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Levomilnacipran for the treatment of major depressive disorder

Matthew Macaluso, DO, Hala Kazanchi, MD, and Vikram Malhotra, MD

An SNRI with n July 2013, the FDA approved levomil- Table 1 once-daily dosing, nacipran for the treatment of major de- : Fast facts levomilnacipran pressive disorder (MDD) in adults.1 It is I Brand name: Fetzima decreased core available in a once-daily, extended-release formulation (Table 1).1 The drug is the fifth Class: - symptoms of inhibitor serotonin-norepinephrine reuptake inhibi- MDD and was well Indication: Treatment of major depressive tor (SNRI) to be sold in the disorder in adults tolerated in clinical and the fourth to receive FDA approval for FDA approval date: July 26, 2013 trials treating MDD. Availability date: Fourth quarter of 2013 Levomilnacipran is believed to be the Manufacturer: Forest Pharmaceuticals more active of , Dosage forms: Extended–release capsules in which has been available in for 20 mg, 40 mg, 80 mg, and 120 mg strengths years and was approved by the FDA in Recommended dosage: 40 mg to 120 mg 2009 for treating . Efficacy of capsule once daily with or without food levomilnacipran for treating patients with Source: Reference 1 MDD was established in three 8-week ran- domized controlled trials (RCTs).1 cial and occupational functioning in addi- Clinical implications tion to improvement in the core symptoms Levomilnacipran is indicated for treating of depression.5 MDD in adults and is unique compared Levomilnacipran is the more active en- with other SNRIs because it is relatively antiomer of milnacipran, an SNRI that is more selective for norepinephrine reuptake approved for treating fibromyalgia in the inhibition (NRI) compared with serotonin United States and approved for treating reuptake inhibition (SRI).1 In vitro stud- depression in many other countries.6 In ies demonstrate that the drug has >10-fold general, enantiomeric formulations are greater selectivity for norepinephrine reup- believed to have advantages over racemic take inhibition than it does for serotonin formulations because they are less com- reuptake inhibition, compared with dulox- etine or .2 Dr. Macaluso is Assistant Professor, Director of Research and Associate This difference in selectivity could Director of Residency Training, and Drs. Kazanchi and Malhotra are Senior Residents, University of Kansas School of Medicine-Wichita, lend itself to treating symptoms of MDD Wichita, Kansas. that might be related to norepinephrine Disclosures deficiency; these include decreased con- Dr. Macaluso has been the principal investigator in clinical trials for AbbVie, Eisai, Envivo, Janssen, Naurex, and Pfizer. All centration, lassitude, mental and physical and study contracts and payments were made through the Kansas slowing, and decreased self-care.3,4 Some University Medical Center Research Institute. Drs. Kazanchi and Malhotra report no financial relationship with any company whose authors claim that individual patients Current Psychiatry products are mentioned in this article or with manufacturers of 50 December 2013 could experience improvement in their so- competing products. Out of the Pipeline

