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Two-dose killed oral cholera vaccines (OCV) are currently being used widely to control cholera. The standard dose-interval for OCV is 2 weeks; however, during emergency use of the vaccine, it may be more appropriate to use the available doses to quickly give a single dose to more people and give a delayed second dose when more vaccine becomes available. This study is an open label, randomized, phase 2 clinical trial of the vibriocidal response induced by OCV, comparing the responses when the second dose was given either 2 weeks (standard dose interval) or 6 months (extended dose interval) after the first dose. Vaccine was administered to healthy participants 1 year of age living in the Lukanga Swamps area of Zambia. Three age cohorts (5 years, 5-14 years, and ≥ 15 years) were randomized to the either dose-interval. The primary outcome was the vibriocidal GMT 14 days after the second dose. 156 of 172 subjects enrolled in the study were included in this analysis. The Inaba vibriocidal titers were not significantly different 14 days post dose two for a standard dose-interval GMT: 45.6 (32-64.9), as compared to the GMT 47.6 (32.6-69.3), for the extended dose-interval, (p = 0.87). However, the Ogawa vibriocidal GMTs were significantly higher 14 days post dose two for the extended-dose interval at 87.6 (58.9-130.4) compared to the standard dose-interval group at 49.7 (34.1-72.3), p = 0.04. Vibriocidal seroconversion rates (a 4-fold rise in vibriocidal titer) were not significantly different between dose-interval groups. This study demonstrated that vibriocidal titers 14 days after a second dose when given at an extended\ dose interval were similar to the standard dose-interval. The findings suggest that a flexible dosing schedule may be considered when epidemiologically appropriate. The trial was registered at Clinical Trials.gov (NCT03373669).

A review of modern literature on the diagnostic algorithm of bronchial asthma and a detailed examination of all its stages is presented. It is known that bronchial asthma is the most common form of the disease, prone to progression to more severe forms, but fraught with the development of exacerbations, even fatal. Often, general practitioners perceive bronchial asthma as a manageable, understandable disease, for the successful treatment of which it is enough to identify and isolate the allergen, as well as prescribe therapy. Understanding the mechanisms of development of bronchial asthma helps to increase the effectiveness of the diagnosis and treatment of asthma, preferably taking into account the phenotype. Determining the phenotypic characteristics of bronchial asthma is a requirement of the time, because personalized medicine does not yet require the creation of a separate drug, diagnostic or prophylactic method for each individual patient, but it requires the selection of patients (allocation of subpopulations / clusters / phenotypes of bronchial asthma) that are most responsive to a particular drug, a method for diagnosing or preventing a disease. The essence of phenotyping in medicine is the optimization of diagnosis, treatment and prevention. The central and most studied links of the pathogenetic mechanism and its variants of development are described, phenotypes of bronchial asthma are discussed, as well as options for basic and targeted therapy of bronchial asthma. The necessity of studying personalized therapy and flexible dosing of drugs used in the treatment of bronchial asthma is emphasized.

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering &lt, 1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.

The popularity of multiparticulate formulations (MPs) as a paediatric dosage form continues to increase. MPs comprise of multiple small units that are easy-to-swallow. Currently, MPs are commonly manufactured into unit doses that are either swallowed whole or opened prior to administration. While this is an acceptable approach, dosing is envisioned to be optimised with a &ldquo, standard&rdquo, paediatric device which can better harness the flexible dosing potential of MPs. We evaluated a novel oral syringe (SympfinyTM, HS Design, Morristown, NJ, USA) that is being developed as a tool to dispense and administer MPs to children. Forty children, 4&ndash, 12 years old, received 0.5, 1.2, and 2.0 mL doses of placebo MPs using the oral syringe with spring water or a drink of choice to complete sample intake. Acceptability was recorded as those able to completely swallow the dose and participants also rated dose acceptability on a 5-point scale. The ability to completely swallow the dose decreased as dose volume increased, the smallest dose was completely swallowed by 87.5% (35/40) children, and 69.4% (27/39) of children confirmed their willingness to take the sample as a daily medicine. Larger doses, 1.2 and 2.0 mL, gave values of 55% and 57.5% for the doses completely swallowed and 58.8% and 51.72% for willingness to take the sample as a daily medicine, respectively. Use of a drink of choice showed no increase in swallowability as compared with water. The novel oral syringe being developed is an appropriate device for dispensing doses flexibly and administering neutral tasting MPs directly to the mouth in the lower dose range without the need for a co-administration vehicle in children aged 4&ndash, 12 years.

