Analysis of gaps in feline ectoparasiticide purchases from veterinary clinics in the United States.

BACKGROUND: The study objective was to examine cat owner ectoparasiticide purchases in the United States and estimate the impact of purchase gaps on timely ectoparasite protection administration. These purchase gaps lead to periods of time when cats are unprotected from ectoparasites. METHODS: Ectoparasiticide purchase transactions for individual cats from 671 U.S. veterinary clinics from January 1, 2017 through June 30, 2019 were evaluated to determine time "gaps" between doses of ectoparasiticides purchased in a defined 12-month period. Ectoparasiticides examined were topically applied products that contained fluralaner, fipronil/(S)-methoprene/pyriproxyfen, imidacloprid/pyriproxyfen or selamectin as active ingredients. The duration of protection following administration of one dose was 8-12 weeks for the fluralaner-containing product and one month for the other products. RESULTS: Ectoparasiticide purchase records were obtained from 114,853 cat owners and analysis found that most owners bought ≤ 6 months of protection during the year, with 61-75% (depending on the product) purchasing just 1-3 months of protection. The size of the average purchase gap was determined for all dose combinations out to 12 months of protection (5-7 doses for fluralaner and 12 doses for the other three products dosed monthly. The largest gaps occurred between the first and second doses and the second and third doses. Average purchase gaps for the four different products between doses 1 and 2 ranged from 11.2 to 13.9 weeks and between doses 2 and 3 ranged from 7.7 to 12.2 weeks. The fraction of purchases separated by gaps and the average length of the gap tended to decrease with increasing number of doses purchased. Owners purchasing the 8 to 12-week duration product containing fluralaner provided ectoparasite protection ("doses plus gap period") for a larger proportion of each 2-dose period compared with owners purchasing products administered monthly. CONCLUSIONS: When cat owners purchase flea and tick medication, gaps between subsequent purchases reduces the proportion of time ectoparasite protection can be provided. The duration of the gap between doses has an impact on the effectiveness of flea/tick medication because it inserts a period without flea and tick protection between doses of flea and tick medication. The gaps between purchases were shorter and the period of ectoparasite protection was larger for owners purchasing a 12-week product than for owners purchasing a monthly product.

Fluralaner as a novel treatment for sarcoptic mange in the bare-nosed wombat (Vombatus ursinus): safety, pharmacokinetics, efficacy and practicable use.

BACKGROUND: Sarcoptic mange causes significant animal welfare and occasional conservation concerns for bare-nosed wombats (Vombatus ursinus) throughout their range. To date, in situ chemotherapeutic interventions have involved macrocytic lactones, but their short duration of action and need for frequent re-administration has limited treatment success. Fluralaner (Bravecto®; MSD Animal Health), a novel isoxazoline class ectoparasiticide, has several advantageous properties that may overcome such limitations. METHODS: Fluralaner was administered topically at 25 mg/kg (n = 5) and 85 mg/kg (n = 2) to healthy captive bare-nosed wombats. Safety was assessed over 12 weeks by clinical observation and monitoring of haematological and biochemical parameters. Fluralaner plasma pharmacokinetics were quantified using ultra-performance liquid chromatography and tandem mass spectrometry. Efficacy was evaluated through clinical assessment of response to treatment, including mange and body condition scoring, for 15 weeks after topical administration of 25 mg/kg fluralaner to sarcoptic mange-affected wild bare-nosed wombats (n = 3). Duration of action was determined through analysis of pharmacokinetic parameters and visual inspection of study subjects for ticks during the monitoring period. Methods for diluting fluralaner to enable 'pour-on' application were compared, and an economic and treatment effort analysis of fluralaner relative to moxidectin was undertaken. RESULTS: No deleterious health impacts were detected following fluralaner administration. Fluralaner was absorbed and remained quantifiable in plasma throughout the monitoring period. For the 25 mg/kg and 85 mg/kg treatment groups, the respective means for maximum recorded plasma concentrations (Cmax) were 6.2 and 16.4 ng/ml; for maximum recorded times to Cmax, 3.0 and 37.5 days; and for plasma elimination half-lives, 40.1 and 166.5 days. Clinical resolution of sarcoptic mange was observed in all study animals within 3-4 weeks of treatment, and all wombats remained tick-free for 15 weeks. A suitable product for diluting fluralaner into a 'pour-on' was found. Treatment costs were competitive, and predicted treatment effort was substantially lower relative to moxidectin. CONCLUSIONS: Fluralaner appears to be a safe and efficacious treatment for sarcoptic mange in the bare-nosed wombat, with a single dose lasting over 1-3 months. It has economic and treatment-effort-related advantages over moxidectin, the most commonly used alternative. We recommend a dose of 25 mg/kg fluralaner and, based on the conservative assumption that at least 50% of a dose makes dermal contact, Bravecto Spot-On for Large Dogs as the most appropriate formulation for adult bare-nosed wombats.

