Bioequivalence and safety evaluation of two preparations of metformin hydrochloride sustained-release tablets (Boke® and Glucophage®-XR) in healthy Chinese volunteers: a randomized phase I clinical trial.

BACKGROUND: As per the National Medical Products Administration (NMPA) requirements, the quality and efficacy of generic drugs must be consistent with those of the innovator drug. We aimed to evaluate the bioequivalence and safety of generic metformin hydrochloride sustained-release (MH-SR) tablets (Boke®) developed by Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., China and the innovator product metformin hydrochloride extended-release tablets (Glucophage®-XR) manufactured by Bristol-Myers Squibb Company, New York, NY, in healthy Chinese volunteers. MATERIALS AND METHODS: We performed a bioequivalence and safety assessment of MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) tablets in a randomized, open-label, two-period, two-sequence crossover, single-dose oral study in 48 healthy Chinese adult participants under fasting conditions (Chinese Clinical Trial Registration No. CTR20171306). The washout period was seven days. Bioequivalence (80.00-125.00%) was assessed using adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. RESULTS: The 90% CIs of the test/reference preparation for key pharmacokinetic parameters were 97.36-108.30% for AUC0→t, 97.26-108.09% for AUC0→∞ and 96.76-111.37% for Cmax. No severe adverse events (AEs) were observed. However, 38 adverse drug reactions (ADRs) occurred, including metabolic or nutritional conditions (n = 8), infections (n = 2), gastrointestinal conditions (n = 10) and abnormal inspection (n = 18). No significant difference was observed between MH-SR (23 ADRs, 10 participants) and Glucophage®-XR (15 ADRs, 12 participants) (p = .500). Bioequivalence was concluded since the 90% CIs of the main pharmacokinetic parameters were within the equivalence interval (80.00-125.00%). CONCLUSIONS: MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) were found to be bioequivalent and safe under fasting conditions in healthy Chinese participants. Thus, the market demand for MH-SR tablets (500 mg/tablet) can be met using the generic alternative.KEY MESSAGESGeneric MH-SR tablets (500 mg, Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., Beijing, China) and innovator MH-SR tablets (Glucophage®-XR, 500 mg, Bristol-Myers Squibb Company, New York, NY, USA) were bioequivalent and safe in healthy Chinese volunteers under single-dose administration and fasting conditions.The main goal of this study is to support an increase in the supply of MH-SR tablets in China by proving the efficacy and safety of a generic alternative.Although no sugar was administered in the BE trial of the MH-SR tablets under fasting conditions, no hypoglycaemic event occurred. The method used in this study is expected to serve as a reference for BE studies of different MH-SR formulations.

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial.

OBJECTIVE: The purpose of this single-center, randomized, open, two-period, two-sequence crossover, single-dose administration, bioequivalence research was to evaluate the bioequivalence and safety of the generic formulations of metformin hydrochloride sustained-release (MH-SR) 500 mg tablets (test preparation [T]: Yuantang® SR) and the original formulation (reference preparation [R]: Glucophage® XR) in 36 healthy Chinese volunteers under postprandial conditions. METHODS: Subjects received 500 mg T/R in each period, with a 7-day washout period. Venous blood samples of 4 mL each were collected from each subject 19 times spanning predose (0 h) to 36 h postdose. The metformin concentration in deproteinized plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Bioequivalence (80.00-125.00%) was assessed by adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. SAS 9.4 software was used for statistical analysis and Phoenix WinNonlin software v7 was used to analyze the pharmacokinetic parameters. RESULTS: Thirty-four volunteers completed the clinical study. The 90% CIs (96.12-105.44% for AUC from time zero to the time of the last measurable concentration [AUCt], 96.22-105.54% for AUC extrapolated from time zero to infinity [AUC∞], and 98.42-105.00% for Cmax) of T/R adjusted GMRs were within the bioequivalence acceptance range of 80.00-125.00%, indicating that they are bioequivalent. No serious adverse events occurred in this study, indicating that the two formulations were effective and well tolerated. CONCLUSIONS: Yuantang® SR was confirmed to be a well tolerated and bioequivalent alternative to Glucophage® XR when taken under postprandial conditions in healthy Chinese volunteers. The Clinical Trials Registry Platform used for this study was http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . The trial registration numbers (TRNs) and dates of registrations were CTR20180476 (19 April 2018) for this clinical trial and CTR20171595 (11 January 2018) for the pilot trial.

Assessment of Potentially Inappropriate Prescribing of Opioid Analgesics Requiring Prior Opioid Tolerance.