plex and have a more selective pharmaco- it susceptible to DDIs with drugs that in- dynamic profile, better therapeutic index, hibit or induce this . For example, lower liability for drug-drug interactions a person taking levomilnacipran with a (DDIs), and a less complicated relation- potent CYP3A4 inhibitor, such as keto- ship between plasma concentration and conazole, may require a dosage adjust- pharmacodynamic effect.6 In addition, ment. No dosage adjustment is needed regulatory guidelines in the United States when given with a CYP3A4 inducer or recommend development of substrate. Drinking with levomil- over racemates where appropriate.7 nacipran may cause more rapid release of the drug into the stream.1 How it works Levomilnacipran’s exact mechanism of ac- Efficacy tion is unknown. Similar to other SNRIs, Levomilnacipran decreased core symp- it binds with high affinity to the serotonin toms of MDD and showed a statistically Clinical Point (5-HT) and norepinephrine (NE) trans- significant separation from in 2 Levomilnacipran is porters and potently inhibits 5-HT and NE phase III RCTs (Table 2, page 54).3,5 The first reuptake. Levomilnacipran lacks signifi- study was a 10-week flexible dose (75 or suitable for once-daily cant affinity for any other receptors, ion 100 mg) trial in 563 outpatients age 18 to dosing; maximum channels, or transporters tested in vitro.2 70 who met DSM-IV-TR criteria of MDD plasma concentration It differs from other SNRIs such as ven- for >1 month and had a 17-item Hamilton is 6 to 8 hours, and lafaxine and in having higher Depression Rating Scale (HDRS-17) score the drug has a half-life selectivity for norepinephrine vs serotonin >22 and a Sheehan Disability Scale (SDS) reuptake inhibition. In vitro studies dem- score >10.3 The primary efficacy mea- of 12 hours onstrated a 2-fold preference for NE over sure was change in Montgomery-Åsberg 5-HT reuptake inhibition.2 Depression Rating Scale (MADRS) score from baseline to week 10. Secondary ef- ficacy measures included the HDRS-17, Levomilnacipran reaches maximum plas- SDS, and Clinical Global Impressions- ma concentration within 6 to 8 hours of improvement scale. Efficacy analyses in- oral administration and has a half-life of cluded 276 subjects treated with levomil- approximately 12 hours, which makes it nacipran and 277 treated with placebo.3 suitable for once-daily dosing. The concen- Levomilnacipran was significant- tration of levomilnacipran at steady state ly superior to placebo on the MADRS is proportional to the dosage of the drug and HDRS-17 from baseline to week when administered within the range of 25 10. Response and remission rates were to 300 mg once daily.1 significantly greater for the levomil- The drug’s mean apparent total clear- nacipran group compared with pla- ance is 21 to 29 liters/hour and its bioavail- cebo. Response exceeded the 10% aver- ability is not significantly affected when age advantage for drug vs placebo and taken with food. The drug is widely dis- 46% of levomilnacipran-treated patients tributed in the body and is converted pri- achieved remission.3 marily to 2 metabolites: desethyl levomil- The number needed to treat (NNT), nacipran and p-hydroxy-levomilnacipran. based on the MADRS scores for the levo- Discuss this article at Both metabolites are inactive and undergo milnacipran group compared with the pla- www.facebook.com/ CurrentPsychiatry further conjugation with glucuronide. cebo group, was 6 for response and 5 for The drug is eliminated primarily via renal remission.3 By comparison, most studies of .1 venlafaxine demonstrate a NNT of 8.3 The major enzyme that catalyzes me- Levomilnacipran generally was report- tabolism of levomilnacipram is cyto- ed to be safe and well tolerated. The most Current Psychiatry chrome P 450 (CYP) 3A4, which makes common adverse events leading to discon- Vol. 12, No. 12 51 Out of the Pipeline

tinuation in the levomilnacipran group the number of patients reporting adverse were , , change in systolic events and who discontinued participa- and diastolic , and increase tion because of adverse events was higher in . The favorable tolerability in the 80-mg group than in the 40-mg and profile of levomilnacipran may relate to 120-mg groups.5 the 2-fold greater potency for NE reuptake inhibition compared with 5-HT reuptake Tolerability inhibition.3 Overall, levomilnacipran was well toler- The second study was an 11-week, ated in clinical trials, during which 2,673 fixed-dose trial of levomilnacipran using subjects were exposed to the drug— 40, 80, or 120 mg. A total of 724 outpatients translating to 942 patient-years of expo- age 18 to 65 who met DSM-IV-TR criteria sure. These patients ranged in age from for MDD and who had an ongoing episode 18 to 78; 825 of these subjects were enrolled Clinical Point of depression lasting >8 weeks were ran- in long-term studies for 1 year. Dosing of Levomilnacipran domly assigned to receive placebo (n = 179) levomilnacipran during these studies or levomilnacipran at 40 mg (n = 181), ranged from 40 to 120 mg once daily, with- was well tolerated 80 mg (n = 181), or 120 mg (n = 183) once out regard to food.1 in clinical trials; 9% daily for 8 weeks of double-blind treat- Nine percent of patients who received of patients who ment followed by a 2-week, double-blind levomilnacipran in short-term studies dis- received the drug taper of the drug.5 The primary efficacy continued because of adverse events, com- parameter was change from baseline on pared with 3% of patients who received discontinued because the MADRS and the secondary efficacy placebo. The most common adverse event of adverse events parameter was change from baseline in reported was nausea; other common ad- SDS total score. HDRS-17, CGI-I, and verse events reported included constipa- CGI-S were included as secondary out- tion, , elevated heart rate, come measures.5 , , palpita- Significant difference in MADRS total tions, and vomiting. Of these events, only score were seen in the levomilnacipran erectile dysfunction and urinary hesita- group compared with the placebo group tion were dose-related.1 Among levo­ (least mean squared difference: 40 mg/d, milnacipran-treated female patients, <2% −3.23; 80 mg/d, −3.99; and 120 mg/d, reported adverse events related to sexual −4.86). Higher dosages produced a numer- dysfunction. ically greater change and significant sepa- All SNRIs have well established associa- ration from placebo occurred sooner in the tions with elevation in blood pressure and 80-mg and 120-mg groups compared with heart rate. Levomilnacipran resulted in a the 40-mg group.5 mean increase of 3 mm HG in systolic and Significant differences vs placebo were 3.2 mm Hg in diastolic blood pressure in consistently observed across secondary short-term, placebo-controlled trials.1 outcome measures for the higher dosages Orthostatic hypotension was observed of levomilnacipran, and improvement in in 11.6% of patients in the levomilnacipran SDS total score was noted in all levomil- groups, compared with 9.7% in placebo nacipran groups compared with the pla- groups in all short-term studies. Orthostatic cebo group. When dosed at 120 mg/d, reductions of blood pressure occurred in levomilnacipran produced significant im- 5.8%, 6.1%, and 9.8% of levomilnacipran- provement vs placebo on all SDS subscales treated patients with dosages of 40, 80, and and was as well tolerated as the 80 mg 120 mg/d, respectively, indicating a dose- dosage.5 dependent adverse event. A mean increase No new safety concerns were observed in heart rate of 7.2 beats per minute (bpm) in the study. A dose-response relationship also was seen in short-term studies in the Current Psychiatry 52 December 2013 in tolerability was not demonstrated and levomilnacipran-treated group compared continued on page 54 Out of the Pipeline

