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Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder Megan M. Saraceni, Jineane V. Venci and Mona A. Gandhi Journal of Pharmacy Practice published online 31 December 2013 DOI: 10.1177/0897190013516504 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/12/31/0897190013516504
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Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder
Journal of Pharmacy Practice 201X, Vol XX(X) 1-7 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013516504 jpp.sagepub.com
Megan M. Saraceni, PharmD candidate1, Jineane V. Venci, PharmD2, and Mona A. Gandhi, PharmD1
Abstract In July 2013, the US Federal Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotoninnorepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy. Keywords levomilnacipran, F2695, major depressive disorder, SNRI, antidepressant, Fetzima
Introduction Major depressive disorder (MDD) is associated with significant functional impairment, morbidity, and mortality.1 Surveys of adults living in the community found that the lifetime prevalence of major depression is 17% in the United States, with rates ranging from 8% to 12% in other countries around the world.2 Affecting more than 14.8 million adults, MDD is a chief cause of disability. Women are more likely to be affected than men and the median age of onset is 32 years.3 According to the World Health Organization predictions, MDD will become the world’s leading cause of disability by the year 2030.1 The exact etiology of depression is unknown and complicated, but there is a general consensus that it entails altered regulation of monoaminergic neurotransmission in the brain.4 Specifically, the monoamine neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA) are thought to be involved.4 The cause of this alteration is controversial; however, drug therapies targeting this imbalance are available. As a major public health concern with huge economic implications, the development of effective treatments for MDD is crucial. Older agents, such as tricyclic compounds, target monoamine transporters to prevent presynaptic reuptake, thus prolonging the duration of action at postsynaptic receptors. The inability of these drugs to selectively target
desired neurotransmitters causes a number of unwanted adverse effects (AEs), such as dry mouth, blurred vision, constipation, urinary retention, fatigue, increased appetite leading to weight gain, and orthostatic hypotension.5 In the United States, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) are now considered first-line pharmacotherapy for MDD in adults, particularly in primary care settings.6 Although SSRIs are generally better tolerated and less dangerous in overdose situations than tricyclic compounds, serotonin-mediated AEs such as nausea and sexual dysfunction frequently prompt discontinuation before an adequate clinical response can occur.7 In July 2013, the US Federal Drug Administration (FDA) approved levomilnacipran extended release (ER; Fetzima) for 1
St John Fisher College Wegmans School of Pharmacy, Rochester, NY, USA Department of Pharmacy, University of Rochester Medical Center, Rochester, NY, USA 2
Corresponding Author: Megan M. Saraceni, St John Fisher College Wegmans School of Pharmacy, 3690 East Ave, Rochester, NY 14618, USA. Email: [email protected]
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the treatment of MDD in adult patients. Levomilnacipran is an active enantiomer of milnacipran, which is approved in the United States for fibromyalgia and in Europe for depression.8 Although levomilnacipran is the fourth SNRI to be approved by the FDA for use in MDD, it has distinctive properties that make it a promising option for patients failing current therapies or unable to tolerate other medications within this class.9 Unlike venlafaxine and duloxetine, levomilnacipran is highly selective for norepinephrine transporters (NETs) that, in theory, may allow it to bypass serotonin-mediated AEs associated with the antidepressants currently available.7,10 Additionally, the ability for levomilnacipran to inhibit reuptake at both NETs and serotonin transporters (SERTs) at therapeutic doses could potentially provide increased efficacy at treating certain symptoms of depression.11 Although venlafaxine and duloxetine are classified as SNRIs, only 5-HT reuptake inhibition is achieved at lower doses, with much higher doses (225 mg daily12,13 and 60 mg daily,14 respectively) needed to inhibit the reuptake of NE.10 The purpose of this article is to provide an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER.
Table 1. Overview of Levomilnacipran SR.10,15 Generic name Trade name Drug class Indication Formulation, dosing, and administration
Adverse reactions
Drug interactions Comparable drugs Advantage
Levomilnacipran Fetzima Serotonin-norepinephrine reuptake inhibitor Major depressive disorder Available as 20, 40, 80, and 120 mg SR capsules Recommended dose: 40 to 120 mg orally once daily The maximum recommended dose is 120 mg orally once daily Taken with or without food; do not open, chew, or crush Nausea, constipation, hyperhidrosis, hypertension, erectile dysfunction, tachycardia, vomiting, diarrhea, and palpitations Strong CYP3A4 inhibitors, such as ketoconazole Duloxetine, venlafaxine, desvenlafaxine Increased potency for norepinephrine reuptake inhibition
Abbreviation: CYP, cytochrome P.
Mechanism of Action Methods An unfiltered search of PubMed, International Pharmaceutical Abstracts, and Google Scholar using the key word levomilnacipran was used to identify relevant information for review. To retrieve all available information on levomilnacipran, neither limits nor inclusion/exclusion criteria were applied. Additional information was obtained from fda.gov and through a comprehensive review of the reference lists of identified articles. Posters and abstracts from scientific meetings, such as the US Psychiatric and Mental Health Congress, the American Psychiatric Association Annual Meeting, and the American Conference on Pharmacometrics, for 2011 through 2013 were also consulted.
Results A total of 47 unique articles were identified through a search of the databases mentioned. Of these, 42 were excluded due to irrelevance to the scope of this article. One poster presented at the American Conference on Pharmacometrics provided pertinent information on levomilnacipran. The remainder of the data came from a review of the reference lists of identified articles and fda.gov.
Indication and Dosage The FDA-approved levomilnacipran ER on July 25, 2013, for the treatment of MDD. Available dosage forms are 20 mg, 40 mg, 80 mg, and 120 mg ER capsules. The medication is to be administered orally once daily with or without food.15 An overview of levomilnacipran ER can be found in Table 1.