Importance: Opioid-tolerant only (OTO) medications, such as transmucosal immediate-release fentanyl products and certain extended-release opioid analgesics, require prior opioid tolerance for safe use, as patients without tolerance may be at increased risk of overdose. Studies using insurance claims have found that many patients initiating these medications do not appear to be opioid tolerant. Objectives: To measure prevalence of opioid tolerance in patients initiating OTO medications and to determine whether linked electronic health record (EHR) data contribute evidence of opioid tolerance not found in insurance claims data. Design, Setting, and Participants: This retrospective cohort study used a national database of deidentified longitudinal health information, including medical and pharmacy claims, insurance enrollment, and EHR data, from January 1, 2007, to December 31, 2016. Data included 131 756 US residents with at least 183 days of continuous enrollment in commercial or Medicare Advantage insurance (including medical and pharmacy benefits) who had received an OTO medication and who had no inpatient stays in the 30 days prior to starting an OTO medication; of these, 20 044 individuals had linked EHR data within the prior 183 days. Data were analyzed from July 1, 2017, to August 31, 2018. Exposures: Initiating an OTO medication. Main Outcomes and Measures: Prior opioid tolerance demonstrated through pharmacy fills or EHR data on prescriptions written. Results: Among 153 385 OTO use episodes identified, 89 029 (58.0%) occurred among women, 62 900 (41.0%) occurred among patients with Medicare Advantage insurance, 39 394 (25.7%) occurred in the Midwest, 17 366 (11.3%) occurred in the Northeast, 73 316 (47.8%) occurred in the South, and 23 309 (15.2%) occurred in the West. Less than half of use episodes (73 117 episodes [47.7%]) involved patients with evidence in claims data of opioid tolerance prior to initiating therapy with an OTO medication, including 31 392 of 101 676 episodes (30.9%) involving transdermal fentanyl, 1561 of 2440 episodes (64.0%) involving transmucosal fentanyl, 36 596 of 43 559 episodes (84.0%) involving extended-release oxycodone, and 3568 of 5710 episodes (62.5%) involving extended-release hydromorphone. Among 20 044 OTO use episodes with linked EHR and claims data, less than 1% of OTO episodes identified in claims had evidence of opioid tolerance in structured EHR data that was not present in claims data (108 episodes [0.5%]). After limiting the sample to OTO episodes identified in claims with a matching OTO prescription within 14 days in the structured EHR data, only 40 of 939 episodes (4.0%) occurred among patients with evidence of tolerance that was not present in claims data. Conclusions and Relevance: This cohort study found that most patients initiating OTO medications did not have evidence of prior opioid tolerance, suggesting they were at increased risk of opioid-related harms, including fatal overdose. Data from EHRs did not contribute substantial additional evidence of opioid tolerance beyond the data found in prescription claims. Future research is needed to understand the clinical rationale behind these observed prescribing patterns and to quantify the risk of harm to patients associated with potentially inappropriate prescribing.

Opioid use and harms associated with a sustained-release tapentadol formulation: A post-marketing surveillance study.

AIMS: A sustained-release formulation (SRF) of tapentadol has been marketed in Australia since February 2013. This study examined tapentadol SRF extra-medical use, attractiveness for extra-medical use, and associated harms in Australia. METHODS: This post-marketing study comprises analyses of Australian community sales data (2011-2017) for eleven pharmaceutical opioids (prescription and over-the-counter codeine disaggregated); calls to three poisons information centres (covering five of the eight jurisdictions in Australia) related to pharmaceutical opioids and coded by the centres as 'misuse' or 'abuse' (2011-2017); and interviews with people who inject drugs (n = 888) recruited as part of the Illicit Drug Reporting System (IDRS) from all Australian capital cities (2017). RESULTS: Population-level availability of tapentadol SRF increased from market launch, comprising the sixth largest market share of all opioid unit sales, and third greatest share in oral morphine equivalent milligrams sold, in December 2017. Lifetime tapentadol SRF use among the IDRS sample (n = 888) was low (1.5%; 95%CI 0.9-2.5), with few reporting past-6 month non-prescribed use or injection. Non-fatal overdose following tapentadol use was self-reported by less than 1% (95%CI 0.1-0.8). Between 2013-2017, 1.1% (n = 25) of pharmaceutical opioid 'misuse/abuse' calls were related to tapentadol, and predominantly the SRF. CONCLUSIONS: Increasing utilisation of tapentadol sustained-release formulation was observed, along with indications of extra-medical use and harms associated with use, although on a smaller scale relative to other opioids. These findings need to be interpreted in the context of the low level of exposure to tapentadol sustained-release formulation among the sentinel population of people who inject drugs.

