Change in formulation and its potential clinical and pharmacoeconomic value: example of extended release venlafaxine

ABSTRACT

Introduction: The 505(b)(2) route of a New Drug Application (NDA) allows published literature or previous FDA findings of safety and effectiveness to be used for approval. Such drugs are not therapeutic equivalents (i.e., generics); instead, the FDA calls them pharmaceutical alternatives. A recent example is the approval of venlafaxine extended-release (ER) tablets, developed as an alternative to the widely used ER?venlafaxine capsules. The smaller size of the tablets makes them available in a 225-mg strength, which is the approved maximum dose in major depressive disorder after up-titration but currently unavailable in the capsule formulation, requiring patients on this dose to take two or three capsules; in addition, the tablets are priced at a discount compared to the capsules.

Methods: The objective of this review was to investigate how the change in formulation of ER?venlafaxine from capsules to tablets, as an example of such a change in formulation, can potentially offer value to patients and society, with a specific focus on pill burden, drug cost, and adherence. Based on a MEDLINE literature search, the pertinent literature was reviewed in a qualitative manner.

Review of the literature: Simplifying treatment regimens, reducing pill burden, and reducing drug costs are recognized strategies for improving adherence. This can be of particular benefit in psychiatric illness because of high rates of nonadherence to treatment. Lack of adherence may negatively impact treatment outcomes and increase disease cost. As such, the ER?venlafaxine tablets have the potential to reduce pill burden, improve adherence and outcomes, and reduce cost to patients and society. These preliminary findings need to be corroborated with more primary research and a systematic review of formulation changes.

Conclusion: A change in formulation of established therapies such as ER?venlafaxine has the potential to offer clinical and pharmacoeconomic benefits to patients and society.     

Characterization of intentional-abuse venlafaxine exposures reported to poison control centers in the United States

Background: Venlafaxine use to achieve an amphetamine-like high has been described but data regarding the epidemiology and clinical effects are sparse. Objectives: Describe the prevalence and toxicity of venlafaxine abuse reported to US poison control centers. Methods: This was a retrospective review of venlafaxine exposures reported to the National Poison Data System (NPDS) from 2000 to 2016. Inclusion criteria were: age 12 years and older, reason for exposure intentional-abuse, and either single-substance exposure or venlafaxine was the first substance. The primary outcome was prevalence of intentional-abuse of venlafaxine. Secondary outcomes characterized demographics, geographic distribution, toxicity, and outcomes. Results: Intentional-abuse accounted for 752 of 85,621 venlafaxine exposures. Overall prevalence was 87.8 intentional-abuse exposures/10,000 venlafaxine exposures reported to NPDS (range, 59.3–117.6/10,000). Prevalence decreased from 107/10,000 in 2000 to 59.3/10,000 in 2016. Median age was 23 years and 50% were female. Primary route was ingestion (90.8%) with 4.7% using venlafaxine via inhalation/intranasal insufflation, and 3.7% both routes. There were 227 venlafaxine-only exposures; 54.0% were treated/released from the emergency department, 20% were admitted for medical management, 9.0% to a psychiatric facility, and 17.0% managed at home. Known medical outcomes for single-substance exposures were: no effect (24.0%), minor (39.0%), moderate (33.0%), and major (4.0%); no deaths occurred. Most frequent clinical effects were tachycardia (33.9%), drowsiness (20.7%), and agitation (11.5%). Conclusion: The prevalence of venlafaxine abuse reported to poison control centers has decreased. Medical outcomes are usually not serious. Clinicians should be aware that non-medical use is possible but infrequently reported to poison control centers.     

盐酸文拉法辛表观油水分配系数及其溶液化学稳定性的研究

摘 要 目的：测定盐酸文拉法辛（Ven）的表观油水分配系数（P）及其水溶液的化学稳定性,为今后研制Ven的黏膜吸收给药液体制剂奠定基础。方法: 采用HPLC法测定Ven的浓度;测定Ven在正辛醇 水/pH 2~10磷酸缓冲液系统中的P值;测定Ven在pH 2~12磷酸缓冲液以及不同离子强度条件下的降解百分率。结果: Ven在正辛醇 水系统中的P值为0.16;在正辛醇 pH 2~10缓冲液系统中,当pH≤6.0时,Ven的P值接近于1,当pH＞6.0时,随着pH的增加,药物的P值显著增大。Ven溶液在pH≤8.0时,其化学稳定性良好,在碱性pH下,化学稳定性较差;离子强度对Ven溶液的化学稳定性无影响。结论:Ven的油水分配系数及溶液的化学稳定性与pH密切相关。在pH约为7.0时,Ven具有较高油水分配系数及化学稳定性。     

