Balancing efficacy and toxicity of novel therapies in systemic lupus erythematosus

Therapy of systemic lupus erythematosus has been facing the paradox of an overwhelming rate of trials testing novel potential therapeutic agents and the lack of US FDA approval of a single new drug for over five decades. Heterogeneity in disease phenotype, concomitant immunosuppressive medication and a lack of unequivocal hard end points for clinical trials have proven to be significant obstacles in establishing efficacy of candidate therapies. Nevertheless, combination regimens with already existing agents have shown efficacy with acceptable safety profiles, mainly in cases of refractory to conventional treatment disease. At the same time, positive results from trials with belimumab, an antibody that targets B cells, opened the way for approval of this agent for the treatment of lupus and lends hope for a new era in systemic lupus erythematosus therapeutics. Here, we review the latest advances in systemic lupus erythematosus therapy, focusing on the balance between efficacy and safety for combination therapeutic regimens and biologics under development.     

Balancing efficacy and toxicity of novel therapies in systemic lupus erythematosus

Therapy of systemic lupus erythematosus has been facing the paradox of an overwhelming rate of trials testing novel potential therapeutic agents and the lack of US FDA approval of a single new drug for over five decades. Heterogeneity in disease phenotype, concomitant immunosuppressive medication and a lack of unequivocal hard end points for clinical trials have proven to be significant obstacles in establishing efficacy of candidate therapies. Nevertheless, combination regimens with already existing agents have shown efficacy with acceptable safety profiles, mainly in cases of refractory to conventional treatment disease. At the same time, positive results from trials with belimumab, an antibody that targets B cells, opened the way for approval of this agent for the treatment of lupus and lends hope for a new era in systemic lupus erythematosus therapeutics. Here, we review the latest advances in systemic lupus erythematosus therapy, focusing on the balance between efficacy and safety for combination therapeutic regimens and biologics under development.     

Making a case for domperidone in the treatment of gastrointestinal motility disorders

There are very few treatment options currently available for patients with gastrointestinal motility disorders, especially patients with gastroparesis. Domperidone, a peripheral dopamine receptor antagonist, has been successfully used for decades in the US and marketed in many countries for the treatment of gastroparesis. Its use, however, has recently become controversial owing to safety concerns, and it has never been approved for marketing by the FDA. During the 1990s, domperidone was available to US gastroenterologists under a compassionate-use program by Janssen Pharmaceutica, as the manufacturer worked towards, and fell short of, full US market approval. Medical studies, trials and case reports demonstrate the superior efficacy of domperidone when compared with placebo and other pharmaceutical therapies available. Data on the cardiac toxicity associated with oral use of domperidone fail to be convincing.     

Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome?

Functional gastrointestinal disorders such as the irritable bowel syndrome (IBS) cause substantial morbidity and a high amount of healthcare utilisation. However, no direct mortality can be attributed to functional disorders. Hence, drug treatment of IBS must not only be highly efficient to relieve clinical symptoms but also very safe for the long-term use in humans with such chronic disorders. Alosetron is a potent and highly selective serotonin 5-HT(3 )receptor antagonist that in large randomised controlled clinical trials has been shown to be clinically efficient in female patients with diarrhoea-predominant IBS. The efficacy data along with a low number of serious adverse effects in the preclinical and clinical trials suggested a favourable benefit/risk profile that led to US FDA approval of alosetron in early 2000. However, postmarketing experience has proven that several serious adverse effects, including death, occurred in the treated patient population, which resulted (for a time) in the withdrawal of alosetron from the US market by the producer (GlaxoSmithKline). In the meantime, both public pressure and the proposal of a careful postmarketing surveillance have led the FDA to re-approve alosetron to the US drug market under severe restrictions. These restrictions aim to ensure a safer use of the drug with a more favourable safety profile. Under these restrictions, however, it is not very likely that alosetron will become a major treatment option for many patients, but presumably the continued use of this first selective serotonin antagonist will open an avenue for the development of similar drugs with more favourable benefit/risk profiles in the near future.     

