Sodium oxybate for the treatment of fibromyalgia

INTRODUCTION: Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is synthesized within the CNS, mostly from its parent compound gamma amino butyric acid (GABA). GHB acts as a neuromodulator/neurotransmitter to affect neuronal activity of other neurotransmitters and so, stimulate the release of growth hormone. Its sodium salt (sodium oxybate: SXB) was approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. SXB has shown to improve disrupted sleep and increase NR3 (slow-wave restorative) sleep in patients with narcolepsy. It is rapidly absorbed and has a plasma half-life of 30 - 60 min, necessitating twice-nightly dosing. Most of the observed effects of SXB result from binding to GABA-B receptors. AREAS COVERED: Several randomized, controlled trials demonstrated significantly improved fibromyalgia (FM) symptoms with SXB. As seen in narcolepsy trials, SXB improved sleep of FM patients, increased slow-wave sleep duration as well as delta power, and reduced frequent night-time awakenings. Furthermore, FM pain and fatigue was consistently reduced with nightly SXB over time. Commonly reported adverse events included headache, nausea, dizziness and somnolence. Despite its proven efficacy, SXB did not receive FDA approval for the management of FM in 2010, mostly because of concerns about abuse. EXPERT OPINION: Insomnia, fatigue and pain are important clinical FM symptoms that showed moderate improvements with SXB in several large, well-designed clinical trials. Because of the limited efficacy of currently available FM drugs additional treatment options are needed. In particular, drugs like SXB - which belong to a different drug class than other Food and Drug Administration (FDA)-approved FM medications such as pregabalin, duloxetine and milnacipran - would provide a much-needed addition to presently available treatment options. However, the FDA has set the bar high for future SXB re-submissions, with requirements of superior efficacy and improved risk mitigation strategies. At this time, no future FDA submission of SXB for the fibromyalgia indication is planned.     

Pregabalin for the treatment of fibromyalgia

Introduction: Fibromyalgia (FM) is the most common cause of chronic widespread body pain in humans. Co-morbidities include sleep disturbance, fatigue, impaired physical functioning, altered mood and negative effects on health-related quality of life. Pregabalin inhibits presynaptic release of pronociceptive neurotransmitters in the CNS; this likely underpins its therapeutic benefit in patients with FM.

Areas covered: This review addresses pregabalin pharmacokinetics, efficacy and adverse event (AE) profiles from randomized controlled trials and open-label extension studies in patients with FM. These effects are compared with those of the serotonin norepinephrine reuptake inhibitors, duloxetine and milnacipran that also have FDA approval for the treatment of fibromyalgia.

Expert opinion: At the approved dosages, oral pregabalin has at most a moderate therapeutic benefit above placebo with tolerable side-effects, in no more than 50% of patients with FM. Durability of clinically meaningful (≥ 30%) pain relief in pregabalin-responders has been demonstrated for at least 6-months, but longer-term studies are required as most patients have symptoms for decades. Exclusion of patients with common co-morbidities from the pregabalin RCTs in FM raises questions on the generalizability of the RCT findings to the typical patient seen in clinical practice and so additional investigation is required.     

gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness

gamma-Hydroxybutyrate (GHB) is an endogenous short chain fatty acid and a, mostly oral, pharmacological compound that has been utilised in a variety of ways. Endogenously, GHB is synthesised locally within the CNS, mostly from its parent compound GABA. Sodium oxybate is the sodium salt of GHB and is used for the exogenous oral administration of GHB. It is likely that supraphysiological concentrations of GHB from exogenous administration produce qualitatively different neuronal actions than those produced by endogenous GHB concentrations.Evidence suggests a role for GHB as a neuromodulator/neurotransmitter. Under endogenous conditions and concentrations, and depending on the cell group affected, GHB may increase or decrease neuronal activity by inhibiting the release of neurotransmitters that are co-localised with GHB. After exogenous administration, most of the observed behavioural effects appear to be mediated via the activity of GHB at GABA(B) receptors, as long as the concentration is sufficient to elicit binding, which does not happen at endogenous concentrations. Endogenous and exogenous GHB is rapidly and completely converted into CO(2) and H(2)O through the tricarboxylic acid cycle (Krebs cycle). Sodium oxybate has been observed to modulate sleep in nonclinical study participants, and sleep and wakefulness in clinical populations, including groups with insomnia, fibromyalgia and narcolepsy. In narcolepsy, sodium oxybate has shown dose-related effects on various properties of sleep, including increases in slow-wave sleep duration and delta power, and a reduced number of night-time awakenings. Furthermore, multiple measures of daytime sleepiness and cataplexy demonstrated consistent short- and long-term improvement in response to night-time sodium oxybate therapy. The most common reported adverse events include dose-related headache, nausea, dizziness and somnolence.     

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials

Objective: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials.

Methods: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change.

Results: A large proportion of patients exhibited concomitant headache, immunological (allergy), gastroesophageal, and/or psychiatric disorders. The efficacy analyses performed on these subgroups of patients, amongst others, showed – with few exceptions – consistent pain reductions of similar magnitude with pregabalin.

