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Fetzima (Levomilnacipran Hydrochloride) - Description and Clinical Pharmacology



The active ingredient of FETZIMA is levomilnacipran, which is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its empirical formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure is:

FETZIMA capsules are intended for oral administration only. Each FETZIMA capsule contains extended-release beads with 23.0, 45.9, 91.8, or 137.8 mg of levomilnacipran hydrochloride equivalent to 20, 40, 80, or 120 mg of levomilnacipran, respectively. Inactive ingredients include sugar spheres, ethylcellulose, talc, povidone, triethyl citrate, hypromellose, and titanium dioxide. Inactive ingredients also include shellac glaze, black iron oxide, yellow iron oxide (20 mg and 40 mg capsules only), and red iron oxide (80 mg and 120 mg capsules only).


Mechanism of Action

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).


Levomilnacipran binds with high affinity to the human serotonin (5-HT) and norepinephrine (NE) transporters (Ki = 11 and 91 nM, respectively) and potently inhibits 5-HT and NE reuptake (IC50 = 16-19 and 11 nM, respectively). Levomilnacipran lacks significant affinity for any other receptors, ion channels or transporters tested in vitro, including serotonergic (5HT1-7), α- and β- adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO).

Cardiovascular Electrophysiology

At a dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc to any clinically relevant extent.


The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 to 300 mg once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. Steady-state concentrations of levomilnacipran are predictable from single-dose data. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours. After daily dosing of FETZIMA 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans.


The relative bioavailability of levomilnacipran after administration of FETZIMA ER was 92% when compared to oral solution. Levomilnacipran concentration was not significantly affected when FETZIMA was administered with food.

The median time to peak concentration (Tmax) of levomilnacipran is 6-8 hours after oral administration.


Levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L; plasma protein binding is 22% over concentration range of 10 to 1000 ng/mL.


Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation with glucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2 [see Drug Interactions (7.4, 7.5)].


Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). The metabolites are inactive [see Dosage and Administration].


Carcinogenesis, Mutagenesis, Impairment of Fertility


Levomilnacipran administered by oral gavage to rats for 2 years and Tg.rasH2 mice for 6 months did not increase the incidence of tumors in either study.

Rats received levomilnacipran at doses up to 90/70 mg/kg/day (the dose was lowered in males after 45 weeks of dosing). The 90 mg/kg/day dose is 7 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis.

Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. This dose is 6 times the MRHD.


Levomilnacipran was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vivo micronucleus assay in rats. Additionally, levomilnacipran was not genotoxic in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation assay.

Impairment of Fertility

When levomilnacipran was administered orally to male and female rats before mating, through mating and up to Day 7 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is 8 times the MRHD.


Treatment of Major Depressive Disorder

The efficacy of FETZIMA for the treatment of major depressive disorder (MDD) was established in three 8-week randomized, double-blind, placebo-controlled studies (at doses 40-120 mg once daily) in adult (18 - 78 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Two of the studies were fixed dose (Study 1 and Study 2) and one study was flexible dose (Study 3).

In Study 1, patients received 40 mg (n = 178), 80 mg (n = 179), or 120 mg (n = 180) of FETZIMA once daily, or placebo (n = 176).  In Study 2, patients received either 40 mg (n = 188) or 80 mg (n = 188) of FETZIMA once daily, or placebo (n = 186).  In the flexible-dose study (Study 3), patients received 40 to 120 mg (n = 217) of FETZIMA once daily, or placebo (n = 217) with 21%, 34%, and 44% of FETZIMA patients on 40 mg, 80 mg, and 120 mg, respectively at the end of their treatment.

In all three studies, FETZIMA demonstrated superiority over placebo in the improvement of depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score (see Table 5). FETZIMA also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale (SDS) functional impairment total score.

Table 5: Summary of Results for the Primary Efficacy Endpoint MADRS

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval unadjusted for multiplicity.

a Difference (drug minus placebo) in least-squares mean change from baseline to endpoint (Week 8).

* Doses statistically significantly superior to placebo.

Study Number Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI)
Study 1
(fixed dose)
FETZIMA (ER 40 mg/day)* 36.0 (4.1) -14.8 (1.0) -3.2 (-5.9, -0.5)
FETZIMA (ER 80 mg/day)* 36.1 (3.9) -15.6 (1.0) -4.0 (-6.7, -1.3)
FETZIMA (ER 120 mg/day)* 36.0 (3.9) -16.5 (1.0) -4.9 (-7.6, -2.1)
Placebo 35.6 (4.5) -11.6 (1.0) --
Study 2
FETZIMA (ER 40 mg/day)* 30.8 (3.4) -14.6 (0.8) -3.3 (-5.5, -1.1)
FETZIMA (ER 80 mg/day)* 31.2 (3.5) -14.4 (0.8) -3.1 (-5.3, -1.0)
Placebo 31.0 (3.8) -11.3 (0.8) --
Study 3 (flexible-dose) FETZIMA (ER 40 - 120 mg/day)* 35.0 (3.6) -15.3 (0.8) -3.1 (-5.3, -0.9)
Placebo 35.2 (3.8) -12.2 (0.8) --

Post-hoc analyses of the relationships between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

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