LC-MS/MS method for the determination of nine antidepressants and some of their main metabolites in oral fluid and plasma. Study of correlation between venlafaxine concentrations in both matrices

In this paper, a fast, sensitive and selective LC-MS/MS method is described for the simultaneous determination of amitriptyline, imipramine, clomipramine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and venlafaxine, as well as some of their main metabolites (nortriptyline, desipramine, norclomipramine and norfluoxetine), in oral fluid and plasma. The sample (0.2mL) was extracted with an automated solid-phase extraction system (ASPEC XL), using mixed mode OASIS MCX cartridges. Chromatographic separation was performed in a Sunfire C18 IS column (20mmx2.1mm, 3.5mum), using a gradient of acetonitrile and ammonium formate (pH 3; 2mM) as mobile phase, which allowed the elution of all the compounds in less than 5min. The method has been fully validated in both specimens. This method was initially applied to the analysis of oral fluid and plasma samples from patients on antidepressant treatment in order to assess for which compounds it was likely to find a good correlation between both matrices. The best results were obtained for venlafaxine, so the study was extended for this compound, comparing the ratio between oral fluid and plasma concentrations (R(OF/PL)) in five patients on venlafaxine treatment when both samples were collected simultaneously on four different occasions. An important inter and intraindividual variability was found in oral fluid concentrations for 150mg dose (mean=287.5ng/m, range 58.8-531.2ng/mL) and for 75mg dose (mean=186.3ng/mL, range=82.1-289.2ng/mL). R(OF/PL) was calculated for each patient on the four different occasions, showing also a high variability (CV=24.2-69.6%).     

Re-evaluation of the efficacy and tolerability of venlafaxine vs SSRI: meta-analysis

Rationale A number of reviews have claimed that the selective serotonin and noradrenalin re-uptake inhibitor venlafaxine is more effective than selective serotonin re-uptake inhibitors (SSRIs) in achieving remission and symptom reduction in major depression. Objectives The aim of this study was to systematically review studies on the efficacy of venlafaxine vs SSRI and to evaluate the influence of methodological issues on the effect sizes. Materials and methods Following a systematic literature search, we pooled data on depression scores, response, remission and dropout rates. We also performed sub-group analyses. Results Seventeen studies were included. We found no significant superiority in remission rates (risk ratio [RR] = 1.07, 95% confidence intervals [95%CI] = 0.99 to 1.15, numbers needed to treat [NNT] = 34) and a small superiority in response rates (RR = 1.06, 95%CI = 1.01 to 1.12, NNT = 27) over SSRIs. There was a small advantage to venlafaxine in change scores (effect size = −0.09, 95%CI = −0.16 to −0.02, p = 0.013), which did not reach significance when post-treatment scores were used (effect size = −0.06, 95%CI = −0.13 to 0.00). Discontinuation rates due to adverse events were 45% higher in the venlafaxine group. The main reasons for the differences between this analysis and previous reviews were the exclusion of studies with methodological limitations, avoiding to pool selectively reported study results and exclusion of studies available as abstracts only. Conclusions Our analysis does not support a clinically significant superiority of venlafaxine over SSRIs. Differences between our study and previous reviews were not accounted for by technical aspects of data synthesis, but rather by study selection and choice of outcome parameters. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

丁螺环酮对难治性抑郁症的辅助治疗作用

目的观察丁螺环酮联合文拉法辛治疗难治性抑郁症对疗效和不良反应。方法将92例难治性抑郁症患者随机分为两组,合用组为丁螺环酮联合文拉法辛,单用组为单用文拉法辛,疗程6周。以汉密尔顿抑郁量表（HAMD）和汉密尔顿焦虑量表（HAMA）评定不良反应。结果治疗后两组HAMD和HAMA的评分均显著降低（P〈0．01）,以合用组疗效显著（P〈0．01或P〈0．05）。结论丁螺环酮联合文拉法辛治疗难治性抑郁症的疗效优于单用文拉法辛,耐受性好。     