Conclusion: Comorbid conditions are common among patients with fibromyalgia and their presence is not associated with altered pregabalin efficacy.     

A review of sodium oxybate and baclofen in the treatment of sleep disorders

Studies examining GABA(B) receptor agonists have reported effects on sleep including decreased sleep onset latency (SOL), increased sleep consolidation and increases in slow wave sleep (SWS). γ-hydroxybutyrate (GHB) is proposed to act as a GABA(B) receptor agonist; however, the mechanism of action of GHB is controversial. In addition, the GABA(B) receptor agonist, baclofen, has also been proposed to exert similar effects on sleep. The aim of this paper is to provide a review of the human clinical studies of sodium oxybate and baclofen regarding sleep and the treatment of sleep disorders including narcolepsy and insomnia, as well as other disorders involving disrupted sleep such as fibromyalgia.     

Bedaquiline as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis

Introduction: Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials.

Area covered: Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it’s drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy.

Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline.     

The safety and efficacy of pregabalin for treating subjects with fibromyalgia and moderate or severe baseline widespread pain

Objective To evaluate pregabalin’s efficacy (≤12 weeks) for pain relief and sleep improvement in patients with fibromyalgia (FM) and moderate-to-severe baseline pain.

Research design and methods Data were pooled from five randomized, double-blind, placebo-controlled, phase III clinical trials of pregabalin (300–450 mg/day) for FM treatment. Subjects, aged?≥18 years, had moderate (≥4–<7) or severe (≥7–10) mean baseline pain scores. Analyses included mixed effects repeated measures (MMRM), baseline observation carried forward (for parameters without enough data points for MMRM), or logistic regression.

Clinical trial registration Study number/ClinicalTrials.gov number: A0081056/NCT00645398, A0081077/NCT00230776, A0081100/NCT00333866, A0081208/NCT00830167.

Main outcomes measures Endpoints included mean change in pain and sleep quality scores (Weeks 8 and 12), patient-reported outcomes, and adverse events (AEs).

Results Baseline demographic characteristics were comparable between pregabalin and placebo in both baseline pain severity groups. Mean?±?SD baseline pain severity scores were equivalent between pregabalin and placebo within moderate (5.8?±?0.8) or severe pain (7.9?±?0.7) subgroups. All subjects reported reduced pain and improved sleep quality through Weeks 8 and 12, with larger effects observed with pregabalin over placebo and with baseline severe over moderate pain (all p?<?0.01). Pregabalin was generally well tolerated, AE findings were consistent with previously published trials, and AE profiles were similar between moderate and severe baseline pain subgroups. Limitations of this pooled analysis included differences in individual trial designs (e.g., dosing schedules, racial distribution, exclusion criteria that did not enroll mild severity patients).

Conclusions Pregabalin was efficacious through 12 weeks for reducing pain and improving sleep quality in FM patients with baseline moderate or severe pain, with larger effects in the baseline severe pain subgroup. AEs were consistent with pregabalin’s known safety profile and did not differ between moderate and severe pain subgroups.     

美国FDA鼻用制剂相关个药指导原则汇总分析

目的 通过梳理美国食品药品监督管理局（Food and Drug Administration,FDA）发布的鼻用制剂相关个药指导原则,总结FDA对鼻用制剂仿制药的研究要求,为国内鼻用制剂仿制药开发和评价提供参考。方法 在FDA官网发布的个药指导原则中筛选出鼻用制剂相关指导原则,进行汇总分析。结果 目前FDA现行43个鼻用制剂相关个药指导原则,推荐的生物等效性方法包括体外生物等效性研究、药动学研究、比较临床终点研究方法等,因不同品种而有所区别。部分个药指导原则已收录先进的体外检测技术如形态定向拉曼光谱用于代替体内临床试验。本文对不同种类生物等效性试验的试验设计、主要研究终点和等效性标准方面进行了代表性描述。结论 本文对FDA发布的鼻用制剂相关个药指导原则进行了汇总分析,为国内鼻用制剂仿制药开发和评价提供参考。     

Armodafinil in the treatment of excessive sleepiness

Importance of the field: Excessive sleepiness causes impaired quality of life and increases the risk of poor health and accidents. Armodafinil is a wake-promoting agent approved in 2007 by the US Food and Drug Administration for the treatment of excessive sleepiness arising from narcolepsy, obstructive sleep apnea (OSA; even after optimal treatment for the underlying obstruction) and shift-work disorder (SWD). It is the R-enantiomer of modafinil, which is a racemic mixture of R- and S-enantiomers.

Areas covered in this review: This review summarizes the recent primary data on the pharmacokinetics, clinical efficacy and safety of armodafinil using literature published since 2005 that was identified from PubMed.

What the reader will gain: The review describes recent advances in the understanding of the pharmacokinetic profile of the drug and why this may improve wakefulness later after dosing compared with modafinil. It also describes the recent efficacy and safety data supporting the use of armodafinil to treat excessive sleepiness in indicated patients.

