Levomilnacipran: Difference between revisions

{{Short description|SNRI antidepressant drug}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 451552762

| image = Levomilnacipran.svg

| width = 200

| alt =

| tradename = Fetzima

| Drugs.com = {{drugs.com|monograph|levomilnacipran-hydrochloride}}

| routes_of_administration = [[Oral administration|By mouth]] ([[Capsule (pharmacy)|capsules]])

| ATC_prefix = N06

| ATC_suffix = AX28

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=[[Health Canada]] | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=3 April 2024}}</ref><ref>{{cite web | title=Health Canada New Drug Authorizations: 2015 Highlights | website=[[Health Canada]] | date=4 May 2016 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2015-highlights.html | access-date=7 April 2024}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_NZ = <!-- Class A, B, C -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_EU =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_status = Rx-only

| bioavailability = 92%<ref name="Fetzima PI">{{cite web|title=Fetzima (levomilnacipran) Extended-Release Capsules, for Oral Use. Full Prescribing Information|url=http://www.allergan.com/assets/pdf/fetzima_pi#page=1|publisher=Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045 USA|access-date=2 September 2016|date=July 2014}}</ref>

| protein_bound = 22%<ref name="SchatzbergNemeroff2017" />

| metabolism = Hepatic (primarily by [[CYP3A4]])<ref name="Stahl2017" />

| elimination_half-life = 12 hours<ref name="Stahl2017" />

| excretion = [[Kidney]]<ref name="Stahl2017" />

| IUPHAR_ligand = 7435

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 96847-54-0

| CAS_supplemental =

| KEGG = D10072

| KEGG_Ref = {{keggcite|changed|kegg}}

| PubChem = 6917779

| DrugBank = DB08918

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 5293005

| index2_label = HCl

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = 175131-60-9

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = 371U2ZK31U

| IUPAC_name = (1''S'',2''R'')-2-(Aminomethyl)-''N'',''N''-diethyl-1-phenylcyclopropanecarboxamide

| SMILES = CCN(CC)C(=O)[C@]1(C[C@H]1CN)C2=CC=CC=C2

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = GJJFMKBJSRMPLA-DZGCQCFKSA-N

'''Levomilnacipran''' (brand name '''Fetzima''') is an [[antidepressant]] which was approved in the United States in 2013 for the treatment of [[major depressive disorder]] (MDD) in adults.<ref name="Fetzima PI" /> It is the [[dextrorotation and levorotation|levorotatory]] [[enantiomer]] of [[milnacipran]], and has similar effects and [[pharmacology]], acting as a [[serotonin–norepinephrine reuptake inhibitor]] (SNRI).<ref name="urlPierre Fabre Medicament and Forest Laboratories to Collaborate on Development and Commercialization of F2695 for Depression - FierceBiotech">{{cite web | vauthors = Myers C | date = 22 December 2008 | url = http://www.fiercebiotech.com/press-releases/pierre-fabre-medicament-and-forest-laboratories-collaborate-development-and-commerc-0 | title = Pierre Fabre Medicament and Forest Laboratories to Collaborate on Development and Commercialization of F2695 for Depression | work = FierceBiotech }}</ref><ref name="pmid9725476">{{cite journal | vauthors = Deprez D, Chassard D, Baille P, Mignot A, Ung HL, Puozzo C | title = Which bioequivalence study for a racemic drug? Application to milnacipran | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 23 | issue = 2 | pages = 166–171 | year = 1998 | pmid = 9725476 | doi = 10.1007/bf03189334 | s2cid = 24621735 }}</ref>

==Medical uses==

[[File:Fetzima 1.jpg|thumb|left|150px|A bottle of Fetzima.]]

===Depression===

The FDA approved levomilnacipran for treating major depressive disorder. This approval was based on the results of five [[Clinical trial|clinical trials]]. The trials included one 10-week [[Phases of clinical research#Phase II|phase II]] and four 8-week [[Phase III clinical trials|phase III]]. 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]].

==Side effects==

[[Side effect]]s seen more often with levomilnacipran than with [[placebo]] in clinical trials included [[nausea]], [[dizziness]], [[hyperhidrosis|sweating]], [[constipation]], [[insomnia]], increased [[heart rate]] and [[blood pressure]], [[urinary retention|urinary hesitancy]], [[erectile dysfunction]] and [[delayed ejaculation]] in males, [[vomiting]], [[tachycardia]], and [[palpitation]]s.<ref name="pmid24016209" /><ref name="pmid24172209">{{cite journal | vauthors = Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV | title = A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder | journal = Journal of Clinical Psychopharmacology | volume = 34 | issue = 1 | pages = 47–56 | date = February 2014 | pmid = 24172209 | pmc = 4047313 | doi = 10.1097/JCP.0000000000000060 }}</ref>