Assessment of laying-bird welfare following acaricidal treatment of a commercial flock naturally infested with the poultry red mite (Dermanyssus gallinae).

The poultry red mite (PRM), Dermanyssus gallinae, a potential vector of pathogens to animals and humans, causes impaired bird welfare. A study investigated changes in behavioural variables, physiological biomarkers, and health parameters following acaricidal treatment of PRM infestation of laying hens on a commercial farm. Mite traps determined the challenge to 12,700 hens before and after drinking water administration of the acaricide, fluralaner (Exzolt®, 0.5 mg/kg; Weeks 0 and 1). Weekly daytime direct observations and night-time video recordings monitored bird behaviours from Weeks -6 through +6. Blood samples were collected from randomly-selected birds (Weeks -6, -1, and +6). Following treatment, mite count reductions (>99%) were statistically significant (P < 0.0001), as were night-time reductions in the percent of hens showing activity, preening, head scratching (all P < 0.0001), and head shaking (P = 0.0007). Significant daytime reductions were observed in preening and head scratching (both P < 0.0001), head shaking (P = 0.0389), severe feather pecking (P = 0.0002), and aggressive behaviour (P = 0.0165). Post-treatment, comb wounds were significantly reduced (P = 0.0127), and comb colour was significantly improved (P < 0.0001). Heterophil/lymphocyte ratio was significantly reduced at Weeks 1 and 6 (P = 0.0009 and P < 0.0001, respectively). At Week 6, blood corticosterone (P = 0.0041) and total oxidant status (P < 0.0001) were significantly reduced, and haemoglobin and mean corpuscular haemoglobin significantly increased (P < 0.0001). Farm production records indicated that those post-treatment improvements were accompanied by significant reductions in weekly mortality rate (P = 0.0169), and significant recovery in mean weekly egg weights (P < 0.0001) and laying rate (P < 0.0001). The improvements in behavioural variables, physiological biomarkers, and health parameters that were observed following the elimination of PRM on a commercial farm indicate that infestations can be a cause of reduced hen welfare.

A European field assessment of the efficacy of fluralaner (Bravecto®) chewable and spot-on formulations for treatment of dogs with generalized demodicosis.

BACKGROUND: Recent reports indicate that the isoxazoline compounds have the potential to provide safe and effective treatment of canine generalized demodicosis, a condition that has been traditionally difficult to cure. Controlled field studies are needed to confirm this potential. A study was therefore initiated to investigate the efficacy of a single oral or spot-on treatment with fluralaner, an isoxazoline, compared with multiple topical treatments with imidacloprid-moxidectin, in dogs naturally affected by generalized demodicosis. METHODS: Veterinary clinics in 5 European countries enrolled 134 dogs diagnosed with generalized demodicosis. Dogs were randomized to treatment with either fluralaner chewables, fluralaner spot-on, or topical imidacloprid-moxidectin in a 2:2:1 ratio. Both fluralaner formulations were administered once, at the approved dose rate, on Day 0. Imidacloprid-moxidectin was administered per label on Day 0, and every 4 weeks, more frequently if necessary. At each visit (Days 0, 28, 56, 84), dogs were monitored for demodectic mites using deep skin scrapings and observed for health and for severity of skin lesions. Treatment was considered efficacious if more than 90% of the dogs were free of live mites at both Days 56 and 84. RESULTS: Of 124 dogs completing the study, 57 were diagnosed with juvenile-onset demodicosis and 67 with the adult-onset form. A single treatment with oral or spot-on fluralaner was efficacious, each eliminating mites from at least 98.0% of treated dogs on Days 56 and 84. Against juvenile-onset demodicosis, efficacy of the oral and spot-on formulations was 96.0% and 100%, respectively, and against adult-onset demodicosis 100% and 96.7%. Multiple administrations of imidacloprid-moxidectin were not efficacious, eliminating mites from 87.5% of dogs (92.0% with juvenile-onset demodicosis cured; 81.8% with adult-onset demodicosis). All groups showed a marked reduction in skin lesions by Day 28, with continuing clinical improvement at each subsequent visit through Day 84. There were no treatment-related adverse events. CONCLUSIONS: A single administration of fluralaner chewables or fluralaner spot-on is highly effective against with juvenile-onset and adult-onset forms of generalized canine demodicosis. Topically applied imidacloprid-moxidectin at weekly to monthly intervals over the 84-day study did not achieve the proportion of mite-free dogs required to demonstrate efficacy.

