Levomilnacipran: New SNRI for major depressive disorder

New drug

Levomilnacipran (Fetzima—Forest Laboratories, Pierre Fabre Laboratories), a once-daily serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder (MDD) in adults, has received FDA approval. Although the exact mechanism of action is unknown, levomilnacipran is thought to enhance the effect of serotonin and norepinephrine in the central nervous system.

Safety, efficacy data

Safety and efficacy of levomilnacipran were evaluated in three 8-week randomized, double-blind, placebo-controlled studies at doses of 40–120 mg once daily in 2,673 adults (aged 18–78 years) diagnosed with MDD. Among the 2,673 levomilnacipran-treated patients, 1,583 received levomilnacipran in short-term, placebo-controlled studies, and 825 patients continued from short-term studies into a 1-year, open-label extension study. 

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 levomilnacipran 40 mg, 80 mg, or 120 mg once daily or placebo. In Study 2, patients received either levomilnacipran 40 mg or 80 mg once daily or placebo. In Study 3, the flexible-dose study, patients received levomilnacipran 40 mg to 120 mg once daily or placebo, with 21%, 34%, and 44% of levomilnacipran patients on 40 mg, 80 mg, and 120 mg, respectively, at the end of treatment. 

Depression symptoms lifted

In all three studies, statistically significant and clinically meaningful improvement in symptoms of depression occurred across all three levomilnacipran dosage strengths once daily compared with placebo as measured by the Montgomery Åsberg Depression Rating Scale total score (primary endpoint) and the Sheehan Disability Scale functional impairment total score (secondary endpoint).

In the short-term placebo-controlled premarketing studies for MDD, 9% of the 1,583 patients who received levomilnacipran (40–120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients in those studies. Nausea was the most common adverse reaction leading to discontinuation in at least 1% of the levomilnacipran-treated patients in the short-term placebo-controlled studies. 

The most commonly observed adverse events in levomilnacipran-treated MDD patients in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation, hyperhidrosis, increased heart rate, erectile dysfunction, tachycardia, vomiting, and palpitations.

Levomilnacipran extended-release capsules will be available to wholesalers in the fourth quarter of 2013, according to the manufacturers.

Patient counseling

Review the Medication Guide with patients. Educate patients and their family members and caregivers about the risk of serious adverse effects with antidepressant use, including an increase in suicidal thoughts or actions within the first few months of treatment. Advise patients to report any changes in mood, behavior, thoughts, or feelings to their health care provider immediately, especially sudden changes when starting or changing the medication. Urge patients to keep all follow-up visits with their health care provider.

Levomilnacipran (Fetzima)

Manufacturers: Forest Laboratories, Pierre Fabre Laboratories

Drug class: Serotonin and norepinephrine reuptake inhibitor

Indication: Treatment of major depressive disorder in adults

Dosage: 40 mg to 120 mg once daily, beginning with 20 mg once daily for 2 days and then 40 mg once daily. Dosage can be increased in increments of 40 mg at intervals of 2 or more days, with 120 mg the maximum recommended dose.

The drug can be taken with or without food. Patients should not open, chew, or crush capsules.

Of note: SNRIs, including levomilnacipran, have been associated with increases in blood pressure and heart rate; both should be measured and monitored before and periodically throughout treatment. 

Serotonin syndrome may occur with selective serotonin reuptake inhibitors (SSRIs) and SNRIs, especially when coadministered with other serotonergic agents. Levomilnacipran should be discontinued if serotonin syndrome occurs.

The drug has not been approved for the treatment of fibromyalgia or for use with pediatric patients.