This article reports on a survey conducted at four diabetes-related annual conferences in 2017 and 2018 to obtain input from the medical community regarding the most important features of insulin delivery devices to address the unmet needs of people with type 2 diabetes who require basal/bolus insulin therapy. The overall patterns of responses compiled from 742 participating health care providers, each voting for three of eight proposed features of insulin delivery devices, were mostly similar numerically at each conference. The features garnering the top three percentages of votes (n = 2,226) averaged for all four conferences were tube-free patch (14.7%), reduced number of insulin injections (14.7%), and dose capture report (14.2%). Four other features received almost as many votes: flexible dosing (14.0%), patient lifestyle app (13.3%), wireless controller (12.7%), and interconnected glucose monitoring (12.6%). This survey provided valuable information that can aid the development of future insulin delivery devices.

Targeted therapies have revolutionized the treatment of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) metastatic breast cancer (mBC). However, as for many oncology drugs, the dose of targeted therapies may need to be adjusted over time, leading to drug wastage when a dose modification is needed but the dose cannot be split or saved. This has been shown to be the case for palbociclib and has led to concerns among payers. This study described palbociclib dosing patterns and estimated the economic burden of the drug wastage associated with palbociclib dose modifications in postmenopausal women with HR+/HER2− mBC. A large US claims database was used to identify postmenopausal women with HR+/HER2− mBC who received a palbociclib-based therapy during one of their first three lines of therapy for mBC between February 2015 (palbociclib approval) and December 2015. Dosing patterns (dosing modifications and sequences) were reported; a dose modification was defined as an increase/decrease of at least 25 mg daily compared to the preceding dose. Estimates of drug wastage costs were based on days with overlap in prescription fills for different palbociclib doses. A total of 473 postmenopausal palbociclib-treated women with HR+/HER2− mBC were included (first line 214; second line 157; third line 120). Over an average duration of line of therapy of approximately 4 months, dose modification was observed in 17.8%, 31.2%, and 35.0% of patients in first, second, and third line. Average overlap in prescription fills was 9.2, 9.9, and 5.4 days in first, second, and third line. This potential drug wastage resulted in an average cost of $4376, $4740, and $2592 per patient in first, second, and third line. This study showed that drug wastage due to palbociclib dose modification results in substantial costs. Treatment options with more flexible dosing may help reduce the costs of drug wastage. Novartis Pharmaceuticals Corporation.

Introduction For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. Aim This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. Discussion Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. Conclusion Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