生物标志物在药品生命周期中的应用与展望

生物标志物(biomarker)是一种能客观测量并评价正常生物过程、病理过程或对药物干预反应的指示物,可有效提高新药研究开发决策,指导候选药物早期临床试验,降低新药研发失败的风险,其在药品生命周期中的重要作用已引起业内普遍关注.欧美等国家和地区相继出台关于生物标志物研究开发和资格鉴定程序的指南,鼓励医药企业将生物标志物...     

Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.     

Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug–drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class.     

Timing of carcinogenicity studies and predictability of genotoxicity for tumorigenicity in anti-HIV drug development

The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment. We also examine the correlation of genotoxicity data with carcinogenicity data for the varied subclasses of anti-HIV drugs. We suggest that this regulatory policy regarding the timing of carcinogenicity testing does not compromise the safety standards of FDA's drug evaluation and the approval process. The policy does facilitate availability of these agents to meet the medical needs of the target population. Our analysis on the profile of carcinogenicity findings of anti-HIV drugs shows trends of class effects. Additionally, both carcinogenicity and genotoxicity data show significant correlations, which provide useful insights into issues involving these 2 important areas of toxicological investigations.     

Genvir (Flamel Technologies)

Flamel Technologies is developing Genvir (formerly known as Viropump), a twice-daily controlled-release formulation of aciclovir, for potential use in the treatment of herpes simplex virus and varicella zoster virus infections. Genvir utilizes Flamel's proprietary Micropump technology, a microparticle-based drug delivery system designed to extend the time of absorption of drugs in the small intestine. The drug shows a comparable therapeutic efficacy to valaciclovir and famciclovir (both GlaxoSmithKline) [313393]. Phase III trials have been completed [302829]. In August 2000, Flamel filed for regulatory approval for the treatment of herpes in France, as a prelude to a pan-European approval [378641] and is preparing an IND application to begin clinical trials for genital herpes in the US [245970].     

Bleomycin--electrical pulse delivery: electroporation therapy-bleomycin--Genetronics; MedPulser-bleomycin--Genetronics

