Edivoxetine Hydrochloride

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n = 4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

The purpose of this study was to assess the long-term safety and tolerability of edivoxetine, a selective norepinephrine reuptake inhibitor, which was being developed as monotherapy in pediatric attention-deficit/hyperactivity disorder (ADHD).

This was an open-label study of edivoxetine once daily dosing (0.1-0.3 mg/kg) as treatment for ADHD in children (6-11 years) and adolescents (12-17 years) to assess safety for up to 5 years. The safety assessments included the incidence of adverse events, vital signs, electrocardiograms, laboratory tests, percentile changes in weight, height, and body mass index, and Tanner staging. Efficacy of treatment with edivoxetine was also assessed using the Attention-Deficit/Hyperactivity Disorder Rating Scale-Version IV-Parent Reported: Investigator Scored (ADHDRS-IV) and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S).

A total of 267 children and adolescents were enrolled and 20 completed the 5-year study. Most of the participants were male (70.4%) and white (67.4%), and the mean age was 11.6 years. Two hundred three participants (76.9%; N = 264) experienced at least one adverse event. Treatment-emergent adverse events reported in >10% of participants were headache, vomiting, nausea, and upper respiratory tract infection. Serious adverse events (SAEs) were reported by seven participants (2.7%) during study treatment periods, and one participant was diagnosed with suspect epilepsy during the follow-up period after discontinuation of edivoxetine.

Long-term open-label treatment with edivoxetine as monotherapy in children and adolescents with ADHD revealed a safety profile that was consistent with its pharmacological effects on norepinephrine transmission and with that reported in short-term studies of edivoxetine. The study was terminated early due to slow enrollment and the very low number of 5-year completers. Lilly is not proceeding with further development of edivoxetine, as announced in 2013.