Intranasal vitamin B12 administration in elderly patients: A randomized controlled comparison of two dosage regimens.

AIM: Vitamin B12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B12 dosage regimens in elderly vitamin B12-deficient patients. METHODS: Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 µg cobalamin. Total vitamin B12, holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90. RESULTS: Both dosage regimens resulted in a rapid increase of vitamin B12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B12 of 717 pmol/L after 90 days. CONCLUSIONS: Intranasal vitamin B12 administration is an effective and suitable way to replenish and sustain vitamin B12 levels in elderly patients.

Leftover of Amoxicillin Suspension After Use by Children in the Netherlands.

PURPOSE: In clinical practice, a discrepancy may exist between the prescribed amount of a drug and the commercially available pack sizes in the pharmacy, potentially contributing to drug waste. This study aimed-as an example of this phenomena-to quantify leftover of amoxicillin suspension prescribed to children, due to discrepancies between physician-prescribed and pharmacy-dispensed amounts. METHODS: We performed a retrospective cohort study including amoxicillin suspension dispensations for patients aged 0-12 years between 2017 and 2019 utilizing the Dutch PHARMO database. Leftover amount of amoxicillin was estimated by assessing the discrepancy between the prescribed and dispensed amounts. Extrapolated amoxicillin weight and economic spillage estimates for the Netherlands were determined. The impact of two theoretical interventions on leftover amount was assessed: (1) introducing vials with half the volume of the current 100 and 30 mL vials and (2) a combination of the first intervention with a maximum of 10% round-down by the dispensing pharmacy of the prescribed dose. RESULTS: We included 79 512 amoxicillin suspension dispensations for 62 252 patients. The mean leftover amount of amoxicillin suspension per dispensing was 27%. The yearly amount of amoxicillin leftover was 49.8 kg in the study cohort, equivalent to yearly 633 kg and €621 000 when extrapolated to the Netherlands. Employing the first theoretical intervention reduced the mean leftover per dispensing to 20%, reducing the yearly leftover to 31.6 kg amoxicillin in the study cohort, and to 400 kg and €400 000 extrapolated. The second theoretical intervention further reduced leftover to 17%, reducing the yearly leftover to 24.3 kg amoxicillin in the study cohort, and to 300 kg and €300 000 extrapolated. CONCLUSION: Approximately a quarter of amoxicillin suspension remains as leftover per dispensing. Applying different theoretical intervention shows the potential for a significant reduction of amoxicillin leftover.

The effect of a decision support system on the incidence of prescription errors in a PICU.

WHAT IS KNOWN AND OBJECTIVE: Paediatric intensive care patients are at high risk for prescription errors due to the more complex process of medication prescribing. Clinical decision support systems (CDSS) have shown good results in effectively reducing prescription errors. A specific dosing CDSS was developed that can check and suggest normal dose, dose limits and administration frequencies. This study aimed to assess the effect of this CDSS on protocol deviation (as measure of prescription error) types and frequency in a paediatric intensive care unit (PICU). METHODS: A retrospective observational study was conducted evaluating 9342 prescriptions in a 4-month period before and after the implementation of a CDSS in the PICU of the University Medical Center Utrecht. Medication forms were reviewed to identify protocol deviations (and therefore possible prescription errors). The incidence and nature of deviations from evidence-based protocols that were unintended and needed to be adjusted, were determined. RESULTS AND DISCUSSION: In the period before the dosing CDSS, we identified 45 protocol deviations in 5034 prescriptions (0.89%), 28 of which could not be justified (0.56%) and 11 needed to be adjusted (0.22%). In the period after the implementation of the CDSS, there were 21 protocol deviations in 4308 prescriptions (0.49%) of which ten without a valid reason (0.23%) of which two were adjusted (0.05%). WHAT IS NEW AND CONCLUSION: The specific dosing CDSS was able to significantly reduce unintentional prescription dose deviations and the number of prescriptions that needed to be adjusted, in an existing low incidence situation.

Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia.

BACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates. METHODS: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC0-48 h of 4800 ng*h/mL. RESULTS: Exposure in group A was higher than targeted (median AUC0-48 h 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC0-48 h 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred. CONCLUSION: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials.

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.

AIMS: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. METHODS: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. RESULTS: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. CONCLUSION: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.

Clinical rule-guided pharmacists' intervention in hospitalized patients with hypokalaemia: A time series analysis.

WHAT IS KNOWN AND OBJECTIVE: Physicians' response to moderate and severe hypokalaemia in hospitalized patients is frequently suboptimal, leading to increased risk of cardiac arrhythmias and sudden death. While actively alerting physicians on all critical care values using telephone or electronic pop-ups can improve response, it can also lead to alert fatigue and frustration due to non-specific and overdue alerts. Therefore, a new method was tested. A clinical rule built into a clinical decision support system (CDSS) generated alerts for patients with a serum potassium level (SPL) <2.9 mmol/L without a prescription for potassium supplementation. If the alert was deemed clinically relevant, a pharmacist contacted the physician. The aim of this study was to evaluate the impact of the clinical rule-guided pharmacists' intervention compared to showing passive alerts in the electronic health records on outcome in patients who developed hypokalaemia (<2.9 mmol/L) during hospitalization. METHODS: A before (2007-2009) and after (2010-2017) study with time series design was performed. Pre-intervention, physicians were shown passive alerts for hypokalaemia in the electronic health records. During the intervention period, in addition to these passive alerts, a pharmacist provided the physician with a specific advice on patients with untreated hypokalaemia, guided by the generated alerts. Unique patients >18 years with SPL <2.9 mmol/L measured at least 24 hours after hospitalization in whom no potassium supplementation was initiated within 4 hours after measurement and normalization of SPL was not achieved within these 4 hours were included. Haemodialysis patients were excluded. The percentage of hypokalaemic patients with a subsequent prescription for potassium supplementation, time to subsequent potassium supplementation prescription, the percentage of patients who achieved normokalaemia (SPL ≥ 3.0 mmol/L), time to achieve normokalaemia and total duration of hospitalization were compared. RESULTS AND DISCUSSION: A total of 693 patients were included, of whom 278 participated in the intervention phase. The percentage of patients prescribed supplementation as well as time to prescription improved from 76.0% in 31.1 hours to 92.0% in 11.3 hours (P < .01). Time to achieve SPL ≥3.0 mmol/L improved, P < .009. No changes, however, were observed in the percentage of patients who achieved normokalaemia or time to reach normokalaemia, 87.5% in 65.2 hours pre-intervention compared to 90.2% (P = .69) in 64.0 hours (P = .71) in the intervention group. A non-significant decrease of 8.2 days was observed in the duration of hospitalization: 25.4 compared to 17.2 days (P = .29). WHAT IS NEW AND CONCLUSION: Combining CDSS alerting with a pharmacist evaluation is an effective method to improve response rate, time to supplementation and time to initial improvement, defined as SPL ≥3.0 mmol/L. However, it showed no significant effect on the percentage of patients achieving normokalaemia, time to normokalaemia or hospitalization. The discrepancy between rapid supplementation and improvement on the one hand and failure to improve time to normokalaemia on the other warrants further study.

Post-marketing dosing changes in the label of biologicals.