Levomilnacipran is a potent and selective SNRI and an active enantiomer of milnacipran. It acts similar to other medications in its class; however, it has a 2-fold greater potency for the inhibition of NE relative to 5-HT reuptake. Levomilnacipran demonstrates a 27 and 17 times higher selectivity for NE reuptake inhibition compared with duloxetine and venlafaxine, respectively.10 Levomilnacipran has no affinity for muscarinic, histaminic, and alpha-1 adrenergic receptors and does not affect monoamine oxidase.10
In Vitro Activity In vitro studies have demonstrated levomilnacipran to be the more active enantiomer of milnacipran. In rat hypothalamic synaptosomes, levomilnacipran was 50 and 13 times more potent in inhibiting NE and 5-HT reuptake than the other enantiomer of milnacipran, F2696. In selectivity assessments, levomilnacipran did not exhibit affinity for 23 other receptors, which allows for the prevention of AEs seen with more traditional, less selective antidepressants. The investigators also found that in mice, levomilnacipran produced antidepressant effects, had antistress/anxiolytic activity, and did not modify spontaneous locomotor activity.10 The results of this in vitro study display that levomilnacipran has a greater potency for NETs compared to the active comparators, duloxetine and venlafaxine.
Pharmacokinetics A population pharmacokinetic model for levomilnacipran ER was developed based on data from 458 healthy subjects in 13 phase I studies and 798 patients with MDD in 3 phase III
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Table 2. Pharmacokinetic Values of Levomilnacipran ER.15,16 Total clearance Elimination half-life Maximum concentrationa Steady state area under the curvea Bioavailability Time to peak concentration Volume of distribution Plasma protein binding
21-29 L/h 12 hours 341 ng/mL 5196 ng hours/mL 92% 6-8 hours 387-472 L 22%
Abbreviation: ER, extended release. a Value following daily dosing of levomilnacipran ER 120 mg.
studies. Doses of levomilnacipran ER formulation ranged from 20 to 300 mg once daily. Based on this observed data, the pharmacokinetics of levomilnacipran ER can be described as a 1compartment pharmacokinetic model with delayed first-order absorption and first-order elimination.16 Creatinine clearance and body weight were the only clinically relevant covariates influencing the pharmacokinetics of levomilnacipran ER. In healthy subjects, mean clearance was 24 L/h. Clearance was decreased in patients with mild, moderate, and severe renal impairment by 20%, 40%, and 58%, respectively. Based on this data, maximum daily doses should not exceed 80 mg in patients with moderate renal impairment or 60 mg in patients with severe renal impairment, and adjusted dose titration schedules may be warranted.16 In healthy subjects, the mean volume of distribution was 495 L. The influence of body weight on the maximum steady state concentration was meager, only resulting in less than a 20% change over the full range in body weight (45-143 kg) observed in the data set. Consequently, no dose adjustment is required for variance in body weight. Concomitant medications, including those that influence renal transporters, such as P-glycoprotein and cytochrome (CYP) P450, did not show an impact on levomilnacipran exposures, including area under the curve and the maximum and minimum drug concentrations. Of note, fewer than 3% of the subjects studied were taking any of the concomitant medications investigated.16 The dose of levomilnacipran ER should not exceed 80 mg daily when used with strong CYP3A4 inhibitors.15 Pharmacokinetic values are summarized in Table 2.
Clinical Efficacy Outcomes of phase II and III clinical trials are summarized in Table 3. Montgomery et al evaluated the safety and efficacy of levomilnacipran ER in a 10-week phase II randomized, doubleblinded, placebo-controlled, proof-of-concept study.17 A variable drug washout period was followed by 2-week progressive titration, an 8-week double-blinded treatment period, and a 1-week downtitration period. Patients were randomized to receive placebo or levomilnacipran ER 100 mg daily, and if the dose was not tolerated, patients were permitted to downtitrate to 75 mg.17 To be eligible for study participation, males and females aged 18 to 70 who were being seen on an outpatient basis had
to meet the criteria for an episode of MDD as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision).18 A score of >22 on a 17-item Hamilton Depression Rating Scale (HDRS)19 and a score 10 on a Sheehan Disability Scale (SDS)20 with at least 1 subscale score 6 was required. Exclusion criteria were extensive but included a history of other psychiatric disorders, concomitant use of certain psychoactive medications, substance abuse within the past 6 months, and more.17 Total score change from baseline to week 10 on the Montgomery-Asberg Depression Rating Scale (MADRS)21 was the primary efficacy parameter. Secondary efficacy parameters included change from baselines to week 10 in HDRS total score and SDS total and subscale scores. In the guidelines for the investigation of antidepressants from the European Medicines Evaluation Agency, a statistically significant difference in the responder rates between a medication and a placebo is considered to be clinically relevant.22 Thus, the MADRS response rate was also considered in the efficacy analysis to relate any statistical significance in score changes to clinical practice. The efficacy data were analyzed using the per-protocol population. Reduction in MADRS was significantly greater with levomilnacipran ER compared to placebo (18.7 vs 14.5, respectively; P < .01). With regard to secondary outcomes, reductions in HDRS (levomilnacipran 14.9 vs 11.5 placebo) and SDS (levomilnacipran 11.1 vs placebo 7.7) were significantly greater for levomilnacipran ER than placebo (P < .0001 for both). MADRS response ( 50% decrease from baseline) and remission (score 10) was obtained at week 10 by a significantly greater percentage of levomilnacipran ER–treated patients than placebo (P < .0001). The numbers needed to treat (NNT) for response and remission were 6 and 5 patients, respectively. Response rate for HDRS (defined as a 50% decrease in total score) was significantly greater for levomilnacipran ER (56.2%) versus placebo (38.6%, P < .0001).17 Asnis et al conducted a phase III, randomized, doubleblinded, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and tolerability of fixed-dose levomilnacipran ER relative to placebo in patients with MDD.23 Persons aged 18 to 65 with a confirmed diagnosis of MDD and a current ongoing depressive episode >8 weeks’ duration were included in the study; exclusion criteria was similar to that of Montgomery et al.17 Patients were randomized to receive placebo or once-daily levomilnacipran 40, 80, or 120 mg. A 1week, single-blind, placebo lead-in was followed by an 8week, double-blind treatment period and a 2-week doubleblind, downtaper. The primary and secondary efficacy assessments were change in MADRS and SDS scores, respectively.23 Analysis of the prespecified primary efficacy parameter was performed on the modified intent-to-treat population. The change from baseline for MADRS score at the end of week 8 was 11.6 for the placebo group, 14.8 for the levomilnacipran ER 40 mg group (P < .05), 15.6 for the 80 mg group (P < .01), and 16.5 for the 120 mg group (P < .001). By week 4, a significant advantage over placebo was observed with the
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Table 3. Summary of Levomilnacipran SR Efficacy Data.17,23–24 Results Study author and design Montgomery et al17 Phase II
Asnis et al23 Phase III
Blum et al24 Phase III
Number of patientsa 553
704
704
Levomilnacipran SR
Placebo
MADRS score change from MADRS score change from baseline ¼ 18.7 (0.56) baseline ¼ 14.5 (0.56) HDRS score change from HDRS score change from baseline ¼ 14.9 (0.45) baseline ¼ 11.5 (0.46) SDS score change from SDS change from baseline ¼ 11.1 (0.43) baseline ¼ 7.7 (0.44) HDRS response rate ¼ 56.2% HDRS response rate ¼ 38.6% HDRS remission rate ¼ 33.3% HDRS remission rate ¼ 20.6% SDS score change from SDS score change from baseline ¼ 9.7 (0.78) baseline ¼ 7.2 (0.74) HDRS score change from HDRS score change from baseline ¼ 10.8 (0.71) baseline ¼ 8.4 (0.67) MADRS response rate ¼ 41.5% MADRS response rate ¼ 29.1% MADRS remission rate ¼ 20.5% MADRS remission rate ¼ 19.4% SF-36v2 mental component summary least square mean difference ¼ 4.4 + 1.36 SF-36v2 physical component summary least square mean difference ¼ 0.2 + 0.74
Significance P < .0001 P < .0001 P < .0001 P < .0001 P ¼ .0009 P < .05 P < .05 P< P> P¼ P¼
.05 .05 .0013 .8386
Abbreviations: HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; SDS, Sheehan Disability Scale. a Includes number of patients in the modified intent-to-treat population.