continued from page 52

Table 2 Summary of the seminal data that led to FDA approval of levomilnacipran for the treatment of MDD in adults Study type Inclusion criteria Dosing Efficacy assessment Tolerability and safety Study 13 Phase III, RCT -Outpatient Flexible MADRS 0 to 10 week shows: 18 placebo and 26 levomilnacipran-treated patients 10 weeks -Age 18 to 70 75 to 100 mg/d 4.2 point difference in favor of withdrew because of AEs levomilnacipran vs placebo n = 557 (completers) -Meeting DSM-IV-TR Most common AE in the levomilnacipran group was criteria for MDD for NNT = 6 (response) GI upset >1 month NNT = 5 (remission)3 -HDRS-17 >22 -SDS >10 Study 25 Phase III -Outpatient Fixed MADRS total score: shows Well tolerated and safe RCT -Age 18 to 65 40, 80, or 120 mg/d higher dose of levomilnacipran Clinical Point (80, 120 mg) lead to significantly 11 weeks -Meeting DSM-IV-TR greater changes compared criteria for MDD for Contraindications n = 704 (completers) with placebo include >8 weeks -MADRS >30 hypersensitivity to AE: adverse event; GI: gastrointestinal; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery-Åsberg Depression Rating Scale; levomilnacipran or MDD: major depressive disorder; NNT: number needed to treat; RCT: randomized control trial; SDS: Sheehan Disability Scale milnacipran and uncontrolled narrow- angle with 0.3 bpm in the placebo-treated group.1 Contraindications Clinicians should monitor blood pressure Contraindications to levomilnacipran are and heart rate routinely because of poten- similar to those seen with SSRIs and SNRIs, tial increases seen in some subjects in these including concomitant use of a mono- studies, which excluded those who had amine oxidase inhibitor (MAOI) and the significant cardiovascular disease. use of the levomilnacipran within 14 days of stopping an MAOI. Contraindications Unique clinical issues unique to levomilnacipran include hyper- Both in-vitro and in-vivo studies found sensitivity to levomilnacipran, milnacip- that levomilnacipran exhibited more po- ran, or any component specific to the for- tency for NE reuptake inhibition than for mulation; and uncontrolled narrow-angle 5-HT reuptake inhibition at the lowest glaucoma.1 effective dosage (10 mg/kg). However, as the dosage was increased (20 mg/kg and Dosing 40 mg/kg), it was equally potent at NE and The recommended dosage range of 5-HT reuptake inhibition. This is in con- levomilnacipran is 40 to 120 mg once trast to venlafaxine, which demonstrates daily with or without food. The capsules a similar, but opposite, effect in terms of should be swallowed whole and should potentiation at the 5-HT and NE reuptake not be opened or crushed. As with most pumps.2 psychotropics, levomilnacipran should The greater noradrenergic effect of le- be taken at approximately the same time vomilnacipran could lend itself to treating each day.1 certain subgroups of patients whose symp- The manufacturer recommends an ini- toms are believed to be related to deficien- tial dose of levomilnacipran of 20 mg once cies in NE (eg, lassitude).4 This concept is daily for 2 days, increased to 40 mg once theoretical, and was not explicitly studied daily. Based on efficacy and tolerably, le- in clinical trials and the drug is not labeled vomilnacipran can be increased in incre- Current Psychiatry 54 December 2013 in this way. ments of 40 mg every 2 days. Out of the Pipeline