Genetronics Biomedical is using its electroporation therapy technology to deliver bleomycin to tumour cells for the treatment of cancer. Genetronics have developed the MedPulser Electroporation Therapy System, which consists of an electrical pulse generator and disposable electrode applicators. The MedPulser system enables the delivery of large molecules into cells by briefly applying an electric field to the cell. This causes a transient permeability in the cell's outer membrane characterised by the appearance of pores across the membrane. After the field is discontinued, the pores close, trapping the therapeutic molecules inside the target cells. Genetronics is using the MedPulser System in conjunction with bleomycin, an antineoplastic antibiotic that binds to DNA causing strand scissions. Genetronics is seeking a licensing partner for the use of electroporation for the delivery of drugs in chemotherapy. In 1998, Genetronics entered a licensing and development agreement with Ethicon for electroporation and electrofusion. Under the terms of this agreement, Ethicon was to develop and clinically test the Genetronics electroporation delivery system and conduct all regulatory activities throughout the world except Canada. Ethicon would also market the products once regulatory approval has been obtained and Genetronics was to receive a percentage of the net sales and as license fees. However, in July 2000, Ethicon exercised its rights to terminate the agreement without cause. All rights were returned to Genetronics in January 2001. In 1997, Genetronics entered an agreement with Abbott Laboratories for the manufacture of bleomycin for use in the US in its MedPulsar system after regulatory approval had been granted for its use in the treatment of solid tumours. In a separate supply agreement, Faulding Inc. has agreed to manufacture bleomycin for Genetronic for use in Canada after regulatory approval had been granted. The MedPulsar Electroporation Therapy System with bleomycin is currently in phase III pivotal studies in the US as a treatment for recurrent and second primary squamous cell carcinomas of the head and neck. Genetronics received approval for the Electroporation Therapy system as a device in March 1999 when it achieved CE Mark certification. In February 2004, Genetronics announced that it had completed a Special Protocol Assessment review process with the US FDA for two new trials that will compare bleomycin electroporation therapy to surgery. The primary endpoint will be tissue and function preservation rather than survival. One proposal is for recurrent head and neck cancer, and the other is for disfiguring cutaneous cancer. Three Institutional Review Boards in the US have approved the two protocols and Genetronics has initiated enrollment. In June 2004, Genetronics was granted fast-track status for its MedPulsar Electroporation Therapy System clinical development programme for patients with head and neck cancer. Shifting from a primary endpoint of survival to a quality-of-life outcome will enable those clinical trials to be carried out faster with less cost and with a higher likelihood of success. As a result, Genetronic's phase III trials focussing on survival as a primary endpoint have been discontinued. This includes a phase III trial for late-stage, recurrent head and neck cancer in combination with the normal standard of treatment compared with normal standard of treatment alone. Interim results from this trial had suggested bleomycin electroporation therapy demonstrated local tumour control and preservation of organ function, as well as non-inferiority when compared with surgery. This trial was initiated in May 2002. In March 2004, Genetronics initiated a post-European regulatory approval clinical study in patients with primary or recurrent squamous cell carcinoma of the head and neck (SCCHN). This study aims to enroll approximately 100 patients at 12-15 hospitals located in the UK, Germany, Italy, France, Austria and other western European countries. The study is designed to support the commercialisation of the MedPulser Electroporation System in the EU. Prior clinical trials established the safety and performance of the MedPulser System for the treatment of SCCHN, leading to approval for sale in the EU based on achieving the CE Mark. This study will document the clinical and pharmacoeconomic benefit in support of reimbursement approval throughout Western Europe, establish centres of excellence to facilitate early sales, create a reference and customer base for a projected European commercial launch in 2005, and generate safety and efficacy data to support marketing applications in the US. The bleomycin delivery system has completed phase IIB trials in the US, Canada and Europe in patients with squamous cell carcinoma of the head and neck who have failed conventional therapies. Phase II data were submitted to the FDA in the first quarter of 2002 and a phase III trial was launched in May 2002. The therapy is also being used in France in patients with cancers of the head and neck, liver (metastatic) and melanoma. A review of the data from these phase II trials was completed in April 2001. In June 2004, Genetronics was granted two US patents. US patent 6,748,265 covers its trans-surface drug and gene delivery technology and provides additional proprietary rights for an apparatus and method to deliver genes, drugs and other molecules through tissue surfaces. The second US patent, 6,746,441, pertains to the field of ex vivo therapies and covers the introduction of molecules into cells by electroporation, either in a continuous-flow or batch mode, with a variable electric field orientation. In July 2004, Genetronics received a US patent (no. 6,763,264) covering methods for the in vivo delivery of a recombinant expression vector (DNA) or a pharmaceutical agent into tissue cells, and a method for the therapeutic application of electroporation to a patient to introduce macromolecules.     

Moxifloxacin Bayer

Bayer has launched the fluorinated oxoquinolone, moxifloxacin, as a treatment for bacterial infection. It was launched in Germany for the treatment of respiratory tract infections in September 1999, and regulatory approval in the other EU member states was expected to be completed early in 2000, with marketing throughout the EU by the end of 2000 [336340,340358]. Moxifloxacin received FDA approval in December 1999 and it was launched in the same month [350407,350415,365913]. By July 2000, the drug had been launched in Japan [375976]. In February 1999, Lehman Brothers predicted 95% probabilities that moxifloxacin would reach the US and ex-US markets, and launch onto these market in 1999. Peak annual sales of US $500 million in 2005 (US) and US $800 million in 2007 (ex-US) are predicted [319225].     