80 and 120 mg strength of levomilnacipran ER (P < .05 and P < .01, respectively). Change from baseline to week 8 for SDS score was significantly greater for levomilnacipran ER 80 and 120 mg/d versus placebo (P < .05 for both). MADRS response rate was significantly higher for levomilnacipran ER 120 mg patients compared with placebo (41.5% vs 29.1%, P ¼ .0107).23 A post hoc analysis was performed by Blum et al on data from the same phase III trial to assess the functional health and well-being efficacy of levomilnacipran ER.24 The functional health and well-being of participants were measured using change from baseline to week 8 on the SF-36v2 acute health survey.25 Mental component summary (MCS) and physical component summary (PCS) scores, as well as 8 individual health dimensions, were compared for levomilnacipran ER and placebo using an intent-to-treat analysis.24 At week 8, levomilnacipran ER patients demonstrated significantly greater improvement in MCS compared with placebo, with a least squares mean difference (LSMD) of 4.4 + 1.36, P ¼ .0013. Several individual dimensions, such as general health (LSMD ¼ 2.3 + 0.69; P ¼ .0007), vitality (2.4 + 1.05; P ¼ .0228), social functioning (3.1 + 1.17; P ¼ .0086), role emotional (3.1 + 1.20; P ¼ .0097), and mental health (4.3 + 1.16; P ¼ .0003), also improved significantly in patients taking levomilnacipran ER. Other dimension score changes and PCS changes (0.2 + 0.74; P ¼ .8386) were not significant.24 Levomilnacipran ER was also evaluated in a phase II, double-blinded, randomized, placebo- and active-controlled study to determine its safety and efficacy for the treatment of fatigue associated with MDD. Levomilnacipran ER 40 to 120 mg per day was compared with paroxetine, sertraline, and
fluoxetine. The trial enrolled 262 patients with MDD for this 8-week study period. Although final data collection for the primary outcome measure was completed in July 2012, there are no data currently available.26
Safety and Tolerability Levomilnacipran ER was generally well tolerated in clinical trials, and treatment emergent AEs were considered to be mild or moderate in intensity. In the phase II study, 9.4% of levomilnacipran patients discontinued the study due to AEs, compared with 6.5% of placebo patients.17 In the phase III trial, significantly more levomilnacipran ER patients discontinued the study due to AEs in comparison with placebo (9.4% vs 1.7%, respectively; 40 mg: P ¼ .0185, 80 mg: P < .001, 120 mg: P ¼ .0316).23 Common AEs leading to withdrawal were nausea, vomiting, and palpitations. No dose–response relationship in tolerability was observed, as the number of patients with AEs and discontinuation due to AEs was higher in the levomilnacipran ER 80 mg group compared to the 40 and 120 mg group.23 Incidence of AEs are summarized in Table 4.
Concluding Remarks Levomilnacipran ER has the convenience of once-daily dosing, is generally well tolerated, and has displayed favorable effects compared to placebo in adult patients with MDD. Milnacipran, the racemic drug of levomilnacipran and its enantiomer, is only used for fibromyalgia in the United States but has demonstrated its efficacy in the management of MDD in other countries for over a decade, with multiple clinical trials comparing the drug with placebo, tricyclic antidepressants, and SSRIs.27-30 It has
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Table 4. Summary of Levomilnacipran SR Safety Data.17,23 Montgomery et al17 Parameter Serious AEs AEs leading to withdrawal At least 1 AE Nausea Constipation Hyperhidrosis Erectile dysfunction Tachycardia Vomiting Diarrhea Palpitations
Asnis et al23
Levomilnaciprana
Placeboa
Levomilnaciprana
Placeboa
3 (1.1) 26 (9.4) 210 (75.5) 58 (20.0) 20 (7.2) 40 (14.4) NR 19 (6.8) NR 17 (6.1) 18 (6.5)
9 (3.2) 18 (6.5) 180 (64.5) 31 (11.1) 4 (1.4) 12 (4.3) NR 3 (1.1) NR 8 (2.9) 7 (2.5)
3 (0.6) 51 (9.5) 421 (78.4) 81 (15.1) 60 (11.2) 43 (8.0) 12 (6.1) men 18 (3.4) 26 (4.8) 22 (4.1) 27 (5.0)
0 (0) 3 (1.7) 112 (63.6) 4 (2.3) 7 (4.0) 4 (2.3) 2 (2.9) men 0 (0) 0 (0) 3 (1.7) 1 (0.6)
Abbreviations: AE, adverse event; NR, not reported. a Values expressed as number (%) of patients.
