|Other names||Levomilnacipran hydrochloride|
|Drug class||Serotonin–norepinephrine reuptake inhibitor (SNRI)|
|By mouth (capsules)|
|Typical dose||20 to 120 mg OD|
|Metabolism||Liver (primarily by CYP3A4)|
|Elimination half-life||12 hours|
|Chemical and physical data|
|Molar mass||246.354 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Levomilnacipran, sold under the brand name Fetzima, is an antidepressant used to treat major depressive disorder. While not approved for fibromyalgia, the similar medication milnacipran is. It is taken by mouth.
Common side effects include nausea, constipation, increased sweating, sexual dysfunction, and palpitations. Other side effects may include suicide in those under 25 years, serotonin syndrome, high blood pressure, bleeding, mania, and urinary retention. Safety in pregnancy is unclear. It is a serotonin–norepinephrine reuptake inhibitor (SNRI) and an enantiomer of milnacipran.
Levomilnacipran was approved for medical use in the United States in 2013 and Canada in 2015. Approval was rejected in Australia in 2016 and has not been applied for in Europe. In the United States it cost about 430 USD per month as of 2021.
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.
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.
Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine. 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. The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though also increased side effects.
Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites. 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. As such, levomilnacipran is an NMDA receptor antagonist at high concentrations.
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.
Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%. It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4, 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. Levomilnacipran is excreted in urine.
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