Related Resources Summary of the seminal data that led to FDA approval of levomilnacipran • Citrome L. Levomilnacipran for major depressive disorder: a for the treatment of MDD in adults systematic review of the efficacy and safety profile for this newly approved - what is the number need- Study type Inclusion criteria Dosing Efficacy assessment Tolerability and safety ed to treat, number needed to harm and likelihood to be Study 13 Phase III, RCT -Outpatient Flexible MADRS 0 to 10 week shows: 18 placebo and 26 levomilnacipran-treated patients helped or harmed? [published online September 8, 2013]. Int J Clin Pract. doi: 10.1111/ijcp.12298. 10 weeks -Age 18 to 70 75 to 100 mg/d 4.2 point difference in favor of withdrew because of AEs • Mago R, Forero G, Greenberg WM, et al. Safety and toler- levomilnacipran vs placebo Most common AE in the levomilnacipran group was n = 557 (completers) -Meeting DSM-IV-TR ability of levomilnacipran ER in major depressive disorder: criteria for MDD for NNT = 6 (response) GI upset results from an open-label, 48-week extension study. Clin >1 month NNT = 5 (remission)3 Drug Investig. 2013;33(10):761-771. -HDRS-17 >22 Drug Brand Names -SDS >10 Duloxetine • Cymbalta Milnacipran • Savella Study 25 Phase III -Outpatient Fixed MADRS total score: shows Well tolerated and safe Ketoconazole • Nizoral Venlafaxine • Effexor Levomilnacipran • Fetzima RCT -Age 18 to 65 40, 80, or 120 mg/d higher dose of levomilnacipran Clinical Point (80, 120 mg) lead to significantly 11 weeks -Meeting DSM-IV-TR greater changes compared criteria for MDD for The manufacturer n = 704 (completers) with placebo >8 weeks recommends an -MADRS >30 initial dose of AE: adverse event; GI: gastrointestinal; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery-Åsberg Depression Rating Scale; in vitro and in models of depression and anxiety. MDD: major depressive disorder; NNT: number needed to treat; RCT: randomized control trial; SDS: Sheehan Disability Scale Neuropharmacology. 2013;70:338-347. levomilnacipran of 3. Montgomery SA, Mansuy L, Ruth A, et al. Efficacy and Safety of levomilnacipran sustained release in moderate to 20 mg once daily for severe major depressive disorder: a randomized, double- blind, placebo-controlled, proof-of-concept study. J Clin 2 days, increased to Psychiatry. 2013;74(4):363-369. 40 mg once daily Dosage adjustment is recommended 4. Kasper S, Meshkat D, Kutzelnigg A. Improvement of the for patients with moderate or severe renal noradrenergic symptom cluster following treatment with milnacipran. Neuropsychiatric Dis Treat. 2011; 7(suppl 1): impairment; and the maintenance dos- 21-27. age should not exceed 80 mg and 40 mg, 5. Asnis GM, Bose A, Gommoll CP, et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 respectively, in these populations. As with mg in major depressive disorder: a phase 3, randomized, many , gradual dosage re- double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(3):242-248. duction is recommended to avoid discon- 6. Hutt AJ, Vanetová J. The chiral switch: the development tinuation symptoms. of single enantiomer drugs from racemates. Acta Facultatis Pharmaceuticae Universitatis Comenianae. 2003; 50(7):23. References 7. U.S. Food and Drug Administration. Development of new 1. Fetzima [package insert]. St. Louis, MO: ; stereoisomeric drugs. Published May 1, 1992. http://www.fda. 2013. gov/drugs/GuidanceComplianceRegulatoryInformation/ 2. Auclair AL, Martel JC, Assié MB, et al. Levomilnacipran Guidances/ucm122883.htm#.UKHEWm4ZyYE.email. (F2695), a norepinephrine-preferring SNRI: profile Accessed October 8, 2013.

Bottom Line Levomilnacipran is FDA-approved for treating major depressive disorder in adults. In 2 randomized controlled trials, the drug showed a significant separation from placebo. Levomilnacipran generally was reported to be safe and well tolerated; common adverse events were nausea, vomiting, changes in blood pressure, and Current Psychiatry an increase in heart rate. Vol. 12, No. 12 55