Overdose following initiation of naltrexone and buprenorphine medication treatment for opioid use disorder in a United States commercially insured cohort.

BACKGROUND AND AIMS: Despite the growing opioid overdose crisis, medication treatment for opioid use disorder remains uncommon. The comparative effectiveness of buprenorphine and naltrexone treatment in reducing overdose and the comparative risks of discontinuing treatment in the real world, remain uncertain. Our aim was to examine the effectiveness of medications for opioid use disorder in preventing opioid-related overdose. DESIGN: Retrospective cohort study SETTING: United States. PATIENTS: 46,846 commercially insured individuals diagnosed with opioid use disorder and initiating medication treatment between 2010 and 2016. MEASUREMENTS: Opioid-related overdose identified by International Classification of Diseases, Ninth and Tenth Revisions. FINDINGS: In our sample, 1386 individuals were prescribed extended-release injectable naltrexone (median filled prescriptions = 9 months), 7782 were prescribed oral naltrexone (5 months), and 40,441 were prescribed buprenorphine (19 months) at least once during follow-up. Individuals receiving buprenorphine therapy were at significantly reduced risk of opioid-related overdose compared to no treatment (adjusted hazard ratio (HR) = 0.40, 95% CI 0.35-0.46), while a significant association was not observed in extended-release injectable (HR = 0.74, 95% CI 0.42-1.31) or oral (HR = 0.93, 95% CI 0.71-1.22) naltrexone. We found no association with opioid overdose within four weeks of discontinuation of any medication. CONCLUSION: Among commercially-insured patients who initiate medications for opioid use disorder, buprenorphine, but not naltrexone, was associated with lower risk of overdose during active treatment compared to post-discontinuation. More research is needed to understand the benefits and risks unique to each treatment option to better tailor therapies to patients with opioid use disorder.

First Opioid Prescription and Subsequent High-Risk Opioid Use: a National Study of Privately Insured and Medicare Advantage Adults.

BACKGROUND: National guidelines make recommendations regarding the initial opioid prescriptions, but most of the supporting evidence is from the initial episode of care, not the first prescription. OBJECTIVE: To examine associations between features of the first opioid prescription and high-risk opioid use in the 18 months following the first prescription. DESIGN: Retrospective cohort study using data from a large commercial insurance claims database for 2011-2014 to identify individuals with no recent use of opioids and follow them for 18 months after the first opioid prescription. PARTICIPANTS: Privately insured patients aged 18-64 and Medicare Advantage patients aged 65 or older who filled a first opioid prescription between 07/01/2011 and 06/30/2013. MAIN OUTCOMES AND MEASURES: High-risk opioid use was measured by having (1) opioid prescriptions overlapping for 7 days or more, (2) opioid and benzodiazepine prescriptions overlapping for 7 days or more, (3) three or more prescribers of opioids, and (4) a daily dosage exceeding 120 morphine milligram equivalents, in each of the six quarters following the first prescription. KEY RESULTS: All three features of the first prescription were strongly associated with high-risk use. For example, among privately insured patients, receiving a long- (vs. short-) acting first opioid was associated with a 16.9-percentage-point increase (95% CI, 14.3-19.5), a daily MME of 50 or more (vs. less than 30) was associated with a 12.5-percentage-point increase (95% CI, 12.1-12.9), and a supply exceeding 7 days (vs. 3 or fewer days) was associated with a 4.8-percentage-point increase (95% CI, 4.5-5.2), in the probability of having a daily dosage of 120 MMEs or more in the long term, compared to a sample mean of 4.2%. Results for the Medicare Advantage patients were similar. CONCLUSIONS: Long-acting formulation, high daily dosage, and longer duration of the first opioid prescription were each associated with increased high-risk use of opioids in the long term.

Medication Adherence and Discontinuation of Aripiprazole Once-Monthly 400 mg (AOM 400) Versus Oral Antipsychotics in Patients with Schizophrenia or Bipolar I Disorder: A Real-World Study Using US Claims Data.