Novel multimodal analgesia regimen improves post-TACE pain in patients with hepatocellular carcinoma.

BACKGROUD: Transarterial chemoembolization (TACE) is the primary palliative treatment for patients with unresectable hepatocellular carcinoma (HCC). However, it is often accompanied by postoperative pain which hinder patient recovery. This study was to examine whether preemptive parecoxib and sufentanil-based patient controlled analgesia (PCA) could improve the pain management in patients receiving TACE for inoperable HCC. METHODS: From June to December 2016, 84 HCC patients undergoing TACE procedure were enrolled. Because of the willingness of the individuals, it is difficult to randomize the patients to different groups. We matched the patients' age, gender and pain scores, and divided the patients into the multimodal group (n = 42) and control group (n = 42). Patients in the multimodal group received 40 mg of parecoxib, 30 min before TACE, followed by 48 h of sufentanil-based PCA. Patients in the control group received a routine analgesic regimen, i.e., 5 mg of dezocine during operation, and 100 mg of tramadol or equivalent intravenous opioid according to patient's complaints and pain intensity. Postoperative pain intensity, percentage of patients as per the pain category, adverse reaction, duration of hospital stay, cost-effectiveness, and patient's satisfaction were all taken into consideration when evaluated. RESULTS: Compared to the control group, the visual analogue scale scores for pain intensity was significantly lower at 2, 4, 6, and 12 h (all P < 0.05) in the multimodal group and a noticeably lower prevalence of post-operative nausea and vomiting in the multimodal group (31.0% vs. 59.5%). Patient's satisfaction in the multimodal group was also significantly higher than that in the control group (95.2% vs. 69.0%). No significant difference was observed in the duration of hospital stay between the two groups. CONCLUSION: Preemptive parecoxib and sufentanil-based multimodal analgesia regime is a safe, efficient and cost-effective regimen for postoperative pain control in HCC patients undergoing TACE.

In-home assessment of either topical fluralaner or topical selamectin for flea control in naturally infested cats in West Central Florida, USA.

BACKGROUND: An investigation was conducted in West Central Florida, USA to evaluate the efficacy of either topically applied fluralaner or topically applied selamectin to control flea infestations, minimize dermatologic lesions and reduce pruritus in naturally flea infested cats over a 12-week period. When dogs were present in the households, they were treated with either oral fluralaner (if household cats were treated with topical fluralaner) or oral sarolaner (if household cats were treated with topical selamectin). METHODS: Thirty-one cats in 20 homes were treated once with fluralaner topical solution on day 0 and 18 dogs in these homes were administered a single fluralaner chewable. Twenty-nine cats in 18 homes were treated once monthly with a selamectin topical solution for 3 treatments and 13 dogs in these same homes were treated once monthly for 3 treatments with a sarolaner chewable. Fleas on cats were counted by flea combing, fleas on dogs were estimated using visual area counts and fleas in the indoor premises were assessed using intermittent-light flea traps. Blinded-assessments of feline dermatologic lesions were conducted monthly and pruritus severity was evaluated by pet owners. RESULTS: A single topical application of fluralaner reduced flea populations on cats by 96.6% within 7 days and by 100% at 12 weeks post-treatment. This efficacy was significantly greater than selamectin treatment where single topical application reduced flea populations on cats by 79.4% within 7 days of initial treatment and 3 consecutive monthly treatments reduced flea populations by 91.3% at the end of 12 weeks. At the end of the 12-week study, all fluralaner-treated cats were flea-free and this was significantly greater than the 38.5% of selamectin treated cats that were flea-free. At the end of the study, fleas were completely eradicated (from cats, dogs and homes) in 95.0% of fluralaner treatment group homes, significantly greater than the 31.3% of selamectin/sarolaner treatment group homes with complete flea eradication. Owner reported cat pruritus was reduced similarly in both treatment groups. Significant improvements in dermatologic lesion scores were achieved by day 30 in fluralaner treated cats and by day 60 in selamectin treated cats. CONCLUSIONS: An in-home investigation in subtropical Florida found that 1 application of topical fluralaner eliminated flea infestations on cats and in homes significantly more effectively than 3 consecutive monthly doses of selamectin.