Background: With the advent of personalised medicine, the need for flexible dosing is increasingly important. Conventional pharmaceutical manufacturing processes can be constrained in their ability to offer flexible dosing options to meet patient need. This is particularly important in specific populations, for example children, where available formulations are frequently not age-appropriate and need to be modified to achieve an intended dose. 3D-printing of solid dosage forms offers a disruptive technology which enables solid-dosage forms of medicines to be manufactured at flexible, precise doses meeting the needs of individual patients. This technology has relevance for manufacture of existing active pharmaceutical ingredients for a range of conditions including inflammatory diseases. Objectives: To develop 3D-printed oral solid dosage forms of medicines which are age-appropriate for children and young people. To determine the acceptability of 3D-printed medicines to children and young people by conducting interventional studies of tablet administration. Methods: Tablets containing a range of active pharmaceutical ingredients (API) were produced using two stages: (i) holt melt extrusion of a filament containing API and excipients; (ii) 3D printing of the filament using fused deposition modelling (FDM) to produce the desired shape in a layer-by-layer pattern. Acceptability of 3D-printed tablets to children and young people (CYP) aged 4-12 years was assessed by the swallowability and mouthfeel following administration of different size 3D-printed placebo tablets. Results: Using hydrocortisone as an exemplar API, Tablets were successfully produced by the FDM 3D printing process. Thermal analysis indicated that HC remained stable below 160°C and the tablets had very high mechanical strength with friability of 0%. This illustrates the ability of the printer to produce a ready-to-use-tablet without the need for a drying or finishing step. The disintegration took 9.2–14 min confirming immediate release properties. We administered for the first time globally an ingestible 3D-printed tablet to a child. CYP were able to swallow and ingest 3D-printed bi-convex tablets of either 6mm, 8mm or 10mm diameter. The 3D tablets were reported by CYP to have a slightly more discernible mouthfeel than placebo tablets of the same size manufactured in a GMP facility. Conclusion: FDM 3D printing offers a disruptive technology for the manufacture of solid dosage forms of medicines of flexible doses with excellent dose precision and pharmacopeial properties. In circumstances where modification of existing dosage forms is needed, this offers an alternative reliable means of achieving the intended dose. This technology is also suited to the manufacture of solid dosage forms of small molecules which may be particularly important in the treatment of inflammatory disease. Disclosure of Interests: None declared

Background Adherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine. Methods In this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy. Results 400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P

Individualized medicine is relevant to ensure safe and efficient pharmacotherapy. It requires a suitable dosage form and a matching dosing device to enable flexible dosing serving the needs of individual dose requirements. For oral films no flexible dosing option is available until today. This study covers the development of a dosing device that enables flexible dosing of films within the pharmacopoeial requirements. The prototype was produced with the 3D-printing technique fused filament fabrication. The developed and produced prototype of the device was tested for the uniformity of doses according to Ph.Eur. 2.9.27 and 2.9.40. A ribbon as model film and an oral film with HPMC as polymer matrix met the specifications for both tests for three different lengths dispensed with the prototype of the dosing device (HPMC film: AV = 11.30 (1 cm), 12.04 (2 cm) and 10.19 (5 cm)). A second oral film with a polymer matrix from PVA and HPMC exceeded the threshold for the shortest piece of 1 cm (AV = 26.54) because of slight splintering during the cutting process, likely due to too little plasticizer in the formulation. A successful device development and a use within the specifications of the European Pharmacopoeia is demonstrated.

Purpose The purpose of this study was to evaluate subjective sleep quality and daytime sleepiness in patients receiving adjunctive perampanel for focal seizures. Methods We conducted a multicenter, prospective, interventional, open-label study in patients aged > 16 with focal seizures who received adjunctive perampanel (flexible dosing: 2–12 mg). Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness with the Epworth Sleepiness Scale (ESS) at baseline and 3 and 6 months after initiating perampanel. Patients with modifications in their baseline AEDs or sleep medications were excluded. Results In 72 patients with drug-resistant focal seizures, mean baseline PSQI score (± standard deviation) was 7.26 (± 4.6), and ESS was 6.19 (± 4.2). At 3 months (median perampanel dose: 4 mg), there was no significant mean change from baseline in ESS score (n = 61) and a significant improvement in PSQI (− 1.51 points; n = 44; p = 0.007), driven mainly by improved sleep efficiency (p = 0.012). In the 31 patients with 6-month data, ESS (but not PSQI) improved significantly at 6 months vs baseline (p = 0.029). The only factor significantly correlated with sleep parameters was number of baseline AEDs (higher number correlated with worse daytime sleepiness). Seizure frequency was reduced significantly from baseline at 3 and 6 months. In bivariate analysis, neither PSQI nor ESS was associated with seizure frequency, suggesting that the changes in daytime sleepiness and sleep quality may be independent of the direct effect on seizures. Conclusion Adjunctive perampanel did not worsen sleep quality or daytime sleepiness at 3 months and reduced daytime sleepiness in patients continuing perampanel for 6 months. Perampanel may be a suitable AED in patients with sleep disorders, in addition to refractory focal seizures.