==Pharmacology==

===Pharmacodynamics===

Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced [[reuptake inhibitor]]s of [[serotonin]] and [[norepinephrine]].<ref name="pmid24800132">{{cite journal | vauthors = Sansone RA, Sansone LA | title = Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison | journal = Innovations in Clinical Neuroscience | volume = 11 | issue = 3–4 | pages = 37–42 | date = March 2014 | pmid = 24800132 | pmc = 4008300 }}</ref><ref name="pmid24381243">{{cite journal | vauthors = Saraceni MM, Venci JV, Gandhi MA | title = Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder | journal = Journal of Pharmacy Practice | volume = 27 | issue = 4 | pages = 389–395 | date = August 2014 | pmid = 24381243 | doi = 10.1177/0897190013516504 | s2cid = 41502983 }}</ref><ref name="pmid20856597">{{cite journal | vauthors = Kasper S, Pail G | title = Milnacipran: a unique antidepressant? | journal = Neuropsychiatric Disease and Treatment | volume = 6 | issue = Suppl I | pages = 23–31 | date = September 2010 | pmid = 20856597 | pmc = 2938282 | doi = 10.2147/NDT.S11777 | doi-access = free }}</ref> 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.<ref name="pmid24800132" /> The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear,<ref name="pmid24800132" /> but may include improved effectiveness, though also increased side effects.<ref name="pmid24381243" /><ref name="pmid20856597" /><ref name="pmid23832963">{{cite journal | vauthors = Bradley AJ, Lenox-Smith AJ | title = 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 | journal = Journal of Psychopharmacology | volume = 27 | issue = 8 | pages = 740–758 | date = August 2013 | pmid = 23832963 | doi = 10.1177/0269881113494937 | s2cid = 36890464 }}</ref>

Levomilnacipran is [[binding selectivity|selective]] for the [[serotonin transporter|serotonin]] and [[norepinephrine transporter]]s, lacking significant [[affinity (pharmacology)|affinity]] for over 23&nbsp;[[off-target activity|off-target]] [[binding site|site]]s.<ref name="pmid24000002">{{cite journal | vauthors = Hair P, Cameron F, Garnock-Jones KP | title = Levomilnacipran extended release: first global approval | journal = Drugs | volume = 73 | issue = 14 | pages = 1639–1645 | date = September 2013 | pmid = 24000002 | doi = 10.1007/s40265-013-0116-1 | s2cid = 965954 }}</ref> However, it does show some affinity for the [[dizocilpine]] (MK-801/{{abbrlink|PCP|phencyclidine}}) site of the [[NMDA receptor]] (K_i = 1.7&nbsp;μM), and has been found to inhibit [[NR2A]] and [[NR2B]] [[protein subunit|subunit]]-containing NMDA receptors with respective [[IC50|IC₅₀]] values of 5.62 and 4.57&nbsp;μM.<ref name="pmid24000002" /> As such, levomilnacipran is an [[NMDA receptor antagonist]] at high concentrations.<ref name="pmid24000002" />

Levomilnacipran has recently been found to act as an [[enzyme inhibitor|inhibitor]] of [[beta-secretase 1|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]].<ref name="pmid25345508">{{cite journal | vauthors = Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S | title = 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 | journal = CNS & Neurological Disorders Drug Targets | volume = 13 | issue = 8 | pages = 1427–1431 | year = 2014 | pmid = 25345508 | doi = 10.2174/1871527313666141023145703 }}</ref>

===Pharmacokinetics===

Levomilnacipran has a high [[oral administration|oral]] [[bioavailability]] of 92% and a low [[plasma protein binding]] of 22%.<ref name="Fetzima PI" /><ref name="SchatzbergNemeroff2017">{{cite book| vauthors = Norris S, Blier P | chapter = Duloxetine, Milnacipran, and Levomilnacipran | veditors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Association Publishing Textbook of Psychopharmacology| chapter-url = https://books.google.com/books?id=v9wnDwAAQBAJ&pg=PA533 |date=10 May 2017 |publisher=American Psychiatric Pub |isbn=978-1-61537-122-8 |pages=533– }}</ref> It is [[metabolism|metabolized]] in the [[liver]] by the [[cytochrome P450]] [[enzyme]] [[CYP3A4]],<ref name="Stahl2017">{{cite book| vauthors = Stahl SM |title=Prescriber's Guide: Stahl's Essential Psychopharmacology |url= https://books.google.com/books?id=9hssDwAAQBAJ&pg=PA373 |date=31 March 2017|publisher=Cambridge University Press|isbn=978-1-108-22874-9|pages=373–376}}</ref> thereby making the medication susceptible to [[grapefruit-drug interactions]]. The drug has an [[elimination half-life]] of approximately 12&nbsp;hours, allowing for once-daily administration.<ref name="Stahl2017" /> Levomilnacipran is [[excretion|excreted]] in [[urine]].<ref name="Stahl2017" />

==History==

Levomilnacipran was developed by [[Forest Laboratories]] and [[Pierre Fabre Group]], and was approved by the [[Food and Drug Administration]] in July 2013.<ref name="pmid24016209">{{cite journal | vauthors = Citrome L | title = 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? | journal = International Journal of Clinical Practice | volume = 67 | issue = 11 | pages = 1089–1104 | date = November 2013 | pmid = 24016209 | doi = 10.1111/ijcp.12298 | s2cid = 205185145 }}</ref>

{{Reflist}}

== External links ==

* {{Commons category-inline|Levomilnacipran}}

{{Ionotropic glutamate receptor modulators}}

{{Monoamine reuptake inhibitors}}

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