Levomilnacipran

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 transporters. Non-clinical studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

• FETZIMA ® is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )]. Limitation of Use: FETZIMA is not approved for the management of fibromyalgia.ICD-10: F32.9

• FETZIMA is contraindicated: in patients with hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation. with the use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated because of an increased risk of serotonin syndrome.contraindicated

Recommended dosage: 40 mg to 120 mg once daily with or without food ( 2.1 ). Initial dosage is 20 mg once daily for 2 days and then increase to 40 mg once daily ( 2.1 ). Based on clinical response and tolerability, increase dose in increments of 40 mg at intervals of 2 or more days ( 2.1 ). The maximum recommended dosage is 120 mg once daily ( 2.1 ). Take capsules whole; do not open, chew or crush ( 2.1 ) Renal impairment ( 2.3 ) : ○ Severe renal impairment: Maximum recommended dosage is 40 mg once daily. ○ Moderate renal impairment: Maximum recommended dosage is 80 mg once daily. Discontinuation : Reduce dose gradually whenever possible ( 2.4 ) 2.1 Recommended Dosage The recommended dosage range for FETZIMA is 40 mg to 120 mg once daily, with or without food. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on clinical response and tolerability, FETZIMA may be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dosage is 120 mg once daily. Take FETZIMA at approximately the same time each day. Swallow FETZIMA whole; do not open, chew, or crush the capsule. 2.2 Screen for Bipolar Disorder Prior to Starting FETZIMA Prior to initiating treatment with FETZIMA or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.8 ) ] . 2.

Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue FETZIMA and serotonergic agents and initiate supportive treatment ( 5.2 ). Elevated Blood Pressure and Heart Rate : Control hypertension before initiating therapy with FETZIMA. 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 ). A ngle C losure 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 FETZIMA 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: FETZIMA may cause symptoms of sexual dysfunction ( 5.12 ) .

The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see Contraindications ( 4 )] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Elevated Blood Pressure [see Warnings and Precautions ( 5.3 )] Elevated Heart Rate [see Warnings and Precautions ( 5.4 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Angle Closure Glaucoma [see Warnings and Precautions ( 5.6 )] Urinary Hesitation or Retention [see Warnings and Precautions ( 5.7 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8 )] Seizure [see Warnings and Precautions ( 5.9 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.10 )] Hyponatremia [see Warnings and Precautions ( 5.11 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Pregnancy : Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants . Risk Summary Based on data from 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 Warnings and Precautions ( 5.5 ) and Clinical Considerations] . The available data on FETZIMA use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including FETZIMA, during pregnancy (see Clinical Considerations ).

Metabolism

The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 mg to 300 mg (2.5 times the maximum recommended dosage of FETZIMA) once daily. Steady-state concentrations of levomilnacipran are predictable from single-dose data.

10.1 Human Experience There is limited clinical experience with FETZIMA overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. 10.2 Management of Overdose No specific antidotes for FETZIMA are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.

• Jul 25, 2013NDANDA204168Abbvie

1. 1Off Label Use33318%
2. 2Drug Ineffective25113%
3. 3Pain21511%
4. 4Vomiting21211%
5. 5Memory Impairment19510%
6. 6Hypoaesthesia1849.8%
7. 7Paraesthesia1849.8%
8. 8Abdominal Pain Upper1839.7%
9. 9Gastrooesophageal Reflux Disease1759.3%
10. 10Migraine1749.3%
11. 11Drug Intolerance1678.9%
12. 12Taste Disorder1608.5%
13. 13Epilepsy1598.5%
14. 14Blepharospasm1588.4%
15. 15Nausea1457.7%

Recent PubMed references pinned to Levomilnacipran as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

• Levomilnacipran ameliorates lipopolysaccharide-induced depression-like behaviors and suppressed the TLR4/Ras signaling pathway.
  International immunopharmacology · 2023 · Li S, Zhu Z, Lan T, et al.
  PMID 37413934DOI 10.1016/j.intimp.2023.110595
• Levomilnacipran for Negative Symptom Domain Schizophrenia.
  The primary care companion for CNS disorders · 2021 · Naguy A
  PMID 34890499DOI 10.4088/PCC.20l02873
• Cost-effectiveness of vortioxetine compared with levomilnacipran and vilazodone in patients with major depressive disorder switching from an initial antidepressant.
  Expert review of pharmacoeconomics & outcomes research · 2021 · Atsou K, Ereshefsky L, Brignone M, et al.
  PMID 33307885DOI 10.1080/14737167.2021.1855979
• About the Misleading Use of Stereodescriptors in Labeling the Stereoisomers of Milnacipran and Levomilnacipran.
  Journal of clinical psychopharmacology · 2019 · Baumann P
  PMID 31688383DOI 10.1097/JCP.0000000000001116
• Levomilnacipran: More of the Same?
  The primary care companion for CNS disorders · 2019 · Gautam M, Kaur M, Jagtap P, et al.
  PMID 31509357DOI 10.4088/PCC.19nr02475
• Cortical thickness increases with levomilnacipran treatment in a pilot randomised double-blind placebo-controlled trial in late-life depression.
  Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society · 2020 · Krause-Sorio B, Kilpatrick L, Siddarth P, et al.
  PMID 31332902DOI 10.1111/psyg.12475
• Relapse prevention with levomilnacipran ER in adults with major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study.
  Depression and anxiety · 2019 · Durgam S, Chen C, Migliore R, et al.
  PMID 30675739DOI 10.1002/da.22872
• Measures of suicidality in phase 3 clinical trials of levomilnacipran ER in adults with major depressive disorder.
  CNS spectrums · 2017 · Thase ME, Gommoll C, Chen C, et al.
  PMID 28521846DOI 10.1017/S1092852916000663