Managing insulin therapy is a challenge for both patients and healthcare providers.The primary aim of this trial was to compare the efficacy and safety of insulin degludec (IDeg) in a fixed versus flexible dosing schedule. The secondary aim and subject of this manuscript was to compare a simple versus a stepwise titration algorithm.This was a 26-week, controlled, multicenter, open-label, randomized, treat-to-target phase 3b trial of Japanese patients with type 2 diabetes inadequately treated with insulin glargine and with/without antidiabetic drugs orally. The trial had a 2 × 2 factorial design whereby 458 patients were randomized 1:1:1:1 to one of two titration algorithms and one of two dosing schedules. IDeg dose was adjusted weekly using a clinician-led, treat-to-target approach in order to ensure optimal insulin titration and glycemic control following self-measured blood glucose (SMBG) readings.Mean insulin dose at the end of the trial was similar in both simple and stepwise titration algorithms. Glycemic control improved in both titration algorithms, with noninferiority in glycated hemoglobin (HbAThis trial demonstrated comparable efficacy with noninferior HbA

Objectives: Antidepressants are the first line treatment for moderate to severe major depressive disorder (MDD) in perinatal and general populations. However, there appears to be paucity of evidence around antidepressant use in women with postpartum depression or anxiety. Selection of an appropriate antidepressant is crucial in promoting efficacy, optimizing tolerability, and managing comorbid anxiety or depression. Our aim was to investigate the treatment effect and tolerability profile of desvenlafaxine, and to examine the functionality of women with postpartum depression or anxiety after desvenlafaxine treatment. Methods: Fifteen postpartum women with depression or anxiety completed this 12-week prospective pilot study with a flexible dose of desvenlafaxine (50–100 mg). Participants were recruited at a tertiary care level program. Measures of depression (Montgomery–Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAM-A), worry (Penn State Worry Questionnaire, PSWQ) and functional impairment (Sheehan Disability Scale, SDS) were completed at baseline, 8 weeks, and 12 weeks. Results: In the intention-to-treat analysis ( n = 17), the majority of women responded to medication (88.2%, n = 15), and reached remission of depressive (82.4%, n = 14) and anxiety symptoms (82.4%, n = 14). Remission of depression was achieved in a mean of 6.9 weeks [standard deviation (SD) = 3.01] at a mean dose of 71 mg/day (SD = 25.7). Significant decreases were observed on PSWQ worry scores ( p < 0.0001) and SDS scores for social ( p < 0.0001) and family life impairment ( p < 0.0001). The medication was generally well tolerated. Conclusion: The results of our prospective pilot study suggest that treatment with desvenlafaxine of postpartum mothers with depression or anxiety can lead to symptom remission and restoration of functionality.

Flexible dosing and ease of swallowing are key factors when designing oral drug delivery systems for paediatric and geriatric populations. Multi-particulate oral dosage forms can offer significant benefits over conventional capsules and tablets. This study proposes the use of an in vitro model to quantitatively investigate the swallowing dynamics in presence of multi-particulates. In vitro results were compared against sensory tests that considered the attributes of ease of swallowing and post-swallow residues. Water and hydrocolloids were considered as suspending vehicles, while the suspended phase consisted of cellulose pellets of two different average sizes. Both in vivo and in vitro tests reported easier swallow for smaller multi-particulates. Besides, water thin liquids appeared not optimal for complete oral clearance of the solids. The sensory study did not highlight significant differences between the levels of thickness of the hydrocolloids. Conversely, more discriminant results were obtained from in vitro tests, suggesting that a minimum critical viscosity is necessary to enable a smooth swallow, but increasing too much the carrier concentration affects swallowing negatively. These results highlight the important interplay of particle size and suspending vehicle rheology and the meaningful contribution that in vitro methods can provide to pre-screening multi-particulate oral drug delivery systems before sensory evaluation.

Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the ‘flexible dosing’ method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety.