been found that marketing any medication using just an enantiomer presents several advantages over the racemic mixture, such as a less complex, more selective pharmacodynamic and pharmacokinetic profile, improved therapeutic index, and decreased potential for drug interactions.31 Data from clinical trials of levomilnacipran ER have demonstrated not only statistical significance but also clinical significance. Guidelines from Europe on the investigation of antidepressants have placed considerable emphasis on the use of a clinically relevant outcome measure, such as responders.22 The usual definition of response is a reduction in at least 50% on the pivotal efficacy scale, as is the case for the MADRS and HDRS.17,22,23 To establish the clinical relevance of an advantage, a difference of 10% or more between treatment and placebo has been regarded as sufficient.22 In the phase II study, the HDRS response rate was significantly greater for levomilnacipran ER compared to placebo17; in the phase III study, the MADRS response rate was significantly greater for levomilnacipran ER 120 mg.23 Treatment effect, the difference between medication and placebo in the mean change from baseline to end point on the pivotal efficacy scale, is also used to assess the clinical relevance of an observed significant change. An average 2-point difference from placebo at end point is frequently used in short-term studies to establish clinical relevance of an antidepressant.22 In clinical trials, levomilnacipran ER exceeded the minimally important difference for both MADRS and HDRS, indicating clinical efficacy.17,23 Furthermore, the National Committee of Clinical Excellence in the United Kingdom considers an NNT of 10 or less sufficient evidence that a medication has a clinically relevant advantage.22 The NNT with levomilnacipran ER for response and remission was found to be 6 and 5 patients, respectively.17 Although the results of the clinical trials were robustly positive, there are no head-to-head studies directly comparing levomilnacipran ER to other antidepressants. The inclusion and exclusion criteria limit the ability to generalize these findings to all patients with MDD. The analysis by Blum et al should be viewed with caution due to the nature of the post hoc
design.32 Despite the statistical significance of the study, it is limited by the fact that the hypothesis was created after the fact and has not been proven by experiment or generated from a scientific basis. In general, an 8-week time frame for an acute trial is not long enough to establish remission, especially in patients with high baseline depression severity.23 Conversely, the ability of levomilnacipran ER to display positive results on the SDS and its subscales shows its efficacy in treating functional impairment, a consequence of depression.20 The overall enhancement in wellness, as demonstrated by both symptom and functional improvement, indicates that levomilnacipran ER can address what patients consider important components of recovery.33 The differences in relative potency of SNRIs at blocking NE and 5-HT reuptake are proposed to have clinical implications.9 With such a wide array of symptoms, MDD may be more effectively treated when drug therapies can be administered that target patient-specific symptoms. Things such as attention, working memory, concentration, alertness, energy, and social activity are more associated with NE,11,34 while agitation, appetite disturbance, aggression, sex drive, and irritability are linked to 5-HT.4 Changes in both NE and 5-HT are thought to contribute to the core signs of MDD: depressed mood, sleep disturbance, anhedonia, and anxiety.4 Levomilnacipran binds with high affinity to NE and 5-HT transporters but lacks affinity for 23 off-target receptors, including those that cause AEs. Compared with duloxetine or venlafaxine, levomilnacipran more potently inhibits NE than 5-HT reuptake.10 Additionally, intolerance to 5-HT-related effects may prevent patients from achieving a dose of venlafaxine or duloxetine that will actually inhibit NE reuptake.7 Some clinical data suggest that milnacipran, which also favors NE reuptake inhibition, may offer some benefit in terms of treating the noradrenergic cluster of MDD symptoms.11 SNRIs provide an advantage over older antidepressants in terms of tolerability and safety in overdose situations; the enhanced selectivity for NE reuptake inhibition demonstrated by levomilnacipran may prove to be a promising attribute.
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Additionally, with clinical significance established in phase II and III trials, it is anticipated that levomilnacipran ER has the potential to become a mainstay of treatment in MDD. To further evaluate its role in therapy, additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants should be conducted. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. World Health Organization. The global burden of disease: 2004 update. Geneva: WHO Press; 2008. 2. Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res. 2003;12(1):3. 3. Hasin DS, Goodwin RD, Stinson FS, et al. Epidemiology of major depressive disorder: results from the national epidemiologic survey on alcoholism and related conditions. Arch Gen Psychiatry. 2005;62(10):1097-1106. 4. Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69(E1):4-7. 5. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22(4):343-96. 6. Qaseem A, Snow V, Denberg TD, et al. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American college of physicians. Ann Intern Med. 2008;149(10):725-733. 7. Goethe JW, Woolley SB, Cardoni AA, et al. Selective serotonin reuptake inhibitor discontinuation: side effects and other factors that influence medication adherence. J Clin Psychopharmacol. 2007;27(5):451-458. 8. Kasper S, Gerald Pail. Milnacipran: a unique antidepressant? Neuropsychiatr Dis Treat. 2010;6(1):21-31. 9. Stahl SM, Grady MM, Moret C, et al. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10(9):732-747. 10. Auclair AL, Martel JC, Assie´ MB, et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013;70:338-347. 11. Kasper S, Meshkat D, Kutzelnigg A. Improvement of the norandrenergic symptom cluster following treatment with milancipran. Neuropsychiatr Dis Treat. 2011;7(1):21-27. 12. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57(5):503-509.