AIM: The aim of this study was to evaluate post-marketing label changes in dosing information of biologicals. METHODS: Biologicals authorized between 2007 and 2014 by the European Medicines Agency (EMA) were included and followed up from marketing authorization until 31 December 2016 or date of withdrawal of the marketing authorization. The primary outcome of the study was defined as label change in dosing information for the initially approved indication. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, label changes in dosing information for extended indications were assessed. RESULTS: A total of 71 biologicals were included. Dosing information in the label changed for the initial indication during follow-up for eight products (11%). In one of the eight products the change concerned an increase in dose. Also, a change in dosing frequency was identified in three products, for one product a recommendation was added that therapy could be initiated with or without a loading dose, and for one product the minimum dose was removed and a maximum dose was added. For the remaining product the dose was decreased due to safety issues. For 30 products (42%) the indication was extended at least once. No changes in dosing information were observed for the extended indications (n = 59) during follow-up. CONCLUSIONS: This study showed that in 11% of the biologicals, the dosing for the initial indication in the label was changed. In contrast to small molecules, the dose was rarely reduced for safety reasons.

The effect of a pharmaceutical transitional care program on rehospitalisations in internal medicine patients: an interrupted-time-series study.

BACKGROUND: Medication errors at transition of care can adversely affect patient safety. The objective of this study is to determine the effect of a transitional pharmaceutical care program on unplanned rehospitalisations. METHODS: An interrupted-time-series study was performed, including patients from the Internal Medicine department using at least one prescription drug. The program consisted of medication reconciliation, patient counselling at discharge, and communication to healthcare providers in primary care. The primary outcome was the proportion of patients with an unplanned rehospitalisation within six months post-discharge. Secondary outcomes were drug-related hospital visits, drug-related problems (DRPs), adherence, believes about medication, and patient satisfaction. Interrupted time series analysis was used for the primary outcome and descriptive statistics were performed for the secondary outcomes. RESULTS: In total 706 patients were included. At 6 months, the change in trend for unplanned rehospitalisations between usual care and the program group was non-significant (- 0.2, 95% CI -4.9;4.6). There was no significant difference for drug-related visits although visits due to medication reconciliation problems occurred less often (4 usual care versus 1 intervention). Interventions to prevent DRPs were present for all patients in the intervention group (mean: 10 interventions/patient). No effect was seen on adherence and beliefs about medication. Patients were significantly more satisfied with discharge counselling (68.9% usual care vs 87.1% program). CONCLUSIONS: The transitional pharmaceutical care program showed no effect on unplanned rehospitalisations. This lack of effect is probably because the reason for rehospitalisations are multifactorial while the transitional care program focused on medication. There were less hospital visits due to medication reconciliation problems, but further large scale studies are needed due to the small number of drug-related visits. (Dutch trial register: NTR1519).

Diabetes and Glucose Dysregulation and Transition to Delirium in ICU Patients.

OBJECTIVES: To investigate whether diabetes and glucose dysregulation (hyperglycemia and/or hypoglycemia) are associated with ICU delirium. DESIGN: Prospective cohort study. SETTING: Thirty-two-bed mixed intensive care in a tertiary care center. PATIENTS: Critically ill patients admitted to the ICU with transitions of mental status from awake and nondelirious to delirious or remaining awake and nondelirious on the next day. Patients admitted because of a neurologic illness were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 2,745 patients with 1,720 transitions from awake and nondelirious to delirious and 11,421 nontransitions remaining awake and nondelirious. Generalized mixed effects models with logit link function were performed to study the association between diabetes mellitus, glucose dysregulation, and delirium, adjusting for potential confounders. Diabetes was not associated with delirium (odds ratio adjusted, 0.93; 95% CI, 0.73-1.18). In all patients, the occurrence of hyperglycemia (odds ratio adjusted, 1.35; 95% CI, 1.15-1.59) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.65; 95% CI, 1.12-2.28) compared with normoglycemia were associated with transition to delirium. Hypoglycemia was not associated with transition to delirium (odds ratio adjusted, 1.86; 95% CI, 0.73-3.71). In patients without diabetes, the occurrence of hyperglycemia (odds ratio adjusted, 1.41; 95% CI, 1.16-1.68) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.87; 95% CI, 1.07-2.89) were associated with transition to delirium. In patients with diabetes, glucose dysregulation was not associated with ICU delirium. CONCLUSIONS: Diabetes mellitus was not associated with the development of ICU delirium. For hypoglycemia, only a nonsignificant odds ratio for ICU delirium could be noted. Hyperglycemia and the occurrence of hyperglycemia and hypoglycemia on the same day were associated with ICU delirium but only in patients without diabetes. Our study supports the institution of measures to prevent glucose dysregulation in nondiabetic ICU patients and contributes to the understanding of the determinants of delirium.