Assessment of the insecticidal activity of afoxolaner against Aedes aegypti in dogs treated with NexGard®.

Twelve healthy dogs were studied in this parallel group, blinded, randomised, and negative controlled efficacy study. On Day -1, the 12 dogs included were ranked within sex in descending order of individual pre-treatment (Day -5) fed mosquito counts and randomly allocated by blocks of two dogs to the untreated control group or the afoxolaner-treated group. NexGard® (Merial, now part of Boehringer Ingelheim Animal Health) was administered orally on Day 0 in accordance with the European label instructions. On Days 1, 7, 14, 21 and 28, all dogs were exposed for a duration of 1 hour to 50 ± 5 unfed Aedes aegypti females. After each exposure, mosquitoes were collected after 1 hour and assessed for viability during collection and at 24 ± 2 hours. The arithmetic (and geometric) mean values of live fed mosquito counts at 24 hours after the exposure periods for the negative control group ranged from 33.7 (32.3) to 49.8 (49.7), indicating that this was a vigorous mosquito strain. There was no significant difference between control and treated groups in the number of live and fed mosquitoes at each 1 hour post-exposure collection time. Based on arithmetic and geometric mean values at 24 hours after each exposure, significantly fewer live fed mosquitoes were recorded in the treated group, compared to the negative control group, throughout the study (p < 0.001). The afoxolaner insecticidal efficacy against A. aegypti varied from 98% (Day 2) to 75.3% (Day 29) based on arithmetic means, and 98.7% (Day 2) to 89.8% (Day 29) based on geometric means.

Cost-effectiveness Analysis of Treatment Sequence Initiating With Etanercept Compared With Leflunomide in Rheumatoid Arthritis: Impact of Reduced Etanercept Cost With Patent Expiration in South Korea.

PURPOSE: In south Korea, the price of biologics has been decreasing owing to patent expiration and the availability of biosimilars. This study evaluated the cost-effectiveness of a treatment strategy initiated with etanercept (ETN) compared with leflunomide (LFN) after a 30% reduction in the medication cost of ETN in patients with active rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR). METHODS: A cohort-based Markov model was designed to evaluate the lifetime cost-effectiveness of treatment sequence initiated with ETN (A) compared with 2 sequences initiated with LFN: LFN-ETN sequence (B) and LFN sequence (C). Patients transited through the treatment sequences, which consisted of sequential biologics and palliative therapy, based on American College of Rheumatology (ACR) responses and the probability of discontinuation. A systematic literature review and a network meta-analysis were conducted to estimate ACR responses to ETN and LFN. Utility was estimated by mapping an equation for converting the Health Assessment Questionnaire-Disability Index score to utility weight. The costs comprised medications, outpatient visits, administration, dispensing, monitoring, palliative therapy, and treatment for adverse events. A subanalysis was conducted to identify the influence of the ETN price reduction compared with the unreduced price, and sensitivity analyses explored the uncertainty of model parameters and assumptions. FINDINGS: The ETN sequence (A) was associated with higher costs and a gain in quality-adjusted life years (QALYs) compared with both sequences initiated with LFN (B, C) throughout the lifetime of patients with RA and MTX-IR. The incremental cost-effectiveness ratio (ICER) for strategy A versus B was ₩13,965,825 (US$1726) per QALY and that for strategy A versus C was ₩9,587,983 (US$8050) per QALY. The results indicated that strategy A was cost-effective based on the commonly cited ICER threshold of ₩20,000,000 (US$16,793) per QALY in South Korea. The robustness of the base-case analysis was confirmed using sensitivity analyses. When the unreduced medication cost of ETN was applied in a subanalysis, the ICER for strategy A versus B was ₩20,909,572 (US$17,556) per QALY and that for strategy A versus C was ₩22,334,713 (US$18,753) per QALY. IMPLICATIONS: This study indicated that a treatment strategy initiated with ETN was more cost-effective in patients with active RA and MTX-IR than 2 sequences initiated with LFN. The results also indicate that the reduced price of ETN affected the cost-effectiveness associated with its earlier use.