Introduction Monoclonal antibodies possess unique pharmacokinetic properties that permit flexible dosing. Increased use and high costs of these medications have led to the development of cost-containing strategies. This study aims to quantify the cost savings and clinical impact associated with dose rounding monoclonal antibodies to the nearest vial size. Methods This study was a single-arm, retrospective chart review assessing all monoclonal antibody doses dispensed at an outpatient community infusion center associated with an academic medical center between August 2014 and August 2015. All monoclonal antibody doses were reviewed to determine the cost of drug wasted using two methods. The waste-cost analysis described the amount of drug disposed of due to the use of partial vials. The theoretical dose savings described potential cost avoidance based on rounding the ordered dose to the nearest vial size. The theoretical rounded dose was compared to the actual ordered dose to explore clinical implications. Results A total of 436 doses were included. Of these, 237 were not rounded to the nearest vial size and included in the analysis. The cost of waste associated with these doses was $108,013.64 using actual wholesale price. The potential cost avoidance associated with the theoretical dose calculation was $83,595.53. Rounding these doses to the nearest vial size resulted in a median 6.7% (range, 1.4–20%) deviation from ordered dose. Conclusions Rounding monoclonal antibodies to the nearest vial size could lead to significant cost and waste savings with minimal deviation from the actual ordered dose.

Objective: This study was designed to explore the efficacy and tolerability of oral paliperidone extended release (ER) in a sample of patients who were switched to flexible doses within the crucial first 5 years after receiving a diagnosis of schizophrenia. Methods: Patients were recruited from 23 countries. Adults with nonacute but symptomatic schizophrenia, previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER (3–12 mg/day) and prospectively treated for up to 6 months. The primary efficacy outcome for patients switching for the main reason of lack of efficacy with their previous antipsychotic was at least 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for other main reasons, such as lack of tolerability, compliance or ‘other’, the primary outcome was non-inferiority in efficacy compared with the previous oral antipsychotic. Results: For patients switching for the main reason of lack of efficacy, 63.1% achieved an improvement of at least 20% in PANSS total scores from baseline to endpoint. For each reason for switching other than lack of efficacy, efficacy maintenance after switching to paliperidone ER was confirmed. Statistically significant improvement in patient functioning from baseline to endpoint, as assessed by the Personal and Social Performance scale, was observed ( p < 0.0001). Treatment satisfaction with prior antipsychotic treatment at baseline was rated ‘good’ to ‘very good’ by 16.8% of patients, and at endpoint by 66.0% of patients treated with paliperidone ER. Paliperidone ER was generally well tolerated, with frequently reported treatment-emergent adverse events being insomnia, anxiety and somnolence. Conclusions: Flexibly dosed paliperidone ER was associated with clinically relevant symptomatic and functional improvement in recently diagnosed patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

Nutraceuticals are the bioactive compounds found in many dietary sources. Numerous publications have reported their ability to prevent the development of degenerative diseases through modulation of physiological and physiochemical processes in living systems. Having sufficient concentration at the target site of action is the most critical factor for nutraceuticals to deliver the health benefits. For consumers, it is commonly accepted to ingest these bioactive components through oral delivery route because it is convenient and cost-efficient and allows flexible dosing schedule. Thus, it is important to understand the oral bioavailability of nutraceuticals to evaluate their qualifications as disease preventive agents and to calculate the required ingestion dosages. To predict the oral bioavailability of nutraceuticals, many in vitro and in vivo models have been developed to reduce the need for frequent human pharmacokinetic studies, which are costly and time-consuming and involve ethical complications. These models evaluate one or more of the influential factors that contribute to the oral bioavailability and are efficient screening techniques with the potential of predicting the pharmacokinetic process in humans. To accurately predict human oral bioavailability, further research is required to develop not only a better correlation between the in vitro and in vivo models but also an accurate scaling factor that takes into account interspecies variations.