HPLC-荧光法测定盐酸文拉法辛胶囊的生物等效性

目的 采用HPLC-荧光检测法测定盐酸文拉法辛胶囊的生物等效性.方法 采用液-液萃取法处理血清样品,用Hypersil C18 色谱柱,流动相为乙腈-pH6.8磷酸盐缓冲液-三乙胺(30:70:1,用磷酸调pH2.8);荧光检测器检测,激发和发射波长分别为276、598 nm,流速1.0 ml · min-1. 结果 18名健康志愿者分别空腹po 150 mg盐酸文拉法辛胶囊后,两种制剂在受试者体内的药动学参数Cmax分别为348.38±98.99、344.20±96.22 μg · L-1;t1/2分别为5.079±1.322、5.046±1.503 h;AUC0-∞分别为2425.2±874.5、2431.1±819.1 μg · h · L-1,受试制剂与参比制剂的相对生物利用度为99.94%±14.22%.结论 所建方法灵敏、简便、快速、准确.两种制剂具有生物等效性.     

文拉法辛联合心理干预治疗躯体化障碍临床疗效对照研究

目的 评价文拉法辛联合心理干预治疗躯体化障碍患者的临床疗效和副作用.方法将符合CCMD－3诊断标准的44例躯体化障碍患者随机分为治疗组和对照组各22例.两组病例均给予文拉法辛,起始剂量75 mg·d^-1,1周后増至150 mg·d^-1,并维持此剂量,疗程6周.治疗组同时联合心理干预治疗.采用汉密顿抑郁量表（HAMD）、不良反应量表（TESS）评定疗效及不良反应. 结果 经6周治疗后,治疗组显效率为86.4%,对照组为59.1%（P<0.05）, 两组间HAMD减分率于第2,4,6周末比较差异均有显著性或极显著性（P<0.05或P<0.01）,治疗组起效明显快于对照组.两组各时间点TESS评分差异无显著性（P>0.05）.结论 文拉法辛联合心理干预治疗躯体化障碍的疗效优于单用文拉法辛.     

文拉法辛与阿米替林治疗卒中后抑郁的对照分析

目的:观察文拉法辛与阿米替林治疗卒中后抑郁(PSD)的疗效及副作用。方法:50例PSD患者被随机分为文拉法辛组(25例)与阿米替林组(25例),疗程为6wk。治疗前及治疗后1、2、4、6wk,分别以汉密尔顿抑郁量表(HAMD)、副反应量表(TESS)评定。结果:文拉法辛组与阿米替林组显效率分别为88%、84%,2组无显著性差异(χ2=0.003,P>0.05);治疗后1、2wk末HAMD2组有显著性差异(P<0.05);文拉法辛组治疗后1、2、4、6wk末TESS总分均显著低于阿米替林组,2组有显著性差异(P<0.05)。结论:文拉法辛具有起效快、副作用小的优点,是治疗PSD较为理想的药物。     

司西酞普兰与文拉法辛治疗难治性抑郁症的对照研究

目的:比较司西酞普兰与文拉法辛治疗难治性抑郁症疗效及安全性。方法:120例确诊为难治性抑郁症患者随机分为A、B两组,每组60例,每例给予相同的常规治疗,A组在常规治疗的基础上使用司西酞普兰,B组在常规治疗的基础上使用文拉法辛,疗程为8周。用汉密尔顿抑郁量表(HAMD),临床总体印象改善表(CGI-I),临床总体印象—严重程度量表(CGI-S)和患者总体印象改善量表(PGI)在治疗前及治疗2、4、8周评定疗效;用副反应量表(TESS)评定不良反应。结果:经8周治疗,司西酞普兰组(A)痊愈12例,显著进步16例,进步14例,无效18例;文拉法辛组(B)痊愈18例,显著进步22例,进步12例,无效8例。治疗6周后两组HAMD总分均有显著下降,其中A组下降4分,B组下降6分。两组比较,差别有统计学意义(P0.05)。结论:常规治疗基础上加文拉法辛对难治性抑郁患者的治疗效果较在常规治疗基础上加司西酞普兰更好,有一定的临床推广应用价值。