Levomilnacipran (F2695; Fetzima), the S-enantiomer of Milnacipran, is an antidepressant approved for the treatment of major depressive disorder in the United States. Milnacipran, a medication used in the clinical treatment of fibromyalgia, is a potent inhibitor of both norepinephrine transporter (NET) and norepinephrine transporter (SERT) with IC50 of 77 nM and 420 nM, respectively. Milnacipran is mainly excreted in the urine as the parent and glucoronide (> 80%), and only a small fraction (< 10%) is metabolized via N-de-ethylation by the CYP3A4 enzyme. Milnacipran at high concentration can inhibit certain ligand-gated ion-channel (LGIC) receptors, including NMDA, 5-HT3A and nACh receptors, with IC50 of 58.4 μM, 185 μM, 14.3 μM.

Physicochemical Properties

Molecular Formula	C15H23CLN2O
Molecular Weight	282.8089
Exact Mass	282.149
CAS #	175131-60-9
Related CAS #	Milnacipran hydrochloride;101152-94-7;Milnacipran;92623-85-3;Milnacipran-d5 ((1S-cis) hydrochloride)
PubChem CID	6917778
Appearance	White to off-white solid powder
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	5
Heavy Atom Count	19
Complexity	295
Defined Atom Stereocenter Count	2
SMILES	Cl[H].O=C([C@@]1(C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])[C@@]1([H])C([H])([H])N([H])[H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H]
InChi Key	XNCDYJFPRPDERF-NQQJLSKUSA-N
InChi Code	InChI=1S/C15H22N2O.ClH/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H31H/t13-,15+/m0./s1
Chemical Name	(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide;hydrochloride
Synonyms	F2695 F 2695 F-2695 F2695 hydrochloride Levomilnacipran Levomilnacipran HCl Fetzima.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Toxicity/Toxicokinetics	Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Levomilnacipran has not been studied in nursing mothers. However, the racemic form of milnacipran has low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants. Until more data become available, levomilnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Monitor breastfed infants for agitation, irritability, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Specific published information on levomilnacipran was not found as of the revision date. An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified. A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking milnacipran. In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
References	Bioorg Med Chem Lett.2008 Feb 15;18(4):1346-9;Psychopharmacology (Berl).2004 Sep;175(2):241-6;Psychopharmacology (Berl).2002 Jul;162(3):323-32.
Additional Infomation	The (1S,2R)-isomer of milnacipran that is used for the treatment of MAJOR DEPRESSIVE DISORDER. See also: Levomilnacipran (has active moiety); Milnacipran Hydrochloride (annotation moved to).

Solubility Data

Solubility (In Vitro)	H2O : ≥ 50 mg/mL (~176.80 mM)
Solubility (In Vivo)	Solubility in Formulation 1: 100 mg/mL (353.59 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.5359 mL	17.6797 mL	35.3594 mL
	5 mM	0.7072 mL	3.5359 mL	7.0719 mL
	10 mM	0.3536 mL	1.7680 mL	3.5359 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.