13. Debonnel G, Saint-Andre´ E, He´bert C, et al. Differential physiological effects of a low dose and high doses of venlafaxine in major depression. Int J Neuropsychopharmacol. 2007;10(1): 51-61. 14. Turcotte JE, Debonnel G, de Montigny C, et al. Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001;24(5):511-521. 15. Levomilnacipran [package insert]. St. Louis: Forest Pharmaceuticals, Inc.; 2013. 16. Carrothers TJ, Khariton T, Chen C, et al.Population pharmacokinetic model for levomilnacipran in healthy subjects and patients with major depressive disorder. Presented at: the American Conference on Pharmacometrics. 2013 May 12-15; Fort Lauderdale, FL. 17. Montgomery SA, Mansuy L, Ruth A, et al. Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebocontrolled, proof-of-concept study. J Clin Psychiatry. 2013; 74(4):363-369. 18. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition, text revision. Washington: American Psychiatric Association; 2000. 19. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. 20. Sheehan DV, Harnett KS, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11(3):89-95. 21. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 2006;10(9):732-747. 22. Montgomery SA, Moller HJ. Is the significant superiority of escitalopram compared with other antidepressants clinically relevant? Int Clin Psychopharmacol. 2009;24(3):111-118. 23. Asnis GM, Bose A, Gommoll CP, et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, doubleblind, placebo-controlled study. J Clin Psychiatry. 2013;74(3): 242-248. 24. Blum SI, Tourkodimitris S, Ruth A. Levomilnacipran in the treatment of major depressive disorder: functional health and wellbeing efficacy results from a phase III clinical trial. Value Health. 2012;15(4):A1-A56. 25. Ware JE, Kosinski M, Dewey JE. How to score version two of the SF-36 health survey. Lincoln: QualityMetric, Incorporated; 2000. 26. Gommoll C.A double-blind, randomized, placebo- and activecontrolled study of F2695 SR in adult patients with fatigue associated with major depressive disorder. In: ClinicalTrials.gov [Internet]. Bethesda: National Library of Medicine (US). 2000[cited 2013 Aug 1]. http://clinicaltrials.gov/show/NCT01254305 NLM Identifier: NCT01254305. Accessed August 1, 2013. 27. Lecrubier Y, Pletan Y, Solles A, et al. Clinical efficacy of milnacipran: placebo-controlled trials. Int Clin Psychopharmacol. 1996;11(4):29-33. 28. Kasper S, Pletan Y, Solles A, et al. Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results. Int Clin Psychopharmacol. 1996;11(4):35-39.
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29. Lopez-Ibor J, Guelfi JD, Pletan Y, et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol. 1996;11(4):41-46. 30. Montgomery SA, Prost JF, Solles A, et al. Efficacy and tolerability of milnacipran: an overview. Clin Psychopharmacol. 1996;11(4):47-51. 31. Hutt AJ, Vanetova J. The chiral switch: the development of single enantiomer drugs from racemates. Acta Facult Pharm Univ Comenianae. 2003;50:7-23.
32. Elliott HL. Post hoc analysis: use and dangers in perspective. J Hypertens Suppl. 1996;14(2):S21-S24. 33. Zimmerman M, McGlinchey JB, Posternak MA, et al. How should remission from depression be defined? the depressant patient’s perspective. Am J Psychiatry. 2006;163(1):148-150. 34. Birley M, Moret C. Improvement of social adaptation in depression with serotonin and norepinephrine reuptake inhibitors. Neuropsychiatr Dis Treat. 2011;7(1):15-20.
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Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder Megan M. Saraceni, Jineane V. Venci and Mona A. Gandhi Journal of Pharmacy Practice published online 31 December 2013 DOI: 10.1177/0897190013516504 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/12/31/0897190013516504
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Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder
Journal of Pharmacy Practice 201X, Vol XX(X) 1-7 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013516504 jpp.sagepub.com
Megan M. Saraceni, PharmD candidate1, Jineane V. Venci, PharmD2, and Mona A. Gandhi, PharmD1
Abstract In July 2013, the US Federal Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotoninnorepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy. Keywords levomilnacipran, F2695, major depressive disorder, SNRI, antidepressant, Fetzima
Introduction Major depressive disorder (MDD) is associated with significant functional impairment, morbidity, and mortality.1 Surveys of adults living in the community found that the lifetime prevalence of major depression is 17% in the United States, with rates ranging from 8% to 12% in other countries around the world.2 Affecting more than 14.8 million adults, MDD is a chief cause of disability. Women are more likely to be affected than men and the median age of onset is 32 years.3 According to the World Health Organization predictions, MDD will become the world’s leading cause of disability by the year 2030.1 The exact etiology of depression is unknown and complicated, but there is a general consensus that it entails altered regulation of monoaminergic neurotransmission in the brain.4 Specifically, the monoamine neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA) are thought to be involved.4 The cause of this alteration is controversial; however, drug therapies targeting this imbalance are available. As a major public health concern with huge economic implications, the development of effective treatments for MDD is crucial. Older agents, such as tricyclic compounds, target monoamine transporters to prevent presynaptic reuptake, thus prolonging the duration of action at postsynaptic receptors. The inability of these drugs to selectively target
desired neurotransmitters causes a number of unwanted adverse effects (AEs), such as dry mouth, blurred vision, constipation, urinary retention, fatigue, increased appetite leading to weight gain, and orthostatic hypotension.5 In the United States, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) are now considered first-line pharmacotherapy for MDD in adults, particularly in primary care settings.6 Although SSRIs are generally better tolerated and less dangerous in overdose situations than tricyclic compounds, serotonin-mediated AEs such as nausea and sexual dysfunction frequently prompt discontinuation before an adequate clinical response can occur.7 In July 2013, the US Federal Drug Administration (FDA) approved levomilnacipran extended release (ER; Fetzima) for 1
St John Fisher College Wegmans School of Pharmacy, Rochester, NY, USA Department of Pharmacy, University of Rochester Medical Center, Rochester, NY, USA 2
Corresponding Author: Megan M. Saraceni, St John Fisher College Wegmans School of Pharmacy, 3690 East Ave, Rochester, NY 14618, USA. Email: [email protected]
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the treatment of MDD in adult patients. Levomilnacipran is an active enantiomer of milnacipran, which is approved in the United States for fibromyalgia and in Europe for depression.8 Although levomilnacipran is the fourth SNRI to be approved by the FDA for use in MDD, it has distinctive properties that make it a promising option for patients failing current therapies or unable to tolerate other medications within this class.9 Unlike venlafaxine and duloxetine, levomilnacipran is highly selective for norepinephrine transporters (NETs) that, in theory, may allow it to bypass serotonin-mediated AEs associated with the antidepressants currently available.7,10 Additionally, the ability for levomilnacipran to inhibit reuptake at both NETs and serotonin transporters (SERTs) at therapeutic doses could potentially provide increased efficacy at treating certain symptoms of depression.11 Although venlafaxine and duloxetine are classified as SNRIs, only 5-HT reuptake inhibition is achieved at lower doses, with much higher doses (225 mg daily12,13 and 60 mg daily,14 respectively) needed to inhibit the reuptake of NE.10 The purpose of this article is to provide an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER.