Monitoring of Metabolic, Cardiac, and Endocrine Indicators in Youth Treated With Antipsychotics as Reported by Health Care Professionals.

BACKGROUND: It is unclear how youth treated with antipsychotics are monitored. The purpose of this study was to assess monitoring of metabolic, cardiac, and endocrine indicators in youth (<18 years old) treated with antipsychotics as reported by health care professionals in the Netherlands. METHODS: A questionnaire was designed to collect information from health care professionals regarding the monitoring of youth treated with antipsychotics. Data were collected at a national conference. FINDINGS AND RESULTS: Fifty-nine health care professionals completed the questionnaire, of which 53 (89.8%) were child and adolescent psychiatrists (approximately 20% of all child and adolescent psychiatrists in the Netherlands). More than 80% of respondents reported monitoring physical indicators-weight, height, body mass index, heart rate, and blood pressure-and over 50% reported monitoring laboratory indicators-lipid profile, blood glucose, and prolactin level. Most of the respondents reported monitoring physical indicators more than twice per year and laboratory indicators once per year. Almost all respondents (56/59, 94.9%) reported monitoring according to a clinical guideline or protocol. Only 1 respondent reported monitoring the indicators completely according to the clinical guideline. Respondents mentioned that facilitating factors for monitoring, such as access to electrocardiogram facilities, were insufficiently available. CONCLUSIONS: Although all health care professionals reported monitoring metabolic, cardiac, and endocrine indicators in youth treated with antipsychotics, great variability exists in reported monitoring practices. Factors contributing to this variability must be assessed to optimize the benefit-risk ratio for the individual patient.

The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Nocturnal sialorrhea is one of the most frequent adverse events in clozapine treatment. Symptomatic management of sialorrhea usually consists of off-label treatment with anticholinergic agents. The aim of the current study is to evaluate the efficacy and safety of glycopyrrolate in patients using clozapine that experience sialorrhea. METHODS: In a double-blind randomized crossover trial, patients with nocturnal sialorrhea (n = 32) were randomized to treatment with glycopyrrolate 1 mg or placebo. This double-blinded phase was followed by an optional open label extension phase with glycopyrrolate 2 mg. Exposure periods consisted of 6 consecutive days and were separated with 1 washout week. The primary outcome was clinical improvement of nocturnal sialorrhea assessed by the Patient Global Impression of Improvement (PGI-I). RESULTS: The proportion of patients with a clinical improvement according to PGI-I did not significantly differ between 1 mg and placebo (18.8% vs 6.3%, P = 0.289); however, in patients using glycopyrrolate 2 mg once daily versus placebo, it did (43.5% vs 6.3%, P = 0.039). Glycopyrrolate was not associated with severe adverse events or worsening of cognitive adverse events. CONCLUSIONS: Glycopyrrolate 1 mg was not superior to placebo, whereas 2 mg showed a significant clinical improvement of nocturnal sialorrhea compared with placebo. Glycopyrrolate seemed to be a tolerable anticholinergic agent in the treatment of clozapine-associated sialorrhea.

Guidance by physicians and pharmacists during antidepressant therapy: patients' needs and suggestions for improvement.