The 10 most recently updated of 74 ClinicalTrials.gov registrations naming Levomilnacipran as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Adding Neuromodulation Technique to Cognitive Behavior Therapy on Fibromyalgia in Postmenopausal Women
  Completed · Interventional · 60 enrolled · Cairo University
  NCT07533487updated 2026-06-10
• Evaluation of the Initial Prescription of Ketamine and Milnacipran in Depression in Patients With a Progressive Disease
  Completed · Phase 2 · Phase 3 · Interventional · 42 enrolled · University Hospital, Lille
  NCT02783430updated 2025-12-16
• Efficacy and Safety Study of Levomilnacipran Hydrochloride Extended-Release Capsules in Major Depressive Disorder
  Completed · Phase 3 · Interventional · 392 enrolled · Zhejiang Huahai Pharmaceutical Co., Ltd.
  NCT07253207updated 2025-11-28
• Clemastine for Improving White Matter and Boosting Antidepressant Response in Late-life Depression
  Not yet recruiting · Phase 2 · Interventional · 80 enrolled · University of Illinois at Chicago
  NCT06591091updated 2025-09-04
• A Study to Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 Versus Quetiapine Extended-Release as Adjunctive Therapy to Antidepressants in Adult Participants With Major Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy
  Completed · Phase 2 · Interventional · 107 enrolled · Janssen Research & Development, LLC
  NCT03321526updated 2025-04-29
• Neural Mechanisms of Monoaminergic Engagement in Late-life Depression Treatment Response (NEMO)
  Completed · Phase 4 · Interventional · 57 enrolled · Howard Aizenstein
  NCT03128021updated 2025-03-10
• Effect of Peanut Ball Use ın Prımarıes on Labor Paın, Duratıon of Labor Anxıety and
  Active not recruiting · Interventional · 108 enrolled · Ayşe FİLİZ
  NCT06804577updated 2025-02-03
• Effect of Foot Massage Performed to the Mother After Bırth on Breastfeedıng Success, Sleep Qualıty and Newborn Stress
  Active not recruiting · Interventional · 70 enrolled · Melek Nur KEÇELİ
  NCT06786481updated 2025-01-22
• The Savella Pregnancy Registry
  Terminated · Observational · 350 enrolled · Syneos Health
  NCT01026077updated 2025-01-08
• Comparison of Ba-Duan-Jin and Pregabalin in Patients with Fibromyalgia
  Completed · Interventional · 104 enrolled · Guang'anmen Hospital of China Academy of Chinese Medical Sciences
  NCT03797560updated 2024-10-24

CPIC-curated drug–gene pairs for Levomilnacipran. Levels describe the strength of curated evidence and guideline status — never a recommendation to test or to adjust therapy.

• HTR2ACPIC C
  CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants
• SLC6A4CPIC C
  CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants

Frequently asked questions

How does Levomilnacipran work?

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 transporters. Non-clinical studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

What is Levomilnacipran used for?

According to FDA labeling, Levomilnacipran carries indications including: FETZIMA ® is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )]. Limitation of Use: FETZIMA is not approved for the management of fibromyalgia.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Levomilnacipran?

Levomilnacipran is classified as Other antidepressants, Serotonin and Norepinephrine Reuptake Inhibitor, Monoamine Oxidase Inhibitors, Norepinephrine Uptake Inhibitors, Serotonin Uptake Inhibitors, Increased Central Nervous System Norepinephrine Activity, Increased Central Nervous System Serotonin Activity.

What are the brand names for Levomilnacipran?

Levomilnacipran is marketed under brand names including Fetzima.

What are the contraindications for Levomilnacipran?

Levomilnacipran labeling lists contraindications including: FETZIMA is contraindicated: in patients with hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation. with the use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated because of an increased risk of serotonin syndrome.. Always consult the full prescribing information and a clinician.