Levomilnacipran 120 mg (ER) · Hard-gelatin capsules

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).

The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 mg to 300 mg (2.5 times the maximum recommended dosage of FETZIMA) once daily. Steady-state concentrations of levomilnacipran are predictable from single-dose data. 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.

Absorption — The relative bioavailability of levomilnacipran after administration of FETZIMA was 92% when compared to oral solution. The median time to peak concentration (Tmax) of levomilnacipran is 6-8 hours after oral administration.

Effect of Food — Levomilnacipran concentration was not significantly affected when FETZIMA was administered with food.

Distribution — 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.

Elimination — Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours.

Metabolism — 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.

Excretion — 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 ( 2.3 )].

Clinical Studies — The drug interaction studies for levomilnacipran are summarized in Figure 1.

In vitro Studies — In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp.

In vitro studies have shown that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

Alcohol — An in vitro study indicated increases of levomilnacipran release from FETZIMA extended-release capsules (20, 40, 80, and 120 mg) at 2 hours by approximately 9.5%, 23%, and 56% in the presence of 5%, 20%, and 40% (v/v) alcohol, respectively. Effect of 40% alcohol resulted in nearly complete drug release in 4 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure.

Speci fic Populations — The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented in Figure 2.