Table 1. Overview of Levomilnacipran SR.10,15 Generic name Trade name Drug class Indication Formulation, dosing, and administration
Adverse reactions
Drug interactions Comparable drugs Advantage
Levomilnacipran Fetzima Serotonin-norepinephrine reuptake inhibitor Major depressive disorder Available as 20, 40, 80, and 120 mg SR capsules Recommended dose: 40 to 120 mg orally once daily The maximum recommended dose is 120 mg orally once daily Taken with or without food; do not open, chew, or crush Nausea, constipation, hyperhidrosis, hypertension, erectile dysfunction, tachycardia, vomiting, diarrhea, and palpitations Strong CYP3A4 inhibitors, such as ketoconazole Duloxetine, venlafaxine, desvenlafaxine Increased potency for norepinephrine reuptake inhibition
Abbreviation: CYP, cytochrome P.
Mechanism of Action Methods An unfiltered search of PubMed, International Pharmaceutical Abstracts, and Google Scholar using the key word levomilnacipran was used to identify relevant information for review. To retrieve all available information on levomilnacipran, neither limits nor inclusion/exclusion criteria were applied. Additional information was obtained from fda.gov and through a comprehensive review of the reference lists of identified articles. Posters and abstracts from scientific meetings, such as the US Psychiatric and Mental Health Congress, the American Psychiatric Association Annual Meeting, and the American Conference on Pharmacometrics, for 2011 through 2013 were also consulted.
Results A total of 47 unique articles were identified through a search of the databases mentioned. Of these, 42 were excluded due to irrelevance to the scope of this article. One poster presented at the American Conference on Pharmacometrics provided pertinent information on levomilnacipran. The remainder of the data came from a review of the reference lists of identified articles and fda.gov.
Indication and Dosage The FDA-approved levomilnacipran ER on July 25, 2013, for the treatment of MDD. Available dosage forms are 20 mg, 40 mg, 80 mg, and 120 mg ER capsules. The medication is to be administered orally once daily with or without food.15 An overview of levomilnacipran ER can be found in Table 1.
Levomilnacipran is a potent and selective SNRI and an active enantiomer of milnacipran. It acts similar to other medications in its class; however, it has a 2-fold greater potency for the inhibition of NE relative to 5-HT reuptake. Levomilnacipran demonstrates a 27 and 17 times higher selectivity for NE reuptake inhibition compared with duloxetine and venlafaxine, respectively.10 Levomilnacipran has no affinity for muscarinic, histaminic, and alpha-1 adrenergic receptors and does not affect monoamine oxidase.10
In Vitro Activity In vitro studies have demonstrated levomilnacipran to be the more active enantiomer of milnacipran. In rat hypothalamic synaptosomes, levomilnacipran was 50 and 13 times more potent in inhibiting NE and 5-HT reuptake than the other enantiomer of milnacipran, F2696. In selectivity assessments, levomilnacipran did not exhibit affinity for 23 other receptors, which allows for the prevention of AEs seen with more traditional, less selective antidepressants. The investigators also found that in mice, levomilnacipran produced antidepressant effects, had antistress/anxiolytic activity, and did not modify spontaneous locomotor activity.10 The results of this in vitro study display that levomilnacipran has a greater potency for NETs compared to the active comparators, duloxetine and venlafaxine.
Pharmacokinetics A population pharmacokinetic model for levomilnacipran ER was developed based on data from 458 healthy subjects in 13 phase I studies and 798 patients with MDD in 3 phase III
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Table 2. Pharmacokinetic Values of Levomilnacipran ER.15,16 Total clearance Elimination half-life Maximum concentrationa Steady state area under the curvea Bioavailability Time to peak concentration Volume of distribution Plasma protein binding
21-29 L/h 12 hours 341 ng/mL 5196 ng hours/mL 92% 6-8 hours 387-472 L 22%
Abbreviation: ER, extended release. a Value following daily dosing of levomilnacipran ER 120 mg.
studies. Doses of levomilnacipran ER formulation ranged from 20 to 300 mg once daily. Based on this observed data, the pharmacokinetics of levomilnacipran ER can be described as a 1compartment pharmacokinetic model with delayed first-order absorption and first-order elimination.16 Creatinine clearance and body weight were the only clinically relevant covariates influencing the pharmacokinetics of levomilnacipran ER. In healthy subjects, mean clearance was 24 L/h. Clearance was decreased in patients with mild, moderate, and severe renal impairment by 20%, 40%, and 58%, respectively. Based on this data, maximum daily doses should not exceed 80 mg in patients with moderate renal impairment or 60 mg in patients with severe renal impairment, and adjusted dose titration schedules may be warranted.16 In healthy subjects, the mean volume of distribution was 495 L. The influence of body weight on the maximum steady state concentration was meager, only resulting in less than a 20% change over the full range in body weight (45-143 kg) observed in the data set. Consequently, no dose adjustment is required for variance in body weight. Concomitant medications, including those that influence renal transporters, such as P-glycoprotein and cytochrome (CYP) P450, did not show an impact on levomilnacipran exposures, including area under the curve and the maximum and minimum drug concentrations. Of note, fewer than 3% of the subjects studied were taking any of the concomitant medications investigated.16 The dose of levomilnacipran ER should not exceed 80 mg daily when used with strong CYP3A4 inhibitors.15 Pharmacokinetic values are summarized in Table 2.