Summary Aims To systematically review dose-escalation data from flexible-dose studies of fesoterodine and summarise factors associated with dose-escalation decisions. Methods A PubMed search was conducted using the terms (fesoterodine AND flexible dose), with no limits. Articles were included if they contained fesoterodine dose-escalation data for efficacy or safety outcomes or factors associated with dose-escalation decisions. Results Of 13 articles identified by the search, 10 articles (six clinical studies) met inclusion criteria. In flexible-dose trials of fesoterodine, 51–63% of subjects initially receiving fesoterodine 4 mg opted for dose escalation to fesoterodine 8 mg. Escalators generally reported significantly more severe overactive bladder (OAB) symptoms, greater OAB symptom bother and worse health-related quality of life at baseline than non-escalators. Escalators demonstrated less treatment benefit with fesoterodine 4 mg than non-escalators. Non-escalators generally had a higher rate of dry mouth and constipation with fesoterodine 4 mg than escalators. The decision to escalate appeared to be determined by the efficacy/tolerability responses; fesoterodine escalators demonstrated a lower sensitivity (less efficacy and fewer adverse events) before their decision to escalate. By study end (8–11 weeks after escalation decision), the efficacy and tolerability profiles were similar in escalators and non-escalators. Conclusions Data from flexible-dose studies provide strong evidence that fesoterodine provides treatment benefit to individual subjects with OAB because of its true dose–response effect. In clinical practice, it can be worthwhile to escalate to fesoterodine 8 mg in individual subjects who require additional efficacy benefit.

Biphasic insulin aspart 30 (BIAsp 30) [NovoMix 30®] contains 30 % soluble rapid-acting insulin aspart plus 70 % intermediate-acting protaminated insulin aspart. This mixture provides prandial and basal insulin in a simple and convenient single injection. Clinical studies have shown that BIAsp 30 is an appropriate option for insulin initiation, switching, maintenance and intensification regimens. Flexible dosing (i.e. once to three times daily) and a simple dose-titration algorithm allow patients to self-titrate the dose of BIAsp 30 as required.

Background According to prescribing information for rheumatoid arthritis (RA) treatments in the United States, infliximab should be administered at weeks 1, 2, 6, and then every 8 weeks starting at a 3-mg/kg dose, with flexible dosing up to 10 mg/kg and/or every 4 weeks based on clinical response. Objective This study evaluated dosing and intervals of the first 12 infliximab infusions in patients with RA across multiple large administrative databases. Methods Data were obtained from 4 databases: HealthCore Integrated Research Database (HIRD), IMS LifeLink Health Plan Claims Database (IMS Lifelink), Premier Perspective Database (PPD), and Wolters Kluwer Pharma Solutions (WKPS). Patients were aged ≥18 years, diagnosed with RA, and naive to biologic therapy. Patients with other select inflammatory conditions were excluded. The induction period included infusions 1 through 3; the maintenance period included infusions 4 through 12. Results Observed dosing patterns from the HIRD, IMS LifeLink, PPD, and WKPS databases demonstrated minimal dose increases from the first infusion (93.5, 103.3, 58.8, and 73.2 mg, respectively) and from the first maintenance infusion (69.1, 64.3, 45.7, and 45.7 mg, respectively) to the highest dose during the first 12 infusions. The mean number of days between infusions in the maintenance period ranged from 53.3 to 63.5 in HIRD, 53.7 to 60.3 in IMS LifeLink, 53.4 to 59.4 in PPD, and 52.3 to 55.0 in the WKPS database. Conclusion Data from multiple databases of patients with RA suggest that, in clinical practice, infliximab dosing and intervals are consistent with FDA prescribing information and remain relatively stable during the first 12 infusions.

Supplemental Digital Content is available in the text., Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

A paediatric formulation of valaciclovir with acceptable palatability, good pharmaceutical quality and stability, and with the possibility of flexible dosing is currently not available. A preparation of valaciclovir liquid using crushed tablets as described in the US Food and Drug Administration label information was found not to be adequate for use in daily practice.1 The mean relative bioavailability of this liquid compared with the tablets was reported to be 91.1% (SD, 33.1%), but was not investigated following the regulatory guidance for bioequivalence testing.2 Aim of this study was to develop a new paediatric formulation and to assess the bioequivalence of this new formulation compared with the brand named valaciclovir tablets. An oral liquid was developed because this is generally considered acceptable for use in infants and young children.3 Dosing accuracy, use of non-toxic excipients, palatability and good pharmaceutical stability for an acceptable period of time were taken into account during development. A solution …

