Joachim F. Wernicke

A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder

&NA; This was a 12‐week, randomized, double‐blind, placebo‐controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. Patients (90% Caucasian; mean age, 49.6 years; 26% with current major depressive disorder) received duloxetine 60 mg once daily (QD) (N=118), duloxetine 60 mg twice daily (BID) (N=116), or placebo (N=120). The primary outcome was the Brief Pain Inventory average pain severity score. Response to treatment was defined as ≥30% reduction in this score. Compared with placebo, both duloxetine‐treated groups improved significantly more (P<0.001) on the Brief Pain Inventory average pain severity score. A significantly higher percentage of duloxetine‐treated patients had a decrease of ≥30% in this score (duloxetine 60 mg QD (55%; P<0.001); duloxetine 60 mg BID (54%; P=0.002); placebo (33%)). The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality‐of‐life measures. Both doses of duloxetine were safely administered and well tolerated. In conclusion, both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder.

Atomoxetine and Methylphenidate Treatment in Children With ADHD: A Prospective, Randomized, Open-Label Trial

ABSTRACT Objective To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) Method Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. Results Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. Conclusion These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

Cardiovascular Effects of Atomoxetine in Children, Adolescents, and Adults

AbstractBackground: Atomoxetine is a highly specific presynaptic inhibitor of the noradrenaline (norepinephrine) transporter that was recently approved in the US for the treatment of patients with attention-deficit/hyperactivity disorder (ADHD). Adverse effects on the cardiovascular system, including abnormalities in heart rate, blood pressure, or cardiac rhythm have been associated with several noradrenergic medications. Objective: To further elucidate the magnitude and impact of blood pressure and pulse elevations in patients taking atomoxetine. Study Design: Short-term cardiovascular safety in children, adolescents, and adults with ADHD was assessed in five randomised, double-blind trials (duration up to 10 weeks) with atomoxetine (n = 612) or placebo (n = 474). Long-term cardiovascular safety in children and adolescents (n = 169) was assessed in patients who entered an open-label extension or a blinded continuation following short-term treatment. Methods: Adverse events, blood pressure, sitting pulse, and electrocardiograms (ECGs) were collected throughout the trials. QT intervals were corrected for heart rate by a data-specific correction factor (QTcD; derived from baseline ECGs) as well as standard methods. Results: Atomoxetine treatment was associated with small but statistically significant increases in mean systolic blood pressure in adults and diastolic blood pressure in children and adolescents. Mean pulse rate increased for all atomoxetine treatment groups. The increases in blood pressure and pulse tended to occur early in therapy, stabilised, and returned toward baseline upon drug discontinuation. There was no significant difference between atomoxetine and placebo treatment groups in change in QTcD interval for all study populations. Palpitations in the adult patient population were the only significant cardiovascular adverse event (p = 0.037) occurring more frequently in the atomoxetine treatment group (3.7%) than in the placebo group (0.8%). Discontinuations due to cardiovascular-related events were very uncommon in the adult group, and did not occur in the child/adolescent group. Conclusion: While atomoxetine has noradrenergic activity, increases in pulse and blood pressure were small and of little, if any, clinical significance. Atomoxetine was not associated with QT interval prolongation. Cardiovascular effects of atomoxetine were minimal, and atomoxetine was well tolerated in short- and long-term studies.

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

AbstractBackground and objective: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). Methods: The cardiovascular safety of duloxetine was assessed using all placebocontrolled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebocontrolled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. Results: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia’s formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. Conclusion: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

A retrospective pooled analysis of duloxetine safety in 23 983 subjects

ABSTRACT Objective: The safety and tolerability of duloxetine for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain (DPNP), fibromyalgia, and lower urinary tract disorders (LUTD) (including female stress urinary incontinence [SUI] and other LUTDs) has been established in individual clinical studies. The objective of this manuscript is to characterize the overall safety profile of duloxetine, regardless of indication, based on data from the duloxetine exposures integrated safety database. Research design and methods: The duloxetine exposures integrated safety database was examined using pooled data from 23 983 patients randomized to receive duloxetine in 64 studies for MDD, GAD, DPNP, fibromyalgia, or LUTDs. Evaluated aspects of drug safety included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. Results: Common TEAEs included nausea, headache, dry mouth, insomnia, constipation, dizziness, fatigue, somnolence, diarrhea, and hyperhidrosis. Most TEAEs emerged early; the majority were mild to moderate in severity, and did not worsen. Overall, discontinuation rates due to AEs were 20.0%. SAEs occurred at a rate of 3.5% and no single event was predominant. Mean pulse increased by < 2 beats per minute. Mean increases in systolic and diastolic blood pressure were < 1 mmHg. Mean alanine transaminase and aspartate transaminase values increased by < 2 U/L. Conclusions: The safety profile for the molecule from the overall duloxetine exposures integrated safety database suggests that benign and common pharmacologic side effects occur with duloxetine treatment. Because these pooled analyses do not allow for statistical comparison to placebo or active comparator, and include data from five different studied indications, these data do not suggest causality for AEs, nor are they necessarily generalizable to each disease stated studied.

Seizure risk in patients with attention‐deficit‐hyperactivity disorder treated with atomoxetine

The comorbidity of seizures, epilepsy, and attention‐deficit‐hyperactivity disorder (ADHD) prompted the examination of whether atomoxetine use for ADHD is associated with an increased risk of seizures. Seizures and seizure‐related symptoms were reviewed from two independent Eli Lilly and Company databases: the atomoxetine clinical trials database and the atomoxetine postmarketing spontaneous adverse event database. Review of clinical trial data indicated that the crude incidence rates of seizure adverse events were between 0.1 and 0.2%, and were not significantly different between atomoxetine, placebo, and methylphenidate. Only 2% of the postmarketing spontaneous reports of seizure events were classified as having no clear contributing or confounding factors, and the reporting rate (8 per 100 000 patients exposed) was within the expected range of population‐based incidence. Although children with ADHD are increasingly recognized as being at an elevated risk for seizures, treatment of ADHD symptoms with atomoxetine does not appear to elevate this risk further. The shared vulnerability between ADHD and seizure activity should be taken into account when making treatment decisions for populations of children with epilepsy and children with ADHD.

Hepatic Events Associated with Atomoxetine Treatment for Attention-Deficit Hyperactivity Disorder

AbstractObjective: This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. Methods: Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. Results: Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy’s rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. Conclusions: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment

Abstract: Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.

QT Correction Methods in Children and Adolescents

Introduction: Accurate determination of the QTc interval has become increasingly important in the assessment of a drugs ability to prolong cardiac repolarization. Previous work suggests the most appropriate correction formula for adults is QTc = QT/RR0.40, but little on correction methods for children and adolescents has been published.

Hepatic effects of duloxetine-I: non-clinical and clinical trial data.

OBJECTIVE Review nonclinical and clinical trial data for hepatic effects of duloxetine. METHODS Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials. RESULTS Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases >3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hys rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each). CONCLUSIONS Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.