[ZONISAMIDE: FIRST CHOICE AMONG THE FIRST-LINE ANTIEPILEPTIC DRUGS IN FOCAL EPILEPSY]. / ZONISAMID: AZ ELSOKÉNT VÁLASZTANDÓ ANTIEPILEPTIKUMOK KÖZÖTT FOKÁLIS EPILEPSZIÁBAN.

Chronic administration of antiepileptic drugs without history of unprovoked epileptic seizures are not recommended for epilepsy prophylaxis. Conversely, if the patient suffered the first unprovoked seizure, then the presence of epileptiform discharges on the EEG, focal neurological signs, and the presence of epileptogenic lesion on the MRI are risk factors for a second seizure (such as for the development of epilepsy). Without these risk factors, the chance of a second seizure is about 25-30%, while the presence of these risk factors (for example signs of previous stroke, neurotrauma, or encephalitis on the MRI) can predict >70% seizure recurrence. Thus the International League Against Epilepsy (ILAE) re-defined the term 'epilepsy' which can be diagnosed even after the first seizure, if the risk of seizure recurrence is high. According to this definition, we can start antiepileptic drug therapy after a single unprovoked seizure. There are four antiepileptic drugs which has the highest evidence (level "A") as first-line initial monotherapy for treating newly diagnosed epilepsy. These are: carbamazepine, phenytoin, levetiracetam, and zonisamide (ZNS). The present review focuses on the ZNS. Beacuse ZNS can be administrated once a day, it is an optimal drug for maintaining patient's compliance and for those patients who have a high risk for developing a non-compliance (for example teenagers and young adults). Due to the low interaction potential, ZNS treatment is safe and effective in treating epilepsy of elderly people. ZNS is an ideal drug in epilepsy accompanied by obesity, because ZNS has a weight loss effect, especially in obese patients.

Assessment of the onset of action of afoxolaner against existing adult flea (Ctenocephalides felis) infestations on dogs.

The speed of kill of afoxolaner against experimental infestations by Ctenocephalides felis was evaluated after oral administration of afoxolaner in a soft chew (NEXGARD(®)) at a dose to achieve 2.5mg/kg bodyweight. Forty beagles were allocated to two treatment groups. Dogs in Treatment Group 1 were untreated controls. Dogs in Treatment Group 2 were treated on Day-0 with afoxolaner, according to their pre-treatment bodyweight. All dogs were infested with approximately 100 C. felis on Day-1. Live fleas were counted upon removal at 5 time points after treatment (i.e., 2, 4, 8, 12 and 24h after treatment). For each time point, counts were performed on 4 dogs from each of the treated and the untreated groups. Early curative flea killing efficacy was evaluated with respect to the untreated control group. The afoxolaner treated group had significantly fewer fleas than the untreated control group at 8, 12, and 24h (p<0.001). The percent efficacies of orally administered afoxolaner were 15.0%, 87.8%, 99.5%, 100.0%, and 100.0% at 2, 4, 8, 12, and 24h, respectively. In this study, afoxolaner began killing fleas by 2h after treatment with increasing efficacy at subsequent time points and had >99.5% efficacy at 8, 12, and 24h after treatment demonstrating an early onset of action.

Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States.

OBJECTIVE: To develop a decision-analytic model to estimate the cost-effectiveness of initiating maintenance treatment with aripiprazole once-monthly (AOM) vs paliperidone long-acting injectable (PLAI) once-monthly among patients with schizophrenia in the US. METHODS: A decision-analytic model was developed to evaluate a hypothetical cohort of patients initiating maintenance treatment with AOM or PLAI. Rates of relapse, adverse events (AEs), and direct medical costs were estimated for 1 year. Patients either remained on initial treatment or discontinued treatment due to lack of efficacy, AEs, or other reasons, including non-adherence. Data from placebo-controlled pivotal trials and product prescribing information (PI) were used to estimate treatment efficacy and AEs. Analyses were performed assuming dosing of clinical trials, real-world practice, PIs, and highest therapeutic dose available, because of variation in practice settings. The main outcome of interest was incremental cost per schizophrenia hospitalization averted with AOM vs PLAI. RESULTS: Based on placebo-controlled pivotal trials' dosing, AOM improved clinical outcomes by reducing schizophrenia relapses vs PLAI (0.181 vs 0.277 per person per year [pppy]) at an additional cost of US$1276 pppy, resulting in an incremental cost-effectiveness ratio (ICER) of US$13,280/relapse averted. When PI dosing was assumed, this ICER increased to US$19,968/relapse averted. When real-world dosing and highest available dosing were assumed, AOM was associated with fewer relapses and lower overall treatment costs vs PLAI. CONCLUSIONS: AOM consistently provided favorable clinical benefits. Under various dosing scenarios, AOM results indicated fewer relapses at lower overall costs or a reasonable cost-effectiveness threshold (i.e., less than the cost of a hospitalization relapse) vs PLAI. Given the heterogeneous nature of schizophrenia and variability in treatment response, health plans may consider open access for treatments like AOM. Since model inputs were based on data from separate placebo-controlled trials, generalization of results to the real-world setting is limited.

Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato.

Two studies were conducted to confirm that a single oral dose of the novel insecticide/acaricide afoxolaner is efficacious against existing infestations of Rhipicephalus sanguineus sensu lato in dogs and can control re-infestation for up to 35 days. Each study utilized 16 purpose bred adult dogs using a controlled randomized block design. One or two days prior to treatment, all dogs were infested with 50 unfed adult ticks. On Day 0 one group was treated with an oral chewable formulation of afoxolaner at a dose as close as possible to the minimum dose of 2.5mg/kg. Weekly re-infestations with 50 adult unfed ticks were repeated for five weeks. Forty-eight hours after treatment and after each re-infestation, the number of remaining live ticks on each dog was counted. Treatment with afoxolaner resulted in efficacies of 98.8-100% within 48 h on existing tick infestations, while the efficacy against new tick infestations was >95.7% over five weeks.

Validation of an economic model of paliperidone palmitate for chronic schizophrenia.

OBJECTIVE: Model validation is important, but seldom applied in chronic schizophrenia. Validation consists of verifying the model itself for face validity (i.e., structure and inputs), cross-validation with other models assessing the same issue, and comparison with real-life outcomes. The primary purpose was to cross-validate a recent pharmacoeconomic model comparing long-acting injectable (LAI) antipsychotics for treating chronic schizophrenia in Sweden. The secondary purpose was to provide external validation. METHODS: The model of interest was a decision tree analysis with a 1-year time horizon with costs in 2011 Swedish kroner. Drugs analyzed included paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), haloperidol (HAL-LAI), and oral olanzapine (oral-OLZ). Embase and Medline were searched from 1990-2012 for models examining LAIs. Articles were retrieved, with data extracted for all drugs compared including: expected costs, rates of hospitalization, proportion of time not in relapse, and associated QALYs. Outcomes from the model of interest were compared with those from other articles; costs were projected to 2012 using the consumer price index. RESULTS: Twenty-six studies were used for validation; 14 of them provided evidence for cross-validation, 13 for external validation, and four for cost. In cross-validation, cost estimates varied -1.8% (range: -12.4-20.1%), hospitalizations 5.2% (-12.1-3.1%), stable disease 2.5% (-5.6-1.5%), QALYs 9.0% (4.3% after removing outliers). All estimates of clinical outcomes were within 15%. In external validation, hospitalization rates varied by 6.3% (-0.7-11.3%). The research was limited by data availability and validity of the original results. CONCLUSION: Other models validated the outputs of our model very well.

Cost effectiveness of paliperidone palmitate for the treatment of schizophrenia in Germany.

BACKGROUND: Treatment with antipsychotic medication is an important element of relapse prevention in the management of schizophrenia, and can reduce inpatient stays. Recently, the long-acting atypical antipsychotic paliperidone long-acting injectable (PLAI), a once-monthly LAI antipsychotic, was approved for treatment of schizophrenia in Germany. OBJECTIVE: To estimate, based on a previously published model, the cost effectiveness of PLAI compared with other common antipsychotic treatment strategies in patients diagnosed with schizophrenia in Germany. METHODS: A Markov decision analytic model was adapted to the German healthcare system. The model considers the cost effectiveness for PLAI as a maintenance treatment for patients with schizophrenia from the payer perspective. The patients transition between eight health states on a monthly basis over a 5-year time horizon. As therapeutic strategies, PLAI, quetiapine, risperidone long-acting injections (RLAI), oral olanzapine, oral risperidone, zuclopenthixol decanoate, olanzapine long-acting injections (OLAI), oral typical and oral atypical were compared. Probability of relapse, level of adherence, side effects and treatment discontinuation were derived from the Swedish original model. Input factors regarding resource use and costs were estimated and adjusted for the German healthcare system. A probabilistic sensitivity analyses (PSA) using cost-effectiveness scatter plots was performed to visualize the robustness of the results. RESULTS: In base-case scenario, PLAI is superior to RLAI in gained quality-adjusted life-years (QALYs) and avoided relapses. Relative to all other treatment strategies, PLAI is more effective with regard to gained QALYs and avoided relapses but results in higher treatment costs over a 5-year horizon in base-case scenario. The results were tested in PSA. If a cost-effectiveness threshold of 30,000 is assumed, for example, PLAI can be considered to be cost effective compared with RLAI in about 92.5 % of cases regarding gained QALYs, and in 78.6 % of cases regarding avoided relapse. Compared with OLAI, in about 94.4 % of cases regarding gained QALYs and in 99.9 % of cases regarding avoided relapse, cost effectiveness can be considered. Comparing PLAI and zuclopenthixol decanoate, cost effectiveness can be assumed in about 90.4 % of cases regarding gained QALYs, and in all cases regarding avoided relapse. CONCLUSIONS: PLAI dominates RLAI and compared with the other treatment strategies PLAI has shown to be more effective but results in higher costs in base-case scenario.

