Safety and Tolerability of Levomilnacipran ER in Major Depressive Disorder: Results from an Open-Label, 48-Week Extension Study

Abstract

BackgroundLevomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin (5-HT) and norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of major depressive disorder in adults.ObjectiveThe objective of this study was to evaluate the longer-term safety and tolerability of levomilnacipran extended-release (ER).MethodsPatients who completed double-blind treatment/down-taper in one of three lead-in levomilnacipran ER studies were eligible for this 48-week open-label extension. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), physical examinations, laboratory and vital sign measures, and suicidality, summarized using descriptive statistics for the safety population.ResultsThe completion rate was 47 %; median treatment duration was 280 days. The most frequent reasons for discontinuation were withdrawal of consent (14 %) and adverse events (AEs; 13 %). TEAEs were reported by 712 (86 %) patients; most were mild/moderate and occurred early in treatment. The most common TEAEs were headache (22 %) and nausea (16 %); 36 (4 %) patients had ≥1 serious AEs. No clinically meaningful changes occurred in mean liver enzyme, metabolic, hematologic, urinalysis, or serum values; potentially clinically significant high AST or ALT values (≥3 × upper limit of normal) occurred in five patients. Vital sign changes occurred early and remained relatively stable. Mean increases for pulse rate (9.1 beats per minute [bpm]), and supine systolic (3.9 mmHg) and diastolic (3.3 mmHg) blood pressure were noted. The increase in the mean QT interval corrected using the Bazett formula (10.9 ms) was consistent with heart rate increase (12.8 bpm); there was no meaningful change in mean QT interval corrected using the Fridericia formula (−1.3 ms). Other than tachycardia and heart rate increases, ECG-related TEAEs were low (<0.5 %).ConclusionNo new or inconsistent safety/tolerability findings were discovered during longer-term evaluation.

Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

“…Mean (SD) change in QTcB interval was +11.2 (20.7) ms and in QTcF interval was À1.1 (17.3) ms; changes in other ECG parameters were similar to results in short-term studies. No patient had a QTcF greater than 500 ms (17). Cardiovascular-related AEs that led to discontinuation in greater than two patients were tachycardia (seven patients), hypertension (six patients) and BP increased (three patients).…”

“…The occurrence of C-SSRS-rated suicidal ideation was reported in 22% of patients (primarily 'wish to be dead' in 13% of patients); suicidal behaviour was reported in less than 1% of patients (17). Four patients discontinued the study because of a suicide attempt (two actual and two aborted attempts).…”

“…Four of the five trials demonstrated efficacy as measured by the Montgomery Asberg Depression Rating Scale, with a NNT for response vs. placebo of 9 (95% CI 7-15), and for remission, 14 (95% CI 10-28). NNH vs. placebo for discontinuation because an adverse event (AE) across all five trials was 19 (95% CI [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo), as identified in product labelling, were nausea, hyperhidrosis, constipation, heart rate increased, erectile dysfunction in men, vomiting, tachycardia and palpitations.…”

“…Of these, two were original clinical trial reports for short-term randomised controlled efficacy studies (12,13). Available posters include reports for three other short-term randomised controlled efficacy studies (14)(15)(16), an openlabel 48-week extension study (17), and a randomised controlled study of relapse prevention (18). Additional posters have presented pooled analyses from the five short-term efficacy trials (19)(20)(21), secondary and post hoc analyses from individual trials (22)(23)(24), and information regarding pharmacokinetics (25,26), drug-drug interactions (27), cardiovascular safety (28) and the impact of hepatic (29) and renal (30) function on pharmacokinetic variables.…”

“…Examining the effects on functional outcomes in the fixed-dose study testing levomilnacipran 40, 80 and 120 mg/day (23), levomilnacipran 80 and 120 mg significantly improved SDS scores and the largest and most robust treatment effects were in the levomilnacipran 120 mg group. For functional remission, significant treatment advantage was found in patients with severe MDD (baseline MAD-RS score at least 35) who received the highest dosage of levomilnacipran (120 mg/day), with remission rates of 28% vs. 12%, resulting in a NNT of 7 (95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”