Clindamycin/tretinoin: clindamycin phosphate/tretinoin gel

Connetics Corporation (USA) has licensed a first-in-class, dual-action 1% clindamycin/0.025% tretinoin aqueous gel [Clindamycin phosphate/tretinoin gel, Velac, Velac Gel] from Yamanouchi Europe BV. The product combines the anti-inflammatory and antibacterial properties of clindamycin with the beneficial effects of tretinoin [all-trans-retinoic acid], and is in phase III trials for the treatment of acne. On 1 April 2005, Yamanouchi merged with Fujisawa to form Astellas Pharma. Connetics has exclusive development and commercialisation rights for clindamycin/tretinoin gel in the US and Canada, and has non-exclusive rights to the product in Mexico. Under the licensing agreement terms, Connetics initially paid Yamanouchi a dollar US 2 million licensing fee, as well as milestone payments and royalties on future products. In the fourth quarter of 2002, a dollar US 2 million milestone payment was made to Yamanouchi following the initiation of pivotal phase III trials in the US and Canada, and in the third quarter of 2004 a dollar US 3 million milestone payment was made to Yamanouchi following the filing of an NDA to the US FDA. In March 2004, Connectics reported that clindamycin/tretinoin is approved in Europe. It appears that this approval was specifically for France. In October 2004, Connetics announced that the US FDA has accepted its NDA filing for clindamycin/tretinoin. Two pivotal phase III trials of clindamycin/tretinoin have been conducted in the US and Canada. These trials included 2219 patients with acne who received 12 weeks' treatment in the double-blind, placebo- and active-controlled trials. Results of these trials were reported in March 2004. Connetics anticipates launch of the product during mid-2005. An action date of 25 June 2005 has been given by the FDA for it to respond to the NDA submission. Phase III trials in patients with acne in Europe have shown clindamycin/tretinoin gel to be as effective and safe as other leading topical therapies. Data from a combined analysis of six controlled efficacy and safety trials of clindamycin/tretinoin have been reported. The patent for clindamycin/tretinoin gel is held by Yamanouchi in the US and internationally. Other analysts, at CIBC World Markets, were quoted saying that Evoclin represents Connetics' 'first foray' into the acne market (followed by others, such as Velac), a market that has been valued at dollar US 1.7 billion, of which that for topical antibiotics is worth approximately dollar US 500 million.     

The US FDAs withdrawal of the breast cancer indication for Avastin (bevacizumab)

On November 18, 2011, the US Food and Drug Administration (US FDA) announced that breast cancer indication for Avastin (bevacizumab) had been withdrawn after concluding that the drug has not been shown to be safe and effective for the treatment of breast cancer. The specific indication that was withdrawn was for the use of bevacizumab in metastatic breast cancer, with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.The US FDAs decision has been met with emotion and confusion among the public and health professionals. The purpose of this article is to review the regulatory history of bevacizumab for breast cancer and to examine the scientific evidence that led to the approval and subsequent withdrawal of this indication. Bevacizumab also provides the opportunity to illustrate the value of free publicly available US FDA reviews that may contain rigorously reviewed unpublished data and analyses and to contrast the decisions made in the US and Europe about bevacizumab and breast cancer.     

Designing clinical trials to assess antiepileptic drugs as monotherapy : difficulties and solutions