BACKGROUND: Guidance of patients treated with antidepressants is paramount for successful therapy. The aim was to assess patients' needs and suggestions for improvement of guidance by physicians and pharmacists during second generation antidepressant (SGA) therapy. METHODS: Five focus group discussions were held with a total of 34 patients using an SGA. The discussions were conducted flexibly and responsively using a semi-structured topic list. All focus group discussions were video-recorded and transcripts were analyzed using ATLAS.ti for coding, thematic and open analysis. RESULTS: Participants stated they were in need of better guidance. They suggested improving content of information during decisional moments, patient-health care professional communication and communication between health care professionals, and finally, organization of guidance. Barriers to achieving improved guidance were cited. CONCLUSIONS: Content, communication and organization of guidance are pivotal for achieving optimal guidance. Participants mentioned their current experienced guidance had limitations and brought up solutions for improvement. A next step would be to discuss the suggested solutions with health care professionals to assess their views and to discuss the possibility for implementation. After implementation, future studies could be aimed at determination of its impact on patients' treatment efficacy, quality of life, treatment satisfaction and healthcare costs.

Paediatric Drug Development and Formulation Design-a European Perspective.

The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.

The majority of patients do not store their biologic disease-modifying antirheumatic drugs within the recommended temperature range.

OBJECTIVE: To monitor whether biologic DMARD (bDMARD) home storage temperatures comply with the manufacturers' Summary of Product Characteristics (SmPC) recommendations. METHODS: This observational study included consenting adult patients from eight Dutch pharmacies who received their bDMARDs with a validated temperature logger. Patients were instructed to store their packages according to standard label instructions and to return the temperature logger(s) after use. Primary outcome was defined as the proportion of patients that stored their bDMARDs within the SmPC recommended temperature range. In addition, the proportion of patients storing bDMARDs below 0°C or above 25 °C for longer than two consecutive hours was estimated. RESULTS: A total of 255 (87.0%) patients (mean age 53.2 (s.d.; 13.1) years, 51.4% female) returned their temperature logger(s) to the pharmacy. Of these, 17 patients (6.7%) stored their bDMARD within the recommended temperature range. The proportion of the patients that stored their bDMARD for more than 2 h consecutive time below 0°C or above 25°C was respectively 24.3% (median duration: 3.7 h (IQR 2.2 h; range 2.0-1,097.1 h) and 2.0% (median duration: 11.8 h (IQR 44.3 h; range 2.0-381.9 h). CONCLUSION: The majority of patients do not store their bDMARDs within the SmPC-recommended temperature range.

Movement Disorders in Adults With Intellectual Disability and Behavioral Problems Associated With Use of Antipsychotics.

BACKGROUND: Antipsychotic drugs are prescribed to approximately 30% to 40% of adults with intellectual disability (ID) and behavioral problems despite lack of evidence of effectiveness and potential adverse effects, including movement disorders. AIMS: The aim of this study was to examine the prevalence of movement disorders (dyskinesia, akathisia, dystonia, and parkinsonism) in in-patient adults with mild to borderline ID and behavioral problems associated with use of antipsychotics. METHODS: Prevalence of movement disorders was measured with a standardized protocol. The strength of the association between antipsychotic drug use and movement disorders was assessed using logistic regression analysis. RESULTS: Almost half (44.0%) of 134 in-patient adults with ID and behavioral problems had any movement disorder. Parkinsonism, dyskinesia, akathisia, and dystonia were present in, respectively, 36.6%, 11.2%, 9.0%, and 0.7% of patients with ID. It appeared that current use of any antipsychotic drug (odds ratio, 3.0; 95% confidence interval, 1.0-8.4) and a dose in target range (odds ratio, 5.5; 95% confidence interval, 1.5-20.4) were significantly associated with the risk of having movement disorders. CONCLUSIONS: The prevalence of movement disorders in people with ID and behavioral problems is high, especially in ID patients using antipsychotics. More attention is needed for these movement disorders and their potential impact.

The effect of exposure misclassification in spontaneous ADR reports on the time to detection of product-specific risks for biologicals: a simulation study.

