Milnacipran (Savella) is the SNRI approved for fibromyalgia only, not for depression. It is properly referred to as an antidepressant and is approved for depression in some other countries. It has not shown robust antidepressant efficacy.
At the usual maintenance dose milnacipran is a “balanced” SNRI that enhances serotonin and norepinephrine activity by similar magnitude. At lower doses, e.g., 25 mg BID, noradrenergic effects are more pronounced than serotonergic effects.
Milnacipran is fairly well tolerated, with fewer gastrointestinal issues than SSRIs. Side effects that are more prominent with milnacipran (compared to SSRIs) include dizziness, sweating, and urinary hesitancy.
Levomilnacipran (Fetzima), the pure L-enantiomer of milnacipran, is FDA-approved for depression.
Levomilnacipran (Fetzima), released in 2013, is the pure L-enantiomer of milnacipran (Savella). Fetzima will be expensive until the patent expires in 2031.
Compared to other SNRIs, levomilnacipran enhances norepinephrine >> serotonin, making it more stimulating. By contrast, milnacipran is a “balanced” SNRI that enhances serotonin and norepinephrine activity by similar magnitude at the usual maintenance dose.
Levomilnacipran causes no weight gain. The most relevant side effect is nausea, especially as treatment is initiated. This why the dose should be titrated. Dose dependent urinary retention (5%) and tachycardia and may occur. It increases heart rate by an average of 7 beats/minute, which is a noradrenergic effect.
Levomilnacipran was found effective in patients over age 60, a population that is generally resistant to antidepressants.
It reaches peak serum concentration about 7 hours after ingestion. Half-life is about 12 hours. Kinetic interactions are unlikely to be clinically significant.
Of 56 single-drug exposures to milnacipran reported to Poison Control, there were no deaths or major serious outcomes, although this is a small sample size (Nelson & Spyker, 2017).
Dosing: Start 20 mg QD x 2 days, then increase to 40 mg QD. This can be accomplished with the 28-day starter pack that contains #2 of 20 mg caps and #26 of 40 mg caps. FDA maximum is 120 mg QD if renal function is normal. Do not use if severe renal impairment. Do not exceed 80 mg/day in the presence of a strong 3A4 inHibitor (e.g., ketoconazole, clarithromycin, ritonavir). Taper gradually to discontinue.