INTRODUCTION: Few studies have compared adherence between long-acting injectable antipsychotics, especially for newer agents like aripiprazole once-monthly 400 mg (AOM 400; aripiprazole monohydrate) and oral antipsychotics, in patients with schizophrenia or bipolar I disorder (BD-I) in a real-world setting. METHODS: Two separate retrospective cohort analyses using Truven MarketScan data from January 1, 2012 to June 30, 2016 were conducted to compare medication adherence and discontinuation in patients with schizophrenia or BD-I who initiated treatment with AOM 400 vs. patients changed from one oral antipsychotic monotherapy to another. Adherence was defined as proportion of days covered (PDC) ≥ 0.80 in the year following the index date. Linear regression models examined the association between AOM 400 and oral antipsychotic cohorts and medication adherence. Kaplan-Meier curves and Cox regression estimated time to and risk of discontinuation, while adjusting for baseline covariates. A sensitivity analysis was conducted using a combination of propensity score matching and exact matching to create matched cohorts. RESULTS: Final cohort sizes were as follows-Schizophrenia: AOM 400 n = 408, oral antipsychotic n = 3361; BD-I: AOM 400 n = 413, oral antipsychotic n = 15,534. In patients with schizophrenia, adjusted mean PDC was higher in patients in the AOM 400 cohort vs. the oral antipsychotic cohort (0.57 vs. 0.48 P < 0.001), and patients in the oral antipsychotic cohort had a higher risk of discontinuing treatment vs. the AOM 400 cohort (HR 1.45, 95% CI 1.29-1.64). For patients with BD-I, adjusted mean PDC was higher for the AOM 400 cohort (0.59 vs. 0.44, P < 0.001), and patients in the oral antipsychotic cohort had a higher risk of discontinuation (HR 1.71, 95% CI 1.53-1.92). CONCLUSIONS: In a real-word setting, AOM 400 resulted in a significantly higher percentage of patients with a PDC ≥ 0.80 and significantly longer time to treatment discontinuation compared to patients with schizophrenia or BD-I who received treatment with an oral antipsychotic. FUNDING: Otsuka Pharmaceutical Development and Commercialization, Inc. and Lundbeck.

ILUVIEN® technology in the treatment of center-involving diabetic macular edema: a review of the literature.

Diabetic macular edema (DME) is one of the major causes of blindness, caused primarily by hyperglycemia and results from multiple pathological processes mostly secondary to increased levels of VEGF and other inflammatory cytokines. DME management includes control of systemic risk factors together with laser photocoagulation, frequent intraocular injections of anti-VEGF agents and steroids implants. Recent adoption of novel alternative drug delivery options has led to the development of sustained release ocular implants with longer duration of action with less injection frequency. This article will review the pharmacology and clinical data in terms of efficacy, safety and benefits of the sustained release steroid implants in treatment of DME with special emphasis on the fluocinolone acetonide ILUVIEN® implant.

Safety assessment of niacin in the US Food and Drug Administration's mini-sentinel system.

PURPOSE: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial found higher incidence rates of adverse reactions, including bleeding, in patients receiving the combination of extended-release niacin and laropiprant versus placebo. It is not known whether these adverse events are attributable to laropiprant, not approved in the USA, or to extended-release niacin. We compared rates of major gastrointestinal bleeding and intracranial hemorrhage among initiators of extended-release niacin and initiators of fenofibrate. METHODS: We used Mini-Sentinel (now Sentinel) to conduct an observational, new user cohort analysis. We included data from 5 Data Partners covering the period from January 1, 2007 to August 31, 2013. Individuals who initiated extended-release niacin were propensity score-matched to individuals who initiated fenofibrate. Within the matched cohorts, we used Cox proportional hazards models to compare rates of hospitalization for major gastrointestinal bleeding events and intracranial hemorrhage assessed using validated claims-based algorithms. RESULTS: A total of 234 242 eligible extended-release niacin initiators were identified, of whom 210 389 (90%) were 1:1 propensity score-matched to eligible fenofibrate initiators. In propensity score-matched analyses, no differences were observed between exposure groups in rates of major gastrointestinal bleeding (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.82 to 1.18) or intracranial hemorrhage (HR, 1.21; 95% CI, 0.66 to 2.22). Results were similar in pre-specified sensitivity and subgroup analyses. CONCLUSIONS: We did not observe evidence for an association between extended-release niacin versus fenofibrate and rates of major gastrointestinal bleeding or intracranial hemorrhage.

Treatment persistence and hospitalization rates among patients with schizophrenia: a quasi-experiment to evaluate a patient information program.

