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Trade namesFetzima
Other namesLevomilnacipran hydrochloride
  • (1S,2R)-2-(Aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide
Clinical data
Drug classSerotonin–norepinephrine reuptake inhibitor (SNRI)[1]
Main usesDepression[1]
Routes of
By mouth (capsules)
Typical dose20 to 120 mg OD[1]
External links
Legal status
  • In general: ℞ (Prescription only)
Protein binding22%[3]
MetabolismLiver (primarily by CYP3A4)[4]
Elimination half-life12 hours[4]
Chemical and physical data
Molar mass246.354 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@]1(C[C@H]1CN)C2=CC=CC=C2
  • InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m0/s1 ☒N

Levomilnacipran, sold under the brand name Fetzima, is an antidepressant used to treat major depressive disorder.[1] While not approved for fibromyalgia, the similar medication milnacipran is.[1] It is taken by mouth.[1]

Common side effects include nausea, constipation, increased sweating, sexual dysfunction, and palpitations.[1] Other side effects may include suicide in those under 25 years, serotonin syndrome, high blood pressure, bleeding, mania, and urinary retention.[1] Safety in pregnancy is unclear.[5] It is a serotonin–norepinephrine reuptake inhibitor (SNRI) and an enantiomer of milnacipran.[1]

Levomilnacipran was approved for medical use in the United States in 2013 and Canada in 2015.[1][6] Approval was rejected in Australia in 2016 and has not been applied for in Europe.[6] In the United States it cost about 430 USD per month as of 2021.[7]

Medical uses

A bottle of Fetzima.


The FDA approved levomilnacipran for the treatment of major depressive disorder based on the results of one 10-week phase II and four 8-week phase III clinical trials. Four of the five trials demonstrated a statistically significant superiority to placebo as measured by the Montgomery–Åsberg Depression Rating Scale. Superiority to placebo was also demonstrated by improvement in the Sheehan Disability Scale.


It is taken at a dose of 20 to 120 mg once per day.[1]

Side effects

Side effects seen more often with levomilnacipran than with placebo in clinical trials included nausea, dizziness, sweating, constipation, insomnia, increased heart rate and blood pressure, urinary hesitancy, erectile dysfunction and delayed ejaculation in males, vomiting, tachycardia, and palpitations.[8][9]



Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.[10][11][12] To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2.[10] The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear,[10] but may include improved effectiveness, though also increased side effects.[11][12][13]

Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites.[14] However, it does show some affinity for the dizocilpine (MK-801/PCP) site of the NMDA receptor (Ki = 1.7 μM), and has been found to inhibit NR2A and NR2B subunit-containing NMDA receptors with respective IC50 values of 5.62 and 4.57 μM.[14] As such, levomilnacipran is an NMDA receptor antagonist at high concentrations.[14]

Levomilnacipran has recently been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimer's disease.[15]


Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%.[2][3] It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4,[4] thereby making the medication susceptible to grapefruit-drug interactions. The drug has an elimination half-life of approximately 12 hours, allowing for once-daily administration.[4] Levomilnacipran is excreted in urine.[4]


Levomilnacipran was developed by Forest Laboratories and Pierre Fabre Group, and was approved by the Food and Drug Administration in July 2013.[8]


  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Levomilnacipran Monograph for Professionals". Drugs.com. Archived from the original on 19 January 2021. Retrieved 21 November 2021.
  2. 2.0 2.1 "Fetzima (levomilnacipran) Extended-Release Capsules, for Oral Use. Full Prescribing Information". Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045 USA. July 2014. Archived from the original on 17 August 2016. Retrieved 2 September 2016.
  3. 3.0 3.1 Alan F. Schatzberg; Charles B. Nemeroff (10 May 2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 533–. ISBN 978-1-61537-122-8.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Stephen M. Stahl (31 March 2017). Prescriber's Guide: Stahl's Essential Psychopharmacology. Cambridge University Press. pp. 373–376. ISBN 978-1-108-22874-9.
  5. "Levomilnacipran (Fetzima) Use During Pregnancy". Drugs.com. Archived from the original on 1 December 2020. Retrieved 21 November 2021.
  6. 6.0 6.1 "Australian Public Assessment Report for Levomilnacipran (as hydrochloride)" (PDF). 2016. Archived (PDF) from the original on 21 November 2021. Retrieved 21 November 2021.
  7. "Fetzima Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 30 January 2024. Retrieved 21 November 2021.
  8. 8.0 8.1 Citrome L (November 2013). "Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant--what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?". Int. J. Clin. Pract. 67 (11): 1089–104. doi:10.1111/ijcp.12298. PMID 24016209. S2CID 205185145.
  9. Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV (February 2014). "A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder". J Clin Psychopharmacol. 34 (1): 47–56. doi:10.1097/JCP.0000000000000060. PMC 4047313. PMID 24172209.
  10. 10.0 10.1 10.2 Sansone RA, Sansone LA (March 2014). "Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison". Innov Clin Neurosci. 11 (3–4): 37–42. PMC 4008300. PMID 24800132.
  11. 11.0 11.1 Saraceni MM, Venci JV, Gandhi MA (December 2013). "Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder". J Pharm Pract. 27 (4): 389–395. doi:10.1177/0897190013516504. PMID 24381243. S2CID 41502983.
  12. 12.0 12.1 Kasper S, Pail G (2010). "Milnacipran: a unique antidepressant?". Neuropsychiatr Dis Treat. 6: 23–31. doi:10.2147/NDT.S11777. PMC 2938282. PMID 20856597.
  13. Bradley AJ, Lenox-Smith AJ (August 2013). "Does adding noradrenaline reuptake inhibition to selective serotonin reuptake inhibition improve efficacy in patients with depression? A systematic review of meta-analyses and large randomised pragmatic trials". J. Psychopharmacol. (Oxford). 27 (8): 740–58. doi:10.1177/0269881113494937. PMID 23832963. S2CID 36890464.
  14. 14.0 14.1 14.2 Hair P, Cameron F, Garnock-Jones KP (2013). "Levomilnacipran extended release: first global approval". Drugs. 73 (14): 1639–45. doi:10.1007/s40265-013-0116-1. PMID 24000002. S2CID 965954.
  15. Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S (2014). "Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1". CNS Neurol Disord Drug Targets. 13 (8): 1427–31. doi:10.2174/1871527313666141023145703. PMID 25345508.

External links

External sites: