Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events.

BACKGROUND: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. METHODS: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. RESULTS: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. CONCLUSIONS: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis.

OBJECTIVE: To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. METHODS: Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs. RESULTS: Forty participants were randomized (placebo n = 22; belimumab n = 18). The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG-Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups. One participant receiving placebo died (severe sepsis) during the treatment phase. CONCLUSIONS: The primary endpoint was not met for belimumab in participants with generalized MG receiving SoC. There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo. The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo.

Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

Bupropion, a noradrenaline/dopamine reuptake inhibitor, and venlafaxine, a serotonin/noradrenaline reuptake inhibitor, are both established antidepressants with proven efficacy in randomized controlled clinical trials. The objective of this double-blind, randomized, placebo- and active-controlled, eight-week, flexible-dose study was to evaluate the efficacy and tolerability of the once-daily extended-release formulations of these two antidepressants compared with placebo. Patients with major depressive disorder were randomized to once-daily treatment with bupropion XR 150 mg (n = 204), the extended-release formulation of venlafaxine (venlafaxine XR) 75 mg (n = 198) or placebo (n = 189) during weeks 1 to 4, with the option to double the dose at week 5 if response was inadequate. In this study, bupropion XR did not demonstrate statistically significant evidence of greater improvement from baseline compared with placebo on week 8 Montgomery Asberg Depression Rating scale scores (primary endpoint) or on secondary endpoints including CGI, HAM-A and responder and remitter analyses. Descriptive statistics for venlafaxine XR indicated separation versus placebo on MADRS total scores at week 8 and other intermediate time points, and on other endpoints including CGI, HAM-A and responder and remitter analyses. Both active treatments elicited improvement on the Sheehan Disability Scale and its subscales and were generally well tolerated at the doses studied. Rates of nausea, dry mouth, dizziness, hyperhidrosis, insomnia, constipation, tremor, anorexia and male sexual dysfunction were elevated in the venlafaxine XR group, consistent with its mixed serotonergic/noradrenergic mechanism. Rates of dry mouth, insomnia and hyperhidrosis were elevated in the bupropion XR group, consistent with its catecholaminergic mechanism.

Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder.

BACKGROUND: Paroxetine has demonstrated efficacy in depression and anxiety disorders, including generalized anxiety disorder (GAD). This 32-week study evaluated the maintained efficacy and safety of paroxetine in GAD by assessing the potential for relapse after discontinuation of medication. METHOD: Adults (N = 652) with DSM-IV GAD and a Clinical Global Impressions-Severity of Illness (CGI-S) score > or = 4 received paroxetine (20-50 mg/day) for 8 weeks. Patients whose CGI-S score had decreased by at least 2 points to < or = 3 at week 8 were randomly assigned to double-blind treatment with paroxetine (N = 278) or placebo (N = 288) for a further 24 weeks. The primary efficacy parameter was the proportion of patients relapsing (an increase in CGI-S score of at least 2 points to a score < or = 4 or withdrawal resulting from lack of efficacy) during double-blind treatment. RESULTS: Significantly fewer paroxetine than placebo patients relapsed during the 24-week double-blind phase (10.9% vs. 39.9%; p <.001). Placebo patients were almost 5 times more likely to relapse than paroxetine patients (estimated hazard ratio = 0.213 [95% CI = 0.1 to 0.3]; p <.001). Statistical significance in favor of paroxetine was demonstrated for all secondary efficacy parameters, including functional status. Twice as many paroxetine patients as placebo patients (73%) achieved remission. Paroxetine was well tolerated, with no unexpected adverse events reported. CONCLUSION: Paroxetine was found to be effective and well tolerated for both the short- and long-term treatment of DSM-IV GAD. Continued treatment with paroxetine significantly reduced the potential for relapse of GAD symptoms.

Lack of effect of morphine-3-glucuronide on the spinal antinociceptive actions of morphine in the rat: an electrophysiological study.

Previous studies have shown that morphine-3-glucuronide (M3G), a metabolite of morphine, may functionally antagonize the antinociceptive action of morphine. The interaction between morphine and M3G was therefore investigated in the halothane-anaesthetised rat. Extracellular unit recordings were made of the innocuous A-beta fibre and noxious C-fibre evoked responses of convergent dorsal horn neurones. Intrathecal M3G (5 micrograms, 100 micrograms and 500 micrograms) alone did not show any antinociceptive effect. There was a slight, but not statistically significant, decrease in the antinociceptive effect of 5 micrograms morphine in the M3G-pretreated groups. However, M3G pretreatment (5 micrograms, 100 micrograms and 500 micrograms) had no effect on the higher dose of morphine (50 micrograms) used. We conclude that M3G has, at most, a minor effect on the spinal antinociceptive effects of morphine.