OBJECTIVE: The effective treatment of schizophrenia requires continuous antipsychotic maintenance therapy. However, poor persistence with treatment is common among patients with schizophrenia. The objective of this study was to compare persistence and hospitalization rates among patients with schizophrenia treated with long-acting injectable (LAI) antipsychotics (i.e. paliperidone palmitate and risperidone) and enrolled in a patient information program (program cohort) with patients treated with oral antipsychotics (OAs) who were not enrolled in a patient information program (nonprogram cohort). RESEARCH DESIGN AND METHODS: Using a quasi-experimental design, data from chart reviews (for program patients) and Medicaid claims (for nonprogram patients) was analyzed. Patients were eligible if they had ≥12 months of pre-index data, ≥6 months of post-index data, and no hospitalization at index. MAIN OUTCOME MEASURES: Persistence and hospitalization rates were assessed at 6 months post-index. Propensity score matching was used to control for observed differences in demographics and baseline clinical characteristics. Odds ratios (ORs) were calculated using generalized estimating equation models and adjusted for matched pairs and propensity score. RESULTS: A total of 102 program patients were matched to 408 nonprogram patients with similar baseline characteristics. Adjusted ORs indicated that the persistence rate at 6 months was significantly higher for the program cohort (88.2%) versus the nonprogram cohort (43.9%; OR: 9.70; P < .0001). The 6 month post-index hospitalization rate for the program cohort (14.7%) was significantly lower versus the nonprogram cohort after adjustments (22.5%; OR: 0.55; P = 0.0321). LIMITATIONS: The data for the program and nonprogram patients were from two different and independent data sources (healthcare claims and chart reviews, respectively). Results were based on a relatively small number of program LAI patients. CONCLUSION: Program patients treated with LAI antipsychotics had higher persistence rates and significantly lower adjusted hospitalization rates compared with nonprogram patients treated with OAs.

Health care resource utilization and costs of California Medicaid patients with schizophrenia treated with paliperidone palmitate once monthly or atypical oral antipsychotic treatment.

OBJECTIVE: To compare all-cause health care utilization and costs between patients with schizophrenia treated with once monthly paliperidone palmitate (PP1M; Invega Sustenna 1 ) and atypical oral antipsychotic therapy (OAT). METHODS: This was a retrospective claims-based analysis among adult California Medicaid (Medi-Cal) patients with schizophrenia having ≥2 claims for PP1M or OAT from 1 July 2009 to 31 December 2013 and continuous health plan enrollment for ≥1 year pre- and post-index date (PP1M or OAT initiation date). Baseline characteristics were reported descriptively. Propensity score matching with a 1:1 greedy match method was used to create two matched cohorts. Treatment patterns, all-cause health care utilization, and costs for the 12 month follow-up period were compared between the two matched cohorts. RESULTS: Two well matched cohorts of 722 patients were produced with similar baseline characteristics. During the 12 month follow-up period, PP1M patients were significantly less likely to discontinue treatment (30.6% vs. 39.5%, p < .001) or switch to a new therapy (21.6% vs. 27.7%, p = .007). PP1M patients had fewer inpatient visits (5.0 vs. 7.9, p < .001), lower mean hospitalization days (15.0 vs. 27.7 days, p < .001) and inpatient costs ($5060 vs. $10,880, p < .001). While pharmacy costs were significantly higher in the PP1M cohort ($16,347 vs. $9115, p < .001), total costs were not significantly different between the matched cohorts ($25,546 vs. $25,307, p = 0.853). CONCLUSIONS: Patients with schizophrenia treated with PP1M had significantly fewer inpatient hospitalizations and associated costs with no significant difference in the total costs between the two cohorts. This study is subject to limitations associated with claims data such as miscoding, inability to examine clinical severity, etc.

Benefit-risk assessment of paliperidone oral extended-release tablet versus monthly injectable for maintenance treatment of schizophrenia.