BACKGROUND AND OBJECTIVE: The availability of accurate product-specific exposure information is essential in the pharmacovigilance of biologicals, because differences in the safety profile may emerge between products containing the same active substance. In spontaneous adverse drug reaction (ADR) reports, drug exposure may, however, be misclassified, that is, attributed to the incorrect product. The aim of this study was to explore the effect of exposure misclassification on the time to detection of product-specific risks in spontaneous reporting systems. METHODS: We used data simulations to explore the effect of exposure misclassification. We simulated an active substance-specific subset of a spontaneous reporting system and used the proportional reporting ratio for signal detection. The effect of exposure misclassification was evaluated in three test cases representing product-specific ADRs that may occur for biologicals and studied in relative terms by varying the model parameters (market share and relative risk). RESULTS: We found that exposure misclassification results in the largest delay in identification of risks that have a weak association (relative risk < 2 or 3) with the product of interest and in situations where the product associated with the unique risk has a large (>50%) market share. The absolute public health impact of exposure misclassification, in terms of cases/time to detection, varied considerably across the test cases. CONCLUSION: Exposure misclassification in ADR reports may result in a delayed detection of product-specific risks, particularly in the detection of weak drug-event associations. Our findings can help inform the future implementation and refinement of product-specific and batch-specific signal detection procedures.

Validity of diagnostic codes and laboratory measurements to identify patients with idiopathic acute liver injury in a hospital database.

PURPOSE: The development and validation of algorithms to identify cases of idiopathic acute liver injury (ALI) are essential to facilitate epidemiologic studies on drug-induced liver injury. The aim of this study is to determine the ability of diagnostic codes and laboratory measurements to identify idiopathic ALI cases. METHODS: In this cross-sectional validation study, patients were selected from the hospital-based Utrecht Patient Oriented Database between 2008 and 2010. Patients were identified using (I) algorithms based on ICD-9-CM codes indicative of idiopathic ALI combined with sets of liver enzyme values (ALT > 2× upper limit of normal (ULN); AST > 1ULN + AP > 1ULN + bilirubin > 1ULN; ALT > 3ULN; ALT > 3ULN + bilirubin > 2ULN; ALT > 10ULN) and (II) algorithms based on solely liver enzyme values (ALT > 3ULN + bilirubin > 2ULN; ALT > 10ULN). Hospital medical records were reviewed to confirm final diagnosis. The positive predictive value (PPV) of each algorithm was calculated. RESULTS: A total of 707 cases of ALI were identified. After medical review 194 (27%) patients had confirmed idiopathic ALI. The PPV for (I) algorithms with an ICD-9-CM code as well as abnormal tests ranged from 32% (13/41) to 48% (43/90) with the highest PPV found with ALT > 2ULN. The PPV for (II) algorithms with liver test abnormalities was maximally 26% (150/571). CONCLUSIONS: The algorithm based on ICD-9-CM codes indicative of ALI combined with abnormal liver-related laboratory tests is the most efficient algorithm for identifying idiopathic ALI cases. However, cases were missed using this algorithm, because not all ALI cases had been assigned the relevant diagnostic codes in daily practice.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Structured Medication Review to Improve Pharmacotherapy in People with Intellectual Disability and Behavioural Problems.

BACKGROUND: Polypharmacy and chronic drug use are common in people with intellectual disability and behavioural problems, although evidence of effectiveness and safety in this population is lacking. This study examined the effects of a structured medication review and aimed to improve pharmacotherapy in inpatients with intellectual disability. METHODS: In a treatment facility for people with mild to borderline intellectual disability and severe behavioural problems, a structured medication review was performed. Prevalence and type of drug-related problems (DRPs) and of the recommended and executed actions were calculated. RESULTS: In a total of 55 patients with intellectual disability and behavioural problems, 284 medications were prescribed, in which a DRP was seen in 106 (34%). No indication/unclear indication was the most prevalent DRP (70). Almost 60% of the recommended actions were also executed. CONCLUSIONS: This high prevalence of DRPs is worrying. The structured medication review is a valuable instrument to optimize pharmacotherapy and to support psychiatrists in adequate prescribing of both psychotropic and somatic drugs.