Take home message: Armodafinil is a useful therapy for the treatment of excessive sleepiness arising from a number of clinical conditions. It is generally well tolerated and has a low potential for abuse or tolerance.     

慢性疲劳综合征/肌痛性脑脊髓炎的治疗药物研究指南简介

美国食品和药品监督管理局（FDA）于2014年3月发布了“慢性疲劳综合症/肌痛性脑脊髓炎（CFS/ME）指南草案”。指南草案介绍CFS/ME的临床症状,严重的CFS/ME影响患者的工作、学习和日常生活。目前CFS/ME的诊断比较困难,也没有任何有效药物获批用于该病的治疗,CFS/ME已成为远未得到满足的公众健康问题。在草案中,FDA从药物的临床试验设计等多方面,如目标人群定位、疗效终点、安全性等来指导相关新药的研发。介绍了指南的主要内容,期望为我国这方面的临床试验及药物的开发提供参考。     

FDA“乳糜泻：开发无麸质饮食辅助治疗药物供企业用的指导原则（草案）”介绍

美国食品药品监督管理局（FDA）于2022年4月发布了“乳糜泻：开发无麸质饮食辅助治疗药物供企业用的指导原则（草案）”。该指导原则草案提出了无麸质饮食辅助治疗药物临床试验方案的建议，详细说明了开发这类药物临床试验关键要素的许多具体建议，包括试验人群、试验设计、疗效及安全性评估等方面。而我国目前尚没有类似的指导原则。详细介绍FDA该指导原则草案主要内容，期望对我国这类药物开发的临床研究及其监管有帮助。     

Examination of risk evaluation and mitigation strategies and drug safety in the US

BackgroundThe Food and Drug Administration Amendment Act of 2007 (FDAAA 2007) enabled the US Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) for a drug or biologic to ensure that its benefits outweigh the risks.ObjectiveThis study sought to evaluate REMS approved and released by the FDA since the program inception in 2008, to assess the characteristics of REMS approved and to calculate the time lag between FDA drug application approval and REMS approval.MethodsData were derived from Approved Drug Products with Therapeutic Equivalence Evaluations, Approved REMS and Drugs@FDA. Data included generic availability, application type and approval date, therapeutic class and FDA review class, orphan designation, priority review and market status.ResultsThe FDA approved REMS for 259 marketing applications (217 new drug applications -NDAs, 10 abbreviated NDAs, and 32 biologic license applications) in the study period. The FDA granted orphan designation to 11.4% of active ingredients with REMS and priority review to 38.4% of the NDAs with REMS. The largest number of REMS approvals was for nervous system products (31.8% of total approved REMS) and antineoplastic and immunomodulating agents (15.3%).ConclusionsThe FDA approved REMS for one in three biologics and one in thirteen chemical entities available in the market. A pharmaceutical product can be in the market for an average of 14 years before the FDA identifies and evaluates the risk problems that warrant the approval of a REMS.     

Clinical Investigation in Animals

Abstract

The Code of Federal Regulations Part 511 addresses the requirements for new animal drugs for investigational use. In 1977, the Food and Drug Administration proposed new rules for the conduct of clinical trials. Although these are only proposed regulations, the FDA uses them as guidelines when conducting audits of clinical investigators. These proposed Good Clinical Practice Regulations have resulted in an improvement in the manner animal clinical studies are now conducted. We feel the results have been positive for all concerned, the public, sponsor and the Food and Drug Administration.     

An update on pharmacotherapy for the treatment of fibromyalgia

Introduction: Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised.

Areas covered: Publications describing randomized controlled trials and long-term extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review.

Expert opinion: Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials.     

Reconsidering GHB: orphan drug or new model antidepressant?

For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.     

Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed

Introduction: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry.

Areas covered: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations.

Expert opinion: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments.     

Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape

ABSTRACT

Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.     

Fenofibric acid for hyperlipidemia

Introduction: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) are the mainstay of therapy for hyperlipidemia, as per the current National Cholesterol Education Program (NCEP) recommendation. However, the role of other agents, such as the fibrates, is continually being debated in the context of incremental risk reduction, especially in the setting of mixed dyslipidemia. Results from the ACCORD Trial have further added to the confusion. Fibrates also have a role to play in familial hyperlipidemias and in hypertriglyceridemia. Fenofibric acid is one of the newly approved forms of fenofibrate with enhanced bioavailability and was recently approved by the Food and Drug Administation (FDA) for the treatment of various types of hyperlipidemia, in conjunction with statins.

Areas covered: This article reviews the role of fenofibric acid in the context of results from recent randomized trials on fenofibrate, including the ACCORD Trial. It discusses the current status of fenofibric acid in the management of dyslipidemia, especially in combination with statins, and also addresses the comparative efficacy and safety profile of this new molecule against other agents in its class.

Expert opinion: fenofibric acid in combination with low- to moderate-dose statins is an effective and safe option in the treatment of mixed dyslipidemia, although the long-term effects on cardiovascular risk reduction need to be explored further.