The purpose of this study was to conduct a post-hoc benefit-risk assessment of paliperidone palmitate once-monthly (PP1M) injectable versus oral paliperidone extended-release (ER) in schizophrenia maintenance treatment. The Benefit-Risk Action Team framework was used to structure the analysis based on patient-level data from two similar, double-blind, placebo-controlled relapse studies. Efficacy outcomes were relapse, psychiatric hospitalization, Clinical Global Impression-Severity scale, Personal and Social Performance (PSP) scale, and Positive and Negative Syndrome Scale (PANSS). Safety outcomes were extrapyramidal symptom-related adverse events, weight gain, prolactin-related adverse events, somnolence, orthostatic hypotension, anticholinergic use, fasting plasma glucose, and total cholesterol/high-density lipoprotein. For the first 8 weeks of maintenance treatment, most efficacy outcomes significantly favored PP1M compared with paliperidone ER. Per 1000 patients, there would be 165, 115, 85, and 53 fewer cases of PSP worsening, relapse, PANSS worsening, and hospitalizations, respectively. For the first 40 weeks, PSP worsening significantly favored PP1M (140 fewer cases). Relapse, PANSS, hospitalizations, and Clinical Global Impression-Severity scale showed a consistent pattern favoring PP1M but were not significant. Safety outcomes for both 8-week and 40-week periods demonstrated no statistically significant differences between groups. These analyses suggest a benefit-risk profile favoring PP1M over oral paliperidone ER throughout 40 weeks of treatment, particularly in early treatment.

Ultrasonographical assessment of implanted biodegradable device for long-term slow release of methotrexate into the vitreous.

Our group has developed a biodegradable drug delivery device (micro-implant) for long-term slow intraocular release of methotrexate (MTX) that can be implanted in the peripheral vitreous. The purpose of this study was to assess the position of the implanted devices and the status of the adjacent vitreous and peripheral retina over time using B-scan ocular ultrasonography (US). In each of the eight New Zealand rabbits used in this study, a chitosan (CS) and poly-lactic acid (PLA)-based micro-implant containing approximately 400 µg of MTX and a placebo micro-implant without MTX were inserted into the peripheral vitreous of the right and left eyes, respective, employing minimally invasive surgery. B-scan US imaging was performed on all of the rabbits immediately after implant insertion and on two rabbits at each of several pre-determined time points post-insertion (post-insertion days 5, 12, 19, and 33) to evaluate the position of the micro-implants and identify any evident morphological changes in the micro-implants and in the peripheral retina and vitreous during treatment. US imaging revealed stable positioning of the PLA-coated CS-based MTX micro-implant and the placebo micro-implant in the respective eyes throughout the study and lack of any changes in size, shape or sonoreflectivity of the micro-implants or abnormalities of the peripheral vitreous or retina in any of the study eyes. In summary, US did not show any evident morphological changes in the micro-implants, shifts in post-insertion position of the micro-implants, or identifiable changes in the micro-implants or peripheral vitreous and retina of the study eyes.

Rationale and Safety Assessment of a Novel Intravaginal Drug-Delivery System with Sustained DL-Lactic Acid Release, Intended for Long-Term Protection of the Vaginal Microbiome.

Bacterial vaginosis is a prevalent state of dysbiosis of the vaginal microbiota with wide-ranging impact on human reproductive health. Based on recent insights in community ecology of the vaginal microbiome, we hypothesize that sustained vaginal DL-lactic acid enrichment will enhance the recruitment of lactobacilli, while counteracting bacterial vaginosis-associated bacteria. We therefore aimed to develop an intravaginal device that would be easy to insert and remove, while providing sustained DL-lactic acid release into the vaginal lumen. The final prototype selected is a vaginal ring matrix system consisting of a mixture of ethylene vinyl acetate and methacrylic acid-methyl methacrylate copolymer loaded with 150 mg DL-lactic acid with an L/D-lactic acid ratio of 1:1. Preclinical safety assessment was performed by use of the Slug Mucosal Irritation test, a non-vertebrate assay to evaluate vaginal mucosal irritation, which revealed no irritation. Clinical safety was evaluated in a phase I trial with six healthy nulliparous premenopausal volunteering women, with the investigational drug left in place for 7 days. Colposcopic monitoring according to the WHO/CONRAD guidelines for the evaluation of vaginal products, revealed no visible cervicovaginal mucosal changes. No adverse events related to the investigational product occurred. Total release from the intravaginal ring over 7 days was estimated through high performance liquid chromatography at 37.1 (standard deviation 0.9) mg DL-lactic acid. Semisolid lactic acid formulations have been studied to a limited extent in the past and typically consist of a large volume of excipients and very high doses of lactic acid, which is of major concern to mucosal safety. We have documented the feasability of enriching the vaginal environment with pure DL-lactic acid with a prototype intravaginal ring. Though the efficacy of this platform remains to be established possibly requiring further development, this approach may offer a novel avenue to modulate and protect the vaginal microbiota.

Cost Effectiveness of Paliperidone Long-Acting Injectable Versus Other Antipsychotics for the Maintenance Treatment of Schizophrenia in France.