A cost-effectiveness analysis of parecoxib in the management of postoperative pain in the Greek health care setting.

BACKGROUND: Postoperative pain management represents a significant factor of morbidity and reduced quality of life for patients, as well as a situation that substantially increases perioperative costs. Available analgesia treatments improve patient outcomes and reduce resource use associated with pain management, although with varying costs and adverse effects. OBJECTIVES: The aim of this analysis was to assess the costs and patient outcomes of parecoxib used in combination with opioids versus use of opioids alone (monotherapy) in the postoperative treatment of surgical patients in Greece. METHODS: A model comparing parecoxib plus opioid treatment versus opioids alone was developed that simulated the first 3 days postsurgery. Clinical efficacy was based on a Phase III, randomized, double-blind, clinical trial that also provided the frequencies of the occurrence of clinically meaningful events (CMEs) related to opioid use for both treatment arms. Resource use associated with each CME was elicited via strictly structured questionnaire-based interviews conducted by a panel of experts (surgeons and anesthesiologists), and costs were determined from the perspective of Social Insurance in Greece (2012 euros). Treatment effectiveness was calculated in summed pain intensity scores. A series of 1-way sensitivity analyses were conducted to check the robustness of the outcomes. RESULTS: Patients treated with parecoxib plus opioids had lower summed pain intensity scores (59.20 vs 80.80) and fewer CMEs (0.62 vs 1.04 per patient) compared with opioids alone for a 3-day period. This outcome led to a full offset of the excess cost of the addition of parecoxib and led to potential savings of €858 per patient compared with opioid use alone. Savings were mainly attributable to decreased CMEs due to reduced intensive care unit and general ward bed-days as well as to reduced physician and nurse time. Results were sensitive with regard to probabilities of occurrence or co-occurrence of CMEs (≥2 CMEs occurring simultaneously), although only to a small extent. Medication costs had a minimal impact on the results of the sensitivity analysis. CONCLUSIONS: Parecoxib may be a useful addition to opioid treatment by improving postoperative analgesic management, reducing opioid-related adverse events, and lowering per-patient treatment costs.

The cost-effectiveness of paliperidone extended release in Spain.

BACKGROUND: Paliperidone Extended Release OROS (ER) is a new atypical antipsychotic for the treatment of schizophrenia. The objective is, based on a previously published model, to analyze the clinical and economic effects of Paliperidone ER in a Spanish setting compared to olanzapine oral and aripiprazole. METHODS: An existing discrete event simulation model was adapted to reflect the treatment of schizophrenia in Spain in terms of costs, resource use, and treatment patterns. Inputs for the model were derived from clinical trial data, literature research, database analysis and interviews with local clinical experts. The time horizon is 5 years and Spanish discount rate was applied. Outputs include direct medical costs and Quality Adjusted Life-Years (QALYs). Extensive sensitivity analyses were carried out to assess the robustness of the results, using ordinary least squares analysis and cost-effectiveness scatter plots. RESULTS: The results show that the mean incremental QALYs (95% CI) compared to olanzpine is 0.033 [-0.143, 0.304] and compared to aripiprazole 0.029 [-0.107, 0.300]. The corresponding mean incremental costs and corresponding confidence intervals are -€1425 [-€10,247, €3084] and -€759 [-€10,479, €3404], respectively. The probability that paliperidone ER is cost-saving and health gaining compared to olanzapine and aripiprazole is 76% and 72%, respectively. Paliperidone ER was estimated to have 80% and 81% probability of being cost-effective compared to olanzapine at a willingness to pay of €20,000 and €30,000 and 73% and 74% compared to aripiprazole, respectively. LIMITATIONS: Some of the modeled inter-relationships had to be based on expert opinion due to a lack of information. Also, foreign sources for the disutility of adverse events had been used due to a lack of Spanish data. Prolactin-related side-effects, indirect costs, and potential compliance advantages of paliperidone ER were not considered. It is unlikely that these limitations affected the conclusions. CONCLUSION: Based on differences in drug acquisition costs, side-effects, and risk of relapse, the model predicts that, in the Spanish healthcare setting, paliperidone ER dominates oral olanzapine and aripiprazole, with a probability of 76% and 72%, respectively.