Achieving the best treatment outcome with the least cost should be the goal for buprenorphine office-based treatment.We conducted an observational retrospective chart review to compare the treatment outcome for patients (n = 56) receiving high dose of buprenorphine (above 16 mg daily) and patients (n = 21) receiving moderate doses (8-16 mg daily).The percentages of the first four urine drug screens (UDS) positive for opiates were significantly higher for the high-dose group than for the moderate-dose group (F = 7.93, df = 7, p.0001). However, the percentages of the most recent four UDS positive for opiates were not statistically significant (F = .62, df = 7, p = .74). The difference in the percentages of the first and last UDS for the high-dose group showed significant reduction from admission to most recently but there was no significant difference for the moderate-dose group (t = 3.1, df = 105, p = .002 for the high-dose group and t = 1.1, df = 40, p = .27 for the moderate-dose group).Using flexible buprenorphine dosing schedule with the option of titrating the dose up to 32 mg daily may offer better treatment outcome for patients who would not respond to the lower dose range.

Introduction & Objectives: This was a multicenter, non-interventional study performed in urology practices investigating prescribed dosage regimens as well as the efficacy and tolerability of an oral therapy with trospium chloride in patients with overactive bladder (OAB) under routine conditions. Material and Methods: Naive or insufficiently treated OAB patients in which oral therapy with trospium chloride 1 was prescribed by the physician were eligible to participate. Dosing and duration of treatment were not predetermined. Core symptoms of OAB, a Quality of Life (QoL) score as well as dosage regimens were assessed at the beginning and at two consecutive visits. Adverse events and withdrawals were documented. Results: In 4,092 cases pre and post treatment data was available for the evaluation of efficacy; all 4,167 cases were included in the safety analysis. After a mean treatment period of 40 days, all core symptoms of OAB had improved e.g. the median total of micturitions was reduced from 12 to 8 (day) and from 3 to 1 (night). The percentage of incontinent patients dropped from 54.4% to 29.1%. The proportion of patients requiring incontinence pads was reduced from 47.6% to 30.1%. The median QoL score had improved from 3 to 1. Only 20% of the patients were treated with the standard dose of 45mg trospium chloride. Nearly 50% of the patients received 30mg (or less), and 60mg to 90mg were prescribed in 30% of the cases. There were 300 early treatment withdrawals (7.3%) and 54 patients experienced adverse events (1.3%). Conclusions: The distinct majority of OAB patients benefit from flexible dosing of trospium chloride, a compound with an equally favorable efficacy and tolerability profile.

Aim: To determine the impact of a pharmacist intervention on patient–guided diuretic dose adjustment in ambulatory patients with heart failure. Method: Patients with heart failure were randomised to usual care or usual care plus pharmacist intervention and followed for 3 months. Pharmacist intervention focused on patients improving self-care, recognising symptoms of fluid retention, measuring weight daily and self-adjusting diuretic dose using frusemide. The primary outcome was the number of appropriate weight-titrated frusemide dose adjustments. Secondary outcomes included the number of patients who correctly selfadjusted their frusemide dose, hospital readmissions due to fluid overload, heart failure-related knowledge and understanding, and quality of life (using validated tools). Results: 70 patients were recruited: 35 usual care (control) and 35 usual care plus pharmacist intervention. The average number of appropriate weight-titrated frusemide dose adjustments per patient per month in the control group was 0.32 ± 0.08 and in the intervention group was 0.85 ± 0.13 (p = 0.006). Hospital readmissions due to fluid overload was 31% in the control and 14% in the intervention groups (p = 0.04). There were significant differences between the groups regarding appropriate self-adjusted frusemide doses, heart failure-related knowledge and understanding, and quality of life. Conclusion: A pharmacist intervention improved the ability of heart failure patients to self-adjust their diuretic dose by using a flexible dosing regimen based on weight, resulting in quality of life improvement and a decrease in hospital readmissions due to fluid overload. J Pharm Pract Res 2011; 41: 126-31.

