Pharmacology Update
Levomilnacipran Extended-Release Capsules (Fetzima™?)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A new serotonin and norepinephrine reuptake inhibitor (SNRI) has been approved by the FDA for the treatment of major depressive disorder (MDD). Levomilnacipran is the more active (1S, 2R) enantiomer of the racemic product, milnacipran. Milnacipran is currently approved for the treatment of fibromyalgia. Levomilnacipran has much higher selectivity for norepinephrine vs serotonin compared to duloxetine or venlafaxine. It is licensed from Pierre Fabre Medicament in France and marketed by Forest Pharmaceuticals as Fetzima.
Indications
Levomilnacipran is indicated for the treatment of MDD.1
Dosage
The recommended initial dose is 20 mg once daily for 2 days, then increased to 40 mg once daily. The dose may be increased by 40 mg increments mg once daily after 2 or more days if tolerated.1 The maximum dose is 120 mg daily. The maximum dose for patients with moderate renal impairment is 80 mg once daily and for severe impairment, 40 mg once daily. The capsule should be taken whole at about the same time each day.
Levomilnacipran is available as 20 mg, 40 mg, 80 mg, and 120 mg capsules.
Potential Advantages
Levomilnacipran is predominately a reuptake inhibitor of norepinephrine relative to serotonin (10 fold).1 In contrast, venlafaxine is predominately a serotonin reuptake inhibitor (30 × higher), duloxetine to a lesser degree (10-fold selectivity).2 On the other hand, milnacipran has a 1:1 balance between the two neurotransmitters. With the exception of ketoconazole, levomilnacipran has no drug interactions with the CYP450 isoenzyme system, P-glycoprotein, or the organic anion transporters.1
Potential Disadvantages
The most common adverse events reported were headache, nausea, constipation, heart rate increase, dry mouth, and hyperhidrosis.1-3In both short-term studies and open-label treatment up to 1 year, there was an increase in systolic and diastolic blood pressure of 3-4 mmHg.1 Levomilnacipran carries the same warning as other antidepressants (e.g., suicidal thoughts and behavior).
Comments
The efficacy and safety of levomilnacipran in MDD were evaluated in three 8-week, randomized, double-blind, placebo-controlled studies in adult subjects with MDD.1,2 Two were fixed-dose studies, 40 mg, 80 mg, 120 mg, or placebo (study 1) and 40 mg, 80 mg, or placebo (study 2). The third study (study 3) was a flexible-dose study where subjects were titrated up to 120 mg based on efficacy and/or tolerability. The primary efficacy endpoint was the least square mean change in Montgomery-Asberg Depression Rating Scale (MADRS) at week 8 compared to baseline. The secondary efficacy endpoint was the Sheehan Disability Scale. Analysis was based on modified intent-to-treat (i.e., one or more dose of study drug taken and one or more postbaseline MADRS score recorded).2 The number of subjects ranged from 176-188 per group in the fixed-dose studies and 217 each for the flexible-dose study. Baseline MADRS scores were approximately 36, 31, and 35 for each study, respectively. A score of 35 or higher is considered severe depression.5 In both fixed-dose studies, all strengths were statistically better than placebo. The placebo-subtracted least mean square changes (95% confidence interval) in MADRS were -3.2 (-5.9, -0.5) and -3.3 (-5.5, -1.1) for the 40 mg dose, -4.0 (-6.7, -1.3) and -3.1 (-5.3, -1.0) for 80 mg, and -4.9 (-7.6, -2.1) for the 120 mg dose. The MADRS response rate (> 50% total score reduction) was statistically different from placebo only for the 120 mg dose (41.5%) compared to placebo (29.1%).3 However, a 2-point difference in MADRS score of 2 or higher is considered clinically relevant.3 Statistical superiority was also seen with the Sheehan Disability functional impairment total score.1 In the flexible-dose study, the overall placebo-subtracted mean change in MADRS at week 8 was -3.1 (-5.3, -0.9).1 The end of treatment distributions of doses were 21% (40 mg), 34% (80 mg), and 44% (120 mg). There was no statistical difference in MADRS remission rates for any dose compared to placebo.3 However, 8 weeks may not be sufficient time to truly assess remission.
Clinical Implications
Levomilnacipran is the newest SNRI approved for depression. It has a higher selectively for norepinephrine uptake than other SNRIs, including the racemic milnacipran. While it provides another option, its role in the treatment of depression remains to be determined. The choice of antidepressants is generally based on anticipated side effects, potential drug interactions, and cost.4First-line drugs include SSRIs, SNRIs, mirtazapine, and bupropion. The cost of levomilnacipran was not available at the time of this review.
References
1. Fetzima Prescribing Information. New York, NY: Forest Pharmaceuticals; July 2013.
2. Montgomery SA. Tolerability of serotonin norepinephrine reuptake inhibitor antidepressants. CNS Spectr 2008;13(7 Suppl 11):27-33.
3. Asnis GM, et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: A phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2013;74: 242-248.
4. Muller MJ, et al. Moderate and severe depression. Gradations for the Montgomery-Asberg Depression Rating Scale. J Affect Disord 2000;60:137-140.
5. http://www.guideline.gov/content.aspx?id=24158#Section420. Accessed August 20, 2013.