Clinical Efficacy Outcomes of phase II and III clinical trials are summarized in Table 3. Montgomery et al evaluated the safety and efficacy of levomilnacipran ER in a 10-week phase II randomized, doubleblinded, placebo-controlled, proof-of-concept study.17 A variable drug washout period was followed by 2-week progressive titration, an 8-week double-blinded treatment period, and a 1-week downtitration period. Patients were randomized to receive placebo or levomilnacipran ER 100 mg daily, and if the dose was not tolerated, patients were permitted to downtitrate to 75 mg.17 To be eligible for study participation, males and females aged 18 to 70 who were being seen on an outpatient basis had
to meet the criteria for an episode of MDD as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision).18 A score of >22 on a 17-item Hamilton Depression Rating Scale (HDRS)19 and a score 10 on a Sheehan Disability Scale (SDS)20 with at least 1 subscale score 6 was required. Exclusion criteria were extensive but included a history of other psychiatric disorders, concomitant use of certain psychoactive medications, substance abuse within the past 6 months, and more.17 Total score change from baseline to week 10 on the Montgomery-Asberg Depression Rating Scale (MADRS)21 was the primary efficacy parameter. Secondary efficacy parameters included change from baselines to week 10 in HDRS total score and SDS total and subscale scores. In the guidelines for the investigation of antidepressants from the European Medicines Evaluation Agency, a statistically significant difference in the responder rates between a medication and a placebo is considered to be clinically relevant.22 Thus, the MADRS response rate was also considered in the efficacy analysis to relate any statistical significance in score changes to clinical practice. The efficacy data were analyzed using the per-protocol population. Reduction in MADRS was significantly greater with levomilnacipran ER compared to placebo (18.7 vs 14.5, respectively; P < .01). With regard to secondary outcomes, reductions in HDRS (levomilnacipran 14.9 vs 11.5 placebo) and SDS (levomilnacipran 11.1 vs placebo 7.7) were significantly greater for levomilnacipran ER than placebo (P < .0001 for both). MADRS response ( 50% decrease from baseline) and remission (score 10) was obtained at week 10 by a significantly greater percentage of levomilnacipran ER–treated patients than placebo (P < .0001). The numbers needed to treat (NNT) for response and remission were 6 and 5 patients, respectively. Response rate for HDRS (defined as a 50% decrease in total score) was significantly greater for levomilnacipran ER (56.2%) versus placebo (38.6%, P < .0001).17 Asnis et al conducted a phase III, randomized, doubleblinded, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and tolerability of fixed-dose levomilnacipran ER relative to placebo in patients with MDD.23 Persons aged 18 to 65 with a confirmed diagnosis of MDD and a current ongoing depressive episode >8 weeks’ duration were included in the study; exclusion criteria was similar to that of Montgomery et al.17 Patients were randomized to receive placebo or once-daily levomilnacipran 40, 80, or 120 mg. A 1week, single-blind, placebo lead-in was followed by an 8week, double-blind treatment period and a 2-week doubleblind, downtaper. The primary and secondary efficacy assessments were change in MADRS and SDS scores, respectively.23 Analysis of the prespecified primary efficacy parameter was performed on the modified intent-to-treat population. The change from baseline for MADRS score at the end of week 8 was 11.6 for the placebo group, 14.8 for the levomilnacipran ER 40 mg group (P < .05), 15.6 for the 80 mg group (P < .01), and 16.5 for the 120 mg group (P < .001). By week 4, a significant advantage over placebo was observed with the
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Table 3. Summary of Levomilnacipran SR Efficacy Data.17,23–24 Results Study author and design Montgomery et al17 Phase II
Asnis et al23 Phase III
Blum et al24 Phase III
Number of patientsa 553
704
704
Levomilnacipran SR
Placebo
MADRS score change from MADRS score change from baseline ¼ 18.7 (0.56) baseline ¼ 14.5 (0.56) HDRS score change from HDRS score change from baseline ¼ 14.9 (0.45) baseline ¼ 11.5 (0.46) SDS score change from SDS change from baseline ¼ 11.1 (0.43) baseline ¼ 7.7 (0.44) HDRS response rate ¼ 56.2% HDRS response rate ¼ 38.6% HDRS remission rate ¼ 33.3% HDRS remission rate ¼ 20.6% SDS score change from SDS score change from baseline ¼ 9.7 (0.78) baseline ¼ 7.2 (0.74) HDRS score change from HDRS score change from baseline ¼ 10.8 (0.71) baseline ¼ 8.4 (0.67) MADRS response rate ¼ 41.5% MADRS response rate ¼ 29.1% MADRS remission rate ¼ 20.5% MADRS remission rate ¼ 19.4% SF-36v2 mental component summary least square mean difference ¼ 4.4 + 1.36 SF-36v2 physical component summary least square mean difference ¼ 0.2 + 0.74
Significance P < .0001 P < .0001 P < .0001 P < .0001 P ¼ .0009 P < .05 P < .05 P< P> P¼ P¼
.05 .05 .0013 .8386
Abbreviations: HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; SDS, Sheehan Disability Scale. a Includes number of patients in the modified intent-to-treat population.
80 and 120 mg strength of levomilnacipran ER (P < .05 and P < .01, respectively). Change from baseline to week 8 for SDS score was significantly greater for levomilnacipran ER 80 and 120 mg/d versus placebo (P < .05 for both). MADRS response rate was significantly higher for levomilnacipran ER 120 mg patients compared with placebo (41.5% vs 29.1%, P ¼ .0107).23 A post hoc analysis was performed by Blum et al on data from the same phase III trial to assess the functional health and well-being efficacy of levomilnacipran ER.24 The functional health and well-being of participants were measured using change from baseline to week 8 on the SF-36v2 acute health survey.25 Mental component summary (MCS) and physical component summary (PCS) scores, as well as 8 individual health dimensions, were compared for levomilnacipran ER and placebo using an intent-to-treat analysis.24 At week 8, levomilnacipran ER patients demonstrated significantly greater improvement in MCS compared with placebo, with a least squares mean difference (LSMD) of 4.4 + 1.36, P ¼ .0013. Several individual dimensions, such as general health (LSMD ¼ 2.3 + 0.69; P ¼ .0007), vitality (2.4 + 1.05; P ¼ .0228), social functioning (3.1 + 1.17; P ¼ .0086), role emotional (3.1 + 1.20; P ¼ .0097), and mental health (4.3 + 1.16; P ¼ .0003), also improved significantly in patients taking levomilnacipran ER. Other dimension score changes and PCS changes (0.2 + 0.74; P ¼ .8386) were not significant.24 Levomilnacipran ER was also evaluated in a phase II, double-blinded, randomized, placebo- and active-controlled study to determine its safety and efficacy for the treatment of fatigue associated with MDD. Levomilnacipran ER 40 to 120 mg per day was compared with paroxetine, sertraline, and
fluoxetine. The trial enrolled 262 patients with MDD for this 8-week study period. Although final data collection for the primary outcome measure was completed in July 2012, there are no data currently available.26
Safety and Tolerability Levomilnacipran ER was generally well tolerated in clinical trials, and treatment emergent AEs were considered to be mild or moderate in intensity. In the phase II study, 9.4% of levomilnacipran patients discontinued the study due to AEs, compared with 6.5% of placebo patients.17 In the phase III trial, significantly more levomilnacipran ER patients discontinued the study due to AEs in comparison with placebo (9.4% vs 1.7%, respectively; 40 mg: P ¼ .0185, 80 mg: P < .001, 120 mg: P ¼ .0316).23 Common AEs leading to withdrawal were nausea, vomiting, and palpitations. No dose–response relationship in tolerability was observed, as the number of patients with AEs and discontinuation due to AEs was higher in the levomilnacipran ER 80 mg group compared to the 40 and 120 mg group.23 Incidence of AEs are summarized in Table 4.