Designing monotherapy trials in epilepsy is fraught with many hurdles, including diagnostic and classification difficulties, sparse information regarding the natural history of the disorder, and ethical objections to the use of placebo or a suboptimal comparator in a condition where the consequences of therapeutic failure can be serious. These issues are further complicated by regulatory differences between the US and the EU.In the US, the FDA considers that evidence of efficacy requires demonstration of superiority to a comparator. Because available antiepileptic drugs possess relatively high efficacy, in most settings it is unrealistic to expect that a new treatment will be superior to a standard treatment used at optimized dosages. To circumvent this problem, trial designs have been developed whereby patients in the control group are assigned to receive a suboptimal comparator and are required to exit from the trial if seizure deterioration occurs. This allows demonstration of a between-group difference in efficacy endpoints, such as time to exit or time to first seizure. Although these trials have come under increasing criticism because of ethical concerns, extensive information is now available on the outcome of patients with chronic epilepsy randomized to suboptimal treatment in similarly designed conversion to monotherapy trials. This has allowed the construction of a dataset of historical controls against which response to a fully active treatment can be compared. A number of studies using this novel approach are now in progress.In the EU, in addition to requiring data on conversion to monotherapy in refractory patients, the European Medicines Agency stipulates that a monotherapy indication in newly diagnosed epilepsy can only be granted if a candidate drug has shown at least a similar benefit/risk balance compared with an acknowledged standard at its optimal use during an assessment period of no less than 1 year. This has led to the implementation of noninferiority trials, one of which has been completed and which led to approval of the monotherapy indication for levetiracetam in the EU. Noninferiority trials provide valuable data in a setting that most closely resembles routine clinical practice, but their interpretation can be complicated by uncertainties on assay sensitivity.Major evidence gaps in the treatment of epilepsy still remain and it is hoped that these will be addressed in the near future. High quality monotherapy trials are particularly needed to assess the comparative efficacy of older and newer drugs in less common epilepsy syndromes, including most generalized epilepsies, and to investigate the different treatment options in populations homogeneous not only in terms of syndromic classification, but also in terms of underlying aetiology and associated phenotypes.     

Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008

Pharmacometric analyses have become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submissions to the US FDA to support drug approval, labelling and trial design decisions. Pharmacometrics is defined as a science that quantifies drug, disease and trial information to aid drug development, therapeutic decisions and/or regulatory decisions. In this report, we present the results of a survey evaluating the impact of pharmacometric analyses on regulatory decisions for 198 submissions during the period from 2000 to 2008. Pharmacometric review of NDAs included independent, quantitative analyses by FDA pharmacometricians, even when such analysis was not conducted by the sponsor, as well as evaluation of the sponsor's report. During 2000-2008, the number of reviews with pharmacometric analyses increased dramatically and the number of reviews with an impact on approval and labelling also increased in a similar fashion. We also present the impact of pharmacometric analyses on selection of paediatric dosing regimens, approval of regimens that had not been directly studied in clinical trials and provision of evidence of effectiveness to support a single pivotal trial. Case studies are presented to better illustrate the role of pharmacometric analyses in regulatory decision making.     

Mifamurtide: CGP 19835, CGP 19835A, L-MTP-PE, liposomal MTP-PE, MLV 19835A, MTP-PE, muramyltripeptide phosphatidylethanolamine

