀ measures how much drug is needed to inhibit 50% of the reuptake transporters in vitro. The lower the number, the greater the potency of the drug.¹⁶

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IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.

FETZIMA is not approved for use in pediatric patients.

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.

REFERENCES

1. Fetzima (levomilnacipran) extended-release capsules [package insert]. Irvine, CA: Allergan USA, Inc.; 2017. 2. Asnis GM, Bose A, Gommoll CP, Chen C, Greenberg WM. J Clin Psychiatry. 2013;74(3):242-248. 3. Bakish D, Bose A, Gommoll C, et al. J Psychiatry Neurosci. 2014;39(1):40-49. 4. Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV. J Clin Psychopharmacol. 2014;34(1):47-56. 5. World Health Organization. The Global Burden of Disease: 2004 Update. Geneva, Switzerland: World Health Organization; 2008. 6. Major Depression. National Institute of Mental Health website. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Updated November 2017. Accessed February 8, 2018. 7. National Survey on Drug Use and Health. Treatment for past year depression among adults. The NSDUH Report. Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; January 3, 2008. http://www.samhsa.gov/data/2k8/depression/depressionTX.pdf. Accessed January 22, 2018. 8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013. 9. Knoth RL, Bolge SC, Kim E, Tran QV. Am J Manag Care. 2010;16(8): e188-e196. 10. Kessler RC, Berglund P, Demler O, et al. JAMA. 2003;289(23): 3095–3105. 11. Montgomery SA, Asberg M. Br J Psychiatry. 1979;134(4):382-389. 12. Sheehan DV, Harnett-Sheehan K, Raj BA. Int Clin Psychopharmacol. 1996;11(suppl 3):89-95. 13. Data on file. Allergan, Inc. 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000. 15. Mago R, Forero G, Greenberg WM, Gommoll C, Chen C. Clin Drug Investig. 2013;33(10):761-771. 16. Preskorn SH. Basic neuropharmacology of SSRIs. In: Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. 1st ed. Caddo, OK: Professional Communications, Inc; 1996.

Prescribing Information| About Allergan| Legal Policy| Privacy Policy| Contact Us

Prescribing Information

About Allergan|Legal Policy

Privacy Policy|Contact Us

For additional information about FETZIMA^®, call Allergan Medical Information toll-free at 800-678-1605.

Allergan^® and its design are trademarks of Allergan, Inc.

FETZIMA^® and its design are registered trademarks of Pierre Fabre Medicament S.A.S.

© 2018 Allergan. All rights reserved.

The information provided in this site is intended for U.S. healthcare professionals only. The products described on this site may have different product labeling in countries outside of the United States.

FTZ72369_v4 02/18

IMPORTANT SAFETY INFORMATION

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IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.

FETZIMA is not approved for use in pediatric patients.

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.