Levomilnacipran generally was reported to be safe and well tolerated. The most common adverse events leading to discontinuation in the levomilnacipran group were nausea, vomiting, change in systolic and diastolic blood pressure, and increase in heart rate. The favorable tolerability profile of levomilnacipran may relate to the 2-fold greater potency for NE reuptake inhibition compared with 5-HT reuptake inhibition.3
The second study was an 11-week, fixed-dose trial of levomilnacipran using 40, 80, or 120 mg. A total of 724 outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD and who had an ongoing episode of depression lasting >8 weeks were randomly assigned to receive placebo (n = 179) or levomilnacipran at 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment followed by a 2-week, double-blind taper of the drug.5 The primary efficacy parameter was change from baseline on the MADRS and the secondary efficacy parameter was change from baseline in SDS total score. HDRS-17, CGI-I, and CGI-S were included as secondary outcome measures.5
Significant difference in MADRS total score were seen in the levomilnacipran group compared with the placebo group (least mean squared difference: 40 mg/d, −3.23; 80 mg/d, −3.99; and 120 mg/d, −4.86). Higher dosages produced a numerically greater change and significant separation from placebo occurred sooner in the 80-mg and 120-mg groups compared with the 40-mg group.5
Significant differences vs placebo were consistently observed across secondary outcome measures for the higher dosages of levomilnacipran, and improvement in SDS total score was noted in all levomilnacipran groups compared with the placebo group. When dosed at 120 mg/d, levomilnacipran produced significant improvement vs placebo on all SDS subscales and was as well tolerated as the 80 mg dosage.5
No new safety concerns were observed in the study. A dose-response relationship in tolerability was not demonstrated and the number of patients reporting adverse events and who discontinued participation because of adverse events was higher in the 80-mg group than in the 40-mg and 120-mg groups.5
Tolerability
Overall, levomilnacipran was well tolerated in clinical trials, during which 2,673 subjects were exposed to the drug—translating to 942 patient-years of exposure. These patients ranged in age from 18 to 78; 825 of these subjects were enrolled in long-term studies for 1 year. Dosing of levomilnacipran during these studies ranged from 40 to 120 mg once daily, without regard to food.1
Nine percent of patients who received levomilnacipran in short-term studies discontinued because of adverse events, compared with 3% of patients who received placebo. The most common adverse event reported was nausea; other common adverse events reported included constipation, hyperhidrosis, elevated heart rate, erectile dysfunction, tachycardia, palpitations, and vomiting. Of these events, only erectile dysfunction and urinary hesitation were dose-related.1 Among levomilnacipran-treated female patients, <2% reported adverse events related to sexual dysfunction.
All SNRIs have well established associations with elevation in blood pressure and heart rate. Levomilnacipran resulted in a mean increase of 3 mm HG in systolic and 3.2 mm Hg in diastolic blood pressure in short-term, placebo-controlled trials.1
Orthostatic hypotension was observed in 11.6% of patients in the levomilnacipran groups, compared with 9.7% in placebo groups in all short-term studies. Orthostatic reductions of blood pressure occurred in 5.8%, 6.1%, and 9.8% of levomilnacipran-treated patients with dosages of 40, 80, and 120 mg/d respectively, indicating a dose-dependent adverse event. A mean increase in heart rate of 7.2 beats per minute (bpm) also was seen in short-term studies in the levomilnacipran-treated group compared with 0.3 bpm in the placebo-treated group.1 Clinicians should monitor blood pressure and heart rate routinely because of potential increases seen in some subjects in these studies, which excluded those who had significant cardiovascular disease.
Unique clinical issues
Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.2
The greater noradrenergic effect of levomilnacipran could lend itself to treating certain subgroups of patients whose symptoms are believed to be related to deficiencies in NE (eg, lassitude).4 This concept is theoretical, and was not explicitly studied in clinical trials and the drug is not labeled in this way.
Contraindications
Contraindications to levomilnacipran are similar to those seen with SSRIs and SNRIs, including concomitant use of a monoamine oxidase inhibitor (MAOI) and the use of the levomilnacipran within 14 days of stopping an MAOI. Contraindications unique to levomilnacipran include hypersensitivity to levomilnacipran, milnacipran, or any component specific to the formulation; and uncontrolled narrow-angle glaucoma.1