Early Onset and Maintenance Effect of Galcanezumab in Japanese Patients with Episodic Migraine.

PURPOSE: This study aimed to extensively evaluate the onset and maintenance effect of galcanezumab compared with placebo for the prevention of episodic migraine in Japanese patients. PATIENTS AND METHODS: This was a post-hoc analysis of a Phase 2, multicenter, randomized, double-blind, placebo-controlled study conducted between December 2016 and January 2019 (ClinicalTrials.gov: NCT02959177). Patients aged between 18 and 65 years with episodic migraine were randomized to receive a monthly injection of galcanezumab (120 mg: N = 115, 240 mg: N = 114) or placebo (N = 230) for 6 months. Outcome measures included onset of effect at weekly and daily intervals-assessed by change from baseline in the number of migraine headache days and the proportion of patients with migraine headache-with galcanezumab versus placebo. To further confirm the onset and maintenance effect, the 50% response rate was also evaluated. RESULTS: The mean change from baseline in weekly migraine headache days was significantly reduced with galcanezumab (-0.97 days) compared with placebo (-0.10 days) at week 1 (p ≤ 0.0001), which was maintained at all subsequent weeks up to week 4 (all p ≤ 0.0001 vs placebo). A significantly smaller proportion of galcanezumab-treated patients had migraine headache compared with placebo-treated patients at day 1 after the first injection (13.6% vs 31.4%, respectively; p ≤ 0.0001), which was also maintained at all subsequent days during the first week after the first injection. Furthermore, the 50% response rate was significantly higher with galcanezumab compared with placebo from week 1 through month 6. CONCLUSION: The onset of the migraine preventive effect of galcanezumab was rapid compared with placebo, starting from day 1 after the first injection in Japanese patients with episodic migraine. The effect was maintained during the first week and first month, and throughout 6 months of monthly injections of galcanezumab. Galcanezumab is a promising preventive treatment in Japanese patients with episodic migraine.

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2-5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research.

Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

Profile of sexual and genitourinary treatment-emergent adverse events associated with atomoxetine treatment: a pooled analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that begins in childhood. Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. Several studies have demonstrated the safety and efficacy of atomoxetine in the treatment of ADHD. OBJECTIVE: The objective of this analysis was to provide additional information on the frequency, time to onset and time to resolution of sexual and genitourinary (GU) treatment-emergent adverse events (TEAEs) reported during atomoxetine treatment in clinical trials. METHODS: Data from all adult atomoxetine placebo-controlled ADHD trials were pooled for this analysis, for a total of 3,314 patients (atomoxetine, n = 1,738; placebo, n = 1,576). Additionally, data from all adolescent patients (baseline age ≥13 to <18 years) within all ADHD placebo-controlled trials were pooled for analysis, for a total of 538 patients (atomoxetine, n = 329; placebo, n = 209). Rates of sexual and GU TEAEs were summarized by sex for each age group. Time to onset and resolution of sexual and GU TEAEs were summarized and compared using Kaplan-Meier methods. RESULTS: Overall, the baseline characteristics of randomized patients in the atomoxetine and placebo groups were similar. Profiles of sexual and GU TEAEs for atomoxetine appeared clinically similar to placebo in female patients and in adolescent male patients. Adult male patients reported relatively more sexual and GU TEAEs when taking atomoxetine compared with placebo, with libido decreased (4.6 vs. 3.0 %), dysuria (3.7 vs. 1.5 %), urinary hesitation (6.9 vs. 2.4 %), urine flow decreased (2.5 vs. 0.6 %), ejaculation disorder (2.8 vs. 1.1 %) and erectile dysfunction (8.0 vs. 1.9 %) being the most common. The time to onset of the most common TEAEs in adult male patients tended to occur relatively early in dosing: within the first 2 weeks for GU TEAEs, and during the second and third week of dosing for erectile and ejaculation issues. The median time to resolution for these events ranged from around 3-8 weeks after event onset, depending on the event. While the common sexual and GU TEAEs showed numerically higher percentages of discontinuations in atomoxetine-treated patients compared with placebo, most incidences of the sexual and GU TEAEs were not considered severe. CONCLUSIONS: The sexual and GU TEAE profiles of patients taking atomoxetine were generally similar to those of patients taking placebo in the female and adolescent male populations, with greater frequency of TEAEs reported in adult males taking atomoxetine compared with placebo. The time to onset of the TEAEs tended to be shorter, and time to resolution tended to be longer in adult male patients treated with atomoxetine compared with those receiving placebo. The conclusions must be interpreted with caution because the TEAEs were likely underreported.