BACKGROUND: French clinical recommendations suggest prescribing long-acting injectable (LAI) antipsychotics to patients with a maintenance treatment indication in schizophrenia. Despite this, and due to their relatively high acquisition and administration costs, LAIs are still underused in clinical practice in France, thus highlighting the need for pharmacoeconomic evaluations. OBJECTIVE: Our objective was to estimate the cost effectiveness of paliperidone LAI (or paliperidone palmitate), a once-monthly second-generation LAI antipsychotic, compared with the most common antipsychotic medications for the maintenance treatment of schizophrenia in France. METHODS: A Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and to consider up to three lines of treatment to account for changes in treatment management. Paliperidone LAI was compared with risperidone LAI, aripiprazole LAI, olanzapine LAI, haloperidol LAI (or haloperidol decanoate) and oral olanzapine. Costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over 5 years based on 3-month cycles with a discount rate of 4% and from a French health insurance perspective. Patients were considered to be stabilised after a schizophrenic episode and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on real-life French data to capture adherence effects. Safety and utility data were derived from international publications. Additionally, costs were retrieved from French health insurance databases and publications. Finally, expert opinion was used for validation purposes or in case of gaps in data. The robustness of results was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: All LAI antipsychotics were found to have similar costs over 5 years: approximatively €55,000, except for paliperidone LAI which had a discounted cost of €50,880. Oral olanzapine was less costly than LAIs (i.e. €50,379 after 5 years) but was associated with fewer QALYs gained and relapses avoided. Paliperidone LAI dominated aripiprazole LAI, olanzapine LAI and haloperidol LAI in terms of costs per QALY, and it was associated with slightly fewer QALYs when compared with risperidone LAI (i.e. 3.763 vs 3.764). This resulted in a high incremental cost-effectiveness ratio (ICER) (i.e. €4,770,018 per QALY gained) for risperidone LAI compared with paliperidone LAI. Paliperidone LAI was more costly than olanzapine oral but associated with more QALYs (i.e. ICER of €2411 per QALY gained for paliperidone LAI compared with oral olanzapine). Paliperidone LAI had a probability of being the optimal strategy in more than 50% of cases for a willingness-to-pay threshold of €8000 per QALY gained. CONCLUSION: This analysis, to the best of our knowledge, is the first of its kind to assess the cost effectiveness of antipsychotics based on French observational data. Paliperidone LAI appeared to be a cost-effective option in the treatment of schizophrenia from the French health insurance perspective.

Design of Block Copolymer Costabilized Nonionic Microemulsions and Their In Vitro and In Vivo Assessment as Carriers for Sustained Regional Delivery of Ibuprofen via Topical Administration.

Nonionic surfactants (caprylocaproyl macrogol-8 glycerides, octoxynol-12, polysorbate-20, and polyethylene glycol-40 hydrogenated castor oil) (47.03%, w/w), costabilizer (poloxamer 407) (12%-20%, w/w), oil (isopropyl myristate) (5.22%, w/w), water (q.s. ad 100%, w/w), and ibuprofen (5%, w/w) were used to develop oil-in-water microemulsions with Newtonian flow behavior, low viscosity (from 368 ± 38 to 916 ± 46 mPa s), and average droplet size from 14.79 ± 0.31 to 16.54 ± 0.75 nm. Ibuprofen in vitro release from the microemulsions was in accordance with zero-order kinetics (R0(2) > 0.99) for at least 12 h. The maximum drug release rate (3.55%h(-1) ) was from the microemulsion M3 comprising 16%, w/w of poloxamer 407. The release rate of ibuprofen from the reference hydrogel followed Higuchi kinetics (RH(2) > 0.99), and drug amount released after the 6th hour was negligible. In a rat model of inflammation, the microemulsion M3 was significantly more efficacious than the reference hydrogel in exerting antihyperalgesic effects in prophylactic topical treatment, whereas they were comparable in therapeutic treatment as well as in producing antiedematous effect in both protocols. No obvious skin irritation was observed in in vivo studies. The developed nonionic surfactants-based microemulsions containing the optimal concentration of poloxamer 407 could be promising carriers for sustained regional delivery of ibuprofen via topical administration.

Achieving cost-neutrality with long-acting reversible contraceptive methods.