Objectives – To investigate whether zonisamide remains effective and well tolerated in the treatment of refractory partial epilepsy during long-term treatment and with flexible dosing in clinical practice. Materials and methods – Patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind clinical trial were recruited in an open-label extension study with adjustment of zonisamide and other antiepileptic drug dosage according to the treating physician’s usual clinical practice. Results – An intention-to-treat analysis of 317 patients showed that zonisamide was well tolerated with a predictable safety profile. Patient retention rates at 1, 2 and 3 years were 65.3%, 44.5% and 28.8%, respectively. Zonisamide treatment was associated with a maintained reduction in seizure frequency, with some patients achieving prolonged periods of seizure freedom. Conclusions – Flexible dosing with zonisamide demonstrated a good safety profile and sustained efficacy in the long-term adjunctive treatment of refractory partial epilepsy.

Background Vardenafil is a first-line drug in the therapy for erectile dysfunction (ED) of various aetiologies. Methods An open, multi-centre study assessing the efficacy and safety of vardenafil prescribed in flexible doses for 12 weeks to men with ED from various aetiologies was performed in Moscow in 2003–2004. A total of 129 patients aged from 22 to 76 years (mean = 45.7 ± 12.9) were enrolled into the study. The efficacy of the drug was evaluated using the International Index of Erectile Function (IIEF) Questionnaire, individual patients’ diaries and the Global Assessment Questionnaire (GAQ). Results Scores for erectile function, maintenance of erection, satisfaction with sexual experience and satisfaction with overall sexual life all increased between the beginning and the end of this study, which has thus shown vardenafil's high efficacy and safety for patients. Conclusion Alongside its cardiovascular safety, one of the advantages of vardenafil is the opportunity for flexible dosing owing to the variety of dosages available.

Starting insulin therapy earlier can help reduce the risk of micro- and macrovascular complications associated with the progression of type 2 diabetes mellitus (T2DM). However, barriers to the initiation of insulin have been identified. Premixed insulins offer a simpler regimen than basal-bolus therapy for T2DM. Modern premixes, which combine a rapid-acting soluble insulin with a protaminated form of the same insulin, have become increasingly popular. As primary care practitioners and diabetes specialists are encouraged to initiate insulin, premixes that can be used within flexible dosing regimens to improve glycaemic control could be beneficial.

The quest for potent and selective small molecule inhibitors of the Aurora kinases has been long and resource intensive with multiple agents progressed to the clinic. To definitively explore the potential for clinical efficacy at well-tolerated dosing schedules requires a well-characterized, selective inhibitor with pharmacokinetic properties, flexible dosing regimen, and suite of target engagement biomarkers suitable for clinical use. AMG900 is a promising opportunity to definitively test the clinical benefit of dual Aurora kinase A and B inhibition.

Objectives. Prophylaxis regimens for severe hemophilia A allowing more flexible dosing while maintaining efficacy may improve adherence and decrease the cost of prophylaxis. Here, we compared the clinical effectiveness of once- or twice-weekly versus ≥3-times-weekly prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS) in a “real-world” practice setting.Methods. Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on physician-assigned treatment regimens of 1-2 prophylaxis injections/wk (n=63) or ≥3 prophylaxis injections/wk (n=76). Descriptive statistics were determined for annualized bleeding rates (ABRs).Results. Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the 1-2 prophylaxis injections/wk group and 3.9 (1.5; 9.3) in the ≥3 prophylaxis injections/wk group. Median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower with 1-2 prophylaxis injections/wk. As an estimate of prophylaxis success, 63% (≥3 prophylaxis injections/wk) to 84% of patients (1-2 prophylaxis injections/wk) had ≤4 annualized joint bleeds.Conclusions. Dosing flexibility and successful prophylaxis with rFVIII-FS were demonstrated. Very good bleeding control was achieved with both once-twice-weekly and ≥3-times-weekly prophylaxis dosing regimens.