Concluding Remarks Levomilnacipran ER has the convenience of once-daily dosing, is generally well tolerated, and has displayed favorable effects compared to placebo in adult patients with MDD. Milnacipran, the racemic drug of levomilnacipran and its enantiomer, is only used for fibromyalgia in the United States but has demonstrated its efficacy in the management of MDD in other countries for over a decade, with multiple clinical trials comparing the drug with placebo, tricyclic antidepressants, and SSRIs.27-30 It has
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Table 4. Summary of Levomilnacipran SR Safety Data.17,23 Montgomery et al17 Parameter Serious AEs AEs leading to withdrawal At least 1 AE Nausea Constipation Hyperhidrosis Erectile dysfunction Tachycardia Vomiting Diarrhea Palpitations
Asnis et al23
Levomilnaciprana
Placeboa
Levomilnaciprana
Placeboa
3 (1.1) 26 (9.4) 210 (75.5) 58 (20.0) 20 (7.2) 40 (14.4) NR 19 (6.8) NR 17 (6.1) 18 (6.5)
9 (3.2) 18 (6.5) 180 (64.5) 31 (11.1) 4 (1.4) 12 (4.3) NR 3 (1.1) NR 8 (2.9) 7 (2.5)
3 (0.6) 51 (9.5) 421 (78.4) 81 (15.1) 60 (11.2) 43 (8.0) 12 (6.1) men 18 (3.4) 26 (4.8) 22 (4.1) 27 (5.0)
0 (0) 3 (1.7) 112 (63.6) 4 (2.3) 7 (4.0) 4 (2.3) 2 (2.9) men 0 (0) 0 (0) 3 (1.7) 1 (0.6)
Abbreviations: AE, adverse event; NR, not reported. a Values expressed as number (%) of patients.
been found that marketing any medication using just an enantiomer presents several advantages over the racemic mixture, such as a less complex, more selective pharmacodynamic and pharmacokinetic profile, improved therapeutic index, and decreased potential for drug interactions.31 Data from clinical trials of levomilnacipran ER have demonstrated not only statistical significance but also clinical significance. Guidelines from Europe on the investigation of antidepressants have placed considerable emphasis on the use of a clinically relevant outcome measure, such as responders.22 The usual definition of response is a reduction in at least 50% on the pivotal efficacy scale, as is the case for the MADRS and HDRS.17,22,23 To establish the clinical relevance of an advantage, a difference of 10% or more between treatment and placebo has been regarded as sufficient.22 In the phase II study, the HDRS response rate was significantly greater for levomilnacipran ER compared to placebo17; in the phase III study, the MADRS response rate was significantly greater for levomilnacipran ER 120 mg.23 Treatment effect, the difference between medication and placebo in the mean change from baseline to end point on the pivotal efficacy scale, is also used to assess the clinical relevance of an observed significant change. An average 2-point difference from placebo at end point is frequently used in short-term studies to establish clinical relevance of an antidepressant.22 In clinical trials, levomilnacipran ER exceeded the minimally important difference for both MADRS and HDRS, indicating clinical efficacy.17,23 Furthermore, the National Committee of Clinical Excellence in the United Kingdom considers an NNT of 10 or less sufficient evidence that a medication has a clinically relevant advantage.22 The NNT with levomilnacipran ER for response and remission was found to be 6 and 5 patients, respectively.17 Although the results of the clinical trials were robustly positive, there are no head-to-head studies directly comparing levomilnacipran ER to other antidepressants. The inclusion and exclusion criteria limit the ability to generalize these findings to all patients with MDD. The analysis by Blum et al should be viewed with caution due to the nature of the post hoc
design.32 Despite the statistical significance of the study, it is limited by the fact that the hypothesis was created after the fact and has not been proven by experiment or generated from a scientific basis. In general, an 8-week time frame for an acute trial is not long enough to establish remission, especially in patients with high baseline depression severity.23 Conversely, the ability of levomilnacipran ER to display positive results on the SDS and its subscales shows its efficacy in treating functional impairment, a consequence of depression.20 The overall enhancement in wellness, as demonstrated by both symptom and functional improvement, indicates that levomilnacipran ER can address what patients consider important components of recovery.33 The differences in relative potency of SNRIs at blocking NE and 5-HT reuptake are proposed to have clinical implications.9 With such a wide array of symptoms, MDD may be more effectively treated when drug therapies can be administered that target patient-specific symptoms. Things such as attention, working memory, concentration, alertness, energy, and social activity are more associated with NE,11,34 while agitation, appetite disturbance, aggression, sex drive, and irritability are linked to 5-HT.4 Changes in both NE and 5-HT are thought to contribute to the core signs of MDD: depressed mood, sleep disturbance, anhedonia, and anxiety.4 Levomilnacipran binds with high affinity to NE and 5-HT transporters but lacks affinity for 23 off-target receptors, including those that cause AEs. Compared with duloxetine or venlafaxine, levomilnacipran more potently inhibits NE than 5-HT reuptake.10 Additionally, intolerance to 5-HT-related effects may prevent patients from achieving a dose of venlafaxine or duloxetine that will actually inhibit NE reuptake.7 Some clinical data suggest that milnacipran, which also favors NE reuptake inhibition, may offer some benefit in terms of treating the noradrenergic cluster of MDD symptoms.11 SNRIs provide an advantage over older antidepressants in terms of tolerability and safety in overdose situations; the enhanced selectivity for NE reuptake inhibition demonstrated by levomilnacipran may prove to be a promising attribute.
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Additionally, with clinical significance established in phase II and III trials, it is anticipated that levomilnacipran ER has the potential to become a mainstay of treatment in MDD. To further evaluate its role in therapy, additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants should be conducted. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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