OBJECTIVES: This analysis aimed to estimate the average annual cost of available reversible contraceptive methods in the United States. In line with literature suggesting long-acting reversible contraceptive (LARC) methods become increasingly cost-saving with extended duration of use, it aimed to also quantify minimum duration of use required for LARC methods to achieve cost-neutrality relative to other reversible contraceptive methods while taking into consideration discontinuation. STUDY DESIGN: A three-state economic model was developed to estimate relative costs of no method (chance), four short-acting reversible (SARC) methods (oral contraceptive, ring, patch and injection) and three LARC methods [implant, copper intrauterine device (IUD) and levonorgestrel intrauterine system (LNG-IUS) 20 mcg/24 h (total content 52 mg)]. The analysis was conducted over a 5-year time horizon in 1000 women aged 20-29 years. Method-specific failure and discontinuation rates were based on published literature. Costs associated with drug acquisition, administration and failure (defined as an unintended pregnancy) were considered. Key model outputs were annual average cost per method and minimum duration of LARC method usage to achieve cost-savings compared to SARC methods. RESULTS: The two least expensive methods were copper IUD ($304 per women, per year) and LNG-IUS 20 mcg/24 h ($308). Cost of SARC methods ranged between $432 (injection) and $730 (patch), per women, per year. A minimum of 2.1 years of LARC usage would result in cost-savings compared to SARC usage. CONCLUSIONS: This analysis finds that even if LARC methods are not used for their full durations of efficacy, they become cost-saving relative to SARC methods within 3 years of use. IMPLICATIONS: Previous economic arguments in support of using LARC methods have been criticized for not considering that LARC methods are not always used for their full duration of efficacy. This study calculated that cost-savings from LARC methods relative to SARC methods, with discontinuation rates considered, can be realized within 3 years.

Post-injection delirium/sedation syndrome in patients treated with olanzapine pamoate: mechanism, incidence, and management.

Second-generation antipsychotics (SGAs) are a mainstay in the treatment of patients with schizophrenia. However, continuity in intake of the prescribed medication has been one of the greatest challenges in these patients. One option to improve medication adherence is to prescribe depot or long-acting injectable formulations (LAIs) of antipsychotics. Following risperidone, several other SGAs have been introduced as LAIs. Olanzapine pamoate, paliperidone palmitate, and aripiprazole are the new-generation LAIs, which are available for 2- to 4-week intervals of application in many countries. The literature shows a clear advantage of these drugs over placebo regarding symptom reduction and relapse prevention. LAIs show a similar safety profile to oral formulations of the relevant drug, with the exception of olanzapine pamoate, which can lead to rare cases of post-injection delirium/sedation syndrome (PDSS). PDSS is characterized by heavy sedation (possibly including coma) and/or delirium after injection. During PDSS events, patients show higher plasma concentrations of olanzapine, leading to the assumption that unintended partial intravascular injection or blood vessel injury during the injection is causative of PDSS. Therefore, a risk-management plan proposing an observation period of 3 h was introduced. In August 2013, a new proposal by the European Medicines Agency terminated the requirement to accompany these patients to their next destination, although this requirement remains in place according to US FDA recommendations.

Economic evaluation of ropinirole prolonged release for treatment of Parkinson's disease in the Netherlands.

BACKGROUND: By using the findings obtained from the PREPARED study, we aimed to estimate the cost effectiveness of ropinirole prolonged release (PR) [Requip-Modutab(®)] in Parkinson's disease (PD) versus ropinirole immediate release (IR). In the PREPARED study, ropinirole PR provided a significantly greater improvement in time spent 'off' than ropinirole IR when used as an add-on to levodopa. METHODS: A health state transition model was developed-based on Hoehn and Yahr (HY) stages in PD-to compare the two treatment strategies. The Markov model included the following treatment-related aspects: (i) rate of disease progression; (ii) rates of dyskinesia; and (iii) medication adherence. RESULTS: In our approach, the base-case analysis showed a favourable pharmacoeconomic profile of ropinirole PR versus ropinirole IR. In particular, general cost savings were estimated combined with modest gains in quality of life, due to reduced disease progression and lower dyskinesia rates. Sensitivity analyses showed that this result was rather robust for varying parameters deterministically, although cost savings were lost in some instances. In particular, the treatment benefits of lower dyskinesia rates and improved adherence influenced the cost-effectiveness outcome. Nonetheless, the cost effectiveness remained acceptable within the limits that were investigated. Probabilistic sensitivity analysis revealed that the probability of accepting PR over IR exceeded 95 % for all relevant 'willingness-to-pay' thresholds. CONCLUSION: The results of our study indicate a high likelihood of ropinirole PR being cost saving or at least being considered cost effective for use in the Netherlands. However, claims included in our model regarding dyskinesia and improved medication adherence should be further supported by data from daily practice.