Mifamurtide is a conjugate of muramyl tripeptide linked to dipalmitoyl phosphatidyl ethanolamine; the phospholipid facilitates incorporation of the peptide into liposomes. The agent stimulates macrophages to seek out and destroy cancer cells. The compound was originated by Novartis (formerly CIBA-Geigy), and is being developed by IDM Pharma for osteosarcoma. Mifamurtide is being reviewed by regulatory authorities in the US and EU for this indication.CIBA-Geigy originally developed mifamurtide in the early 1980s and the agent was subsequently outlicensed to Jenner Biotherapies in the 1990s. IDM Pharma acquired the rights to the drug from Jenner in April 2003.IDM and Genesis Pharma have entered into an exclusive licensing and marketing agreement for mifamurtide in South East Europe. Under the agreement terms, IDM will receive an upfront fee from Genesis, as well as milestone payments on reaching certain sales levels in the territory. Medison Pharma signed an agreement with IDM Pharma for the sales and marketing of mifamurtide in Israel. IDM will receive an upfront license fee from Medison and will be entitled to receive a milestone payment upon regulatory approval of the agent in Israel, as well as royalties on net sales.IDM outlicensed exclusive marketing rights for mifamurtide in the UK and Ireland to Cambridge Laboratories in June 2005. In exchange, IDM is entitled to an upfront license fee and milestone payments prior to launch, as well as royalties calculated on product sales.Previously, Chiron Vaccines (a joint venture between Novartis and Chiron formed in 1995) investigated mifamurtide as an adjuvant in HIV gp120 vaccine; however, development has been discontinued.IDM Pharma will purchase approximately 7.1 million shares of its common stock to raise approximately $US23.5 million in net proceeds. The company intends to use the funds for working capital and corporate purposes, including the company's activities related to gaining marketing approval of mifamurtide in the US and Europe. Following the announcement by ODAC in May 2007, IDM Pharma decided to amend the NDA for mifamurtide with additional vital status data from the completed phase III trial. This data was not available at the time the original filing was made, and the company believes that capturing this supplemental data will overcome the need for additional trials, further confirm the overall survival benefit of mifamurtide in osteosarcoma, and provide evidence for approvability. IDM Pharma intends to analyse the additional follow-up data and submit an amendment to the agency by the first quarter of 2008; the company is also working on addressing other concerns raised by the US FDA in the non-approvable letter. The US regulatory submission included safety and efficacy data from NCI-funded phase III trials in 678 patients with osteosarcoma conducted by the Pediatric Oncology Group and the Children's Cancer Group in over 147 US centres. The NDA also included safety and biological effects data of mifamurtide from 17 phase I and II studies in 248 patients conducted by Ciba-Geigy. In the EU, IDM Pharma filed a MAA with the EMEA in November 2006 for approval of mifamurtide (Mepacttrade mark) in combination with postoperative chemotherapy for the treatment of patients with newly diagnosed osteosarcoma following complete surgical resection. The company expects that the EMEA will make a decision regarding marketing approval for mifamurtide by the end of 2007. Mifamurtide has orphan drug status for the treatment of osteosarcoma in the US and EU.     

美国食品药品监督管理局接受不确定性:治疗多重耐药的人类免疫缺陷病毒感染的单克隆抗体加速获批

未满足的临床需求影响着临床试验的科学设计和药品审批的监管决策.美国食品药品监督管理局(FDA)于2018年批准了全球首个抗艾滋病的单克隆抗体艾巴利珠单抗(ibalizumab)用于治疗多重耐药的人类免疫缺陷病毒(HIV)感染.该药物的上市批准主要基于1项纳入40例患者的Ⅲ期单臂的简化临床试验.这体现了面对抗HIV多重耐...     

Acamprosate in the treatment of alcohol dependence

Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation in combination with psychosocial support. Acamprosate is a synthetic taurine analogue that seems to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Over the past 15 years, the safety and efficacy of acamprosate for alcohol dependence have been well established in multiple double-blind, placebo-controlled trials. Overall, acamprosate has been consistently associated with greater beneficial effects on measures of alcohol abstinence compared with placebo. Specifically, patients treated with acamprosate achieve greater rates of complete abstinence, longer times to first drink and/or increased duration of cumulative abstinence when compared with placebo. Acamprosate received approval by the US FDA for the treatment of alcohol dependence in July 2004 and is currently prescribed in 28 countries.     

Acamprosate in the treatment of alcohol dependence

Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation in combination with psychosocial support. Acamprosate is a synthetic taurine analogue that seems to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Over the past 15 years, the safety and efficacy of acamprosate for alcohol dependence have been well established in multiple double-blind, placebo-controlled trials. Overall, acamprosate has been consistently associated with greater beneficial effects on measures of alcohol abstinence compared with placebo. Specifically, patients treated with acamprosate achieve greater rates of complete abstinence, longer times to first drink and/or increased duration of cumulative abstinence when compared with placebo. Acamprosate received approval by the US FDA for the treatment of alcohol dependence in July 2004 and is currently prescribed in 28 countries.