Second-generation long-acting injectable antipsychotic agents: an overview.

For over 40 years, antipsychotic drugs have been used as long-term maintenance treatment to control symptoms and reduce relapse rates in patients with schizophrenia. 'First-generation' oral agents such as haloperidol and chlorpromazine are associated with high levels of unwanted neurological effects and poor rates of patient adherence.1,2 Long-acting ('depot') injections of antipsychotics were developed to try to improve adherence. 'Second-generation' antipsychotic agents (also known as atypical antipsychotics) were introduced into clinical practice over 16 years ago. Although these agents have a lower propensity to cause extrapyramidal side effects, they are associated with a range of other unwanted effects (e.g. weight gain and its sequelae).1,3,4 Initially, second-generation agents were only available as orally administered medicines. Three long-acting injectable formulations of second-generation antipsychotics are now available in the UK: olanzapine embonate injection (ZypAdhera), paliperidone injection (Xeplion) and risperidone injection (Risperdal Consta). In this article we review the evidence for these agents and discuss the practical implications of their use.

The threshold rate of oral atypical anti-psychotic adherence at which paliperidone palmitate is cost saving.

OBJECTIVE: To identify, estimate, and compare 'real world' costs and outcomes associated with paliperidone palmitate compared with branded oral atypical anti-psychotics, and to estimate the threshold rate of oral atypical adherence at which paliperidone palmitate is cost saving. METHODS: Decision analytic modeling techniques developed by Glazer and Ereshefsky have previously been used to estimate the cost-effectiveness of depot haloperidol, LAI risperidone, and, more recently, LAI olanzapine. This study used those same techniques, along with updated comparative published clinical data, to evaluate paliperidone palmitate. Adherence rates were based on strict Medication Event Monitoring System (MEMS) criteria. The evaluation was conducted from the perspective of US healthcare payers. RESULTS: Paliperidone palmitate patients had fewer mean annual days of relapse (8.7 days; 6.0 requiring hospitalization, 2.7 not requiring hospitalization vs 17.8 days; 12.4 requiring hospitalization, 5.4 not requiring hospitalization), and lower annual total cost ($20,995) compared to oral atypicals (mean $22,481). Because paliperidone palmitate was both more effective and less costly, it is considered economically dominant. Paliperidone palmitate saved costs when the rate of adherence of oral atypical anti-psychotics was below 44.9% using strict MEMS criteria. Sensitivity analyses showed results were robust to changes in parameter values. For patients receiving 156 mg paliperidone palmitate, the annual incremental cost was $1216 per patient (ICER = $191 per day of relapse averted). Inclusion of generic risperidone (market share 18.6%) also resulted in net incremental cost for paliperidone palmitate ($120; ICER = $13). Limitations of this evaluation include use of simplifying assumptions, data from multiple sources, and generalizability of results. CONCLUSIONS: Although uptake of LAIs in the US has not been as rapid as elsewhere, many thought leaders emphasize their importance in optimizing outcomes in patients with adherence problems. The findings of this analysis support the cost-effectiveness of paliperidone palmitate in these patients.

Assessment of treatment algorithms including amantadine, metformin, and zonisamide for the prevention of weight gain with olanzapine: a randomized controlled open-label study.

OBJECTIVE: This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide. METHOD: Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results. RESULTS: Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for olanzapine, 2.40 ± 0.65 kg for olanzapine + A, and 0.65 ± 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036). CONCLUSIONS: Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00401973.

Are the long-acting intramuscular formulations of risperidone or paliperidone palmitate associated with post-injection delirium/sedation syndrome? An assessment of safety databases.

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical. Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI. Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed. No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI. Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate-that case having been reported in a patient randomized to treatment with placebo. Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.