[Fitness to drive when taking medicines]. / Rijvaardigheid bij het gebruik van geneesmiddelen.

The regulations for driving fitness of people using drugs with potential influence on driving capability are embodied in the 'Regelingeisengeschiktheid 2000' (REG2000). The Health Council of the Netherlands (HCN) adviced to design more strict regulations for professional drivers. This advice has not yet been approved by the minister due to implementation complexity. The HCN recommends to follow the by the KNMP formulated advices when using category II psychostimulants or category III antidepressants, benzodiazepines, antipsychotics, antihistamines, anti-epileptics or opioids. The KNMP advices for driving participation are broadly available via the public websites www.apotheek.nl and www.rijveiligmetmedicijnen.nl. Both websites are written in accessible language level. The HCN advices to enhance scientific research concerning influence on driving fitness before approving a drug, to use standard procedures to prevent ad hoc decisions concerning driving fitness and the use of checklists for doctors when preparing driving fitness attests.

Who cares for syphilis? A cross-sectional study on diagnosis and treatment of syphilis by GPs in Amsterdam, the Netherlands.

BACKGROUND: Syphilis is a re-emerging infection. Sexually transmitted infection (STI) clinics and GPs are important providers of STI care in the Netherlands. The role of GPs in syphilis care is assumed to be small, since most men who have sex with men (MSM) visit STI clinics for STI care. AIM: To explore the role of GPs in the diagnosis and treatment of syphilis. DESIGN & SETTING: Data on syphilis diagnostics by GPs in Amsterdam between 2011 and 2017 were retrieved from laboratories, covering 90% of the GPs. The study also used the academic GPs' network database to explore the management of syphilis by GPs between 2013 and 2018. METHOD: Syphilis tests requested by GPs were analysed and compared with annual reports of the STI clinic. Patients with an International Classification of Primary Care-1 (ICPC-1) syphilis code were identified in the GP database. Cases diagnosed by the GP were evaluated whether they were treated by the GP or referred to secondary care. RESULTS: In the laboratory database, GPs had diagnosed syphilis 522 times, compared with 2515 times by the STI clinics. Based on the 90% coverage of GPs, the contribution of all Amsterdam's GPs was 19% of the total number of diagnoses. Consequently, the annual incidence of syphilis diagnosed by the GP was 10.2 per 100 000 inhabitants. Of the 43 cases identified in the GP database, six (14.0%) were referred and 33 (76.7%) were treated by a GP. CONCLUSION: Although for an individual GP, syphilis is rare to diagnose, GPs in Amsterdam do contribute to the rate of syphilis diagnosis and appear to treat the majority of cases that they have diagnosed.

Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries.

BACKGROUND: Statins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients. OBJECTIVE: To investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients. DESIGN: We invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment. MAIN MEASURES: Cases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs' advice to stop. KEY RESULTS: Two thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6-15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5-1.7) and with frailty (ORadj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99). CONCLUSIONS: The absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.

The Association Between the STOPP/START Criteria and Gastro-Intestinal Track Bleedings in Elderly Patients.

Potentially inappropriate prescribing is a common problem, especially in elderly care. To tackle this problem, Irish medical experts have developed a list of criteria when medication should be added or omitted based upon the patient's physical condition and medication use, known as the STOPP and START criteria. The STOPP and START criteria have been formulated to identify the prescribing of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs). One of the most common problems of inappropriate prescribing is gastro-intestinal track bleedings. For this purpose, nine of the 87 STOPP and START criteria are designed to prevent this. However, the prevalence of gastro-intestinal track bleedings has not been established when these nine STOPP and START criteria are violated. The database contained 182,000 patients belonging to 49 general practitioners in the region of Amsterdam, The Netherlands. We estimated both the incidence of PIMs and PPOs and whether harm, in this case a gastro-intestinal track bleeding, occurred. We found that although violation of the nine STOPP or START criteria were possibly associated with harm (OR = 1.30), this association was not statistically significant (p = 0.323). Searching for evidence for harm informs decision support design aimed at improving quality of medication prescription as it prioritizes the many suggested criteria based on their relevance.

Potentially inappropriate prescribing to older patients in primary care in the Netherlands: a retrospective longitudinal study.

Background: potentially inappropriate prescribing (PIP) is associated with adverse health effects in older patients. PIP comprises prescription of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs). Objective: to estimate the prevalence of PIMs and PPOs among older patients in primary care. Design: retrospective longitudinal study. Setting: routinely collected data of 182,000 patients of 49 general practitioners (GPs) gathered in the GPs' database of the Academic Medical Center of Amsterdam, the Netherlands. Subjects: in each studied year, all patients who were aged 65 years and older at 1st January. Methods: the prevalence of patients with at least one PIM and patients with at least one PPO was measured in 8 subsequent years (2007-14) by application of the Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP)/Screening Tool to Alert doctors to Right Treatment (START) criteria. Multivariate logistic regression was used to evaluate trends in the prevalence of PIMs and PPOs over the years. Results: on average, 4,537 patients were included per investigated year. The mean prevalence of ≥1 PIM was 34.7% (range 34.0-35.6%) and of ≥1 PPO 84.8% (range 77.4-90.6%). Examples were the prescription of salicylates without a proper indication and the absence of a therapeutically indicated vitamin D prescription. The prevalence of ≥1 PPOs showed a statistically significant decrease over the investigated years (OR 0.87, P < 0.001), whereas the prevalence of PIMs did not change significantly. Conclusions: this study underscores the need for more attention to medication prescribing to older patients. The prevalence of PIP among older patients in primary care is substantial and the prevalence of PIMs did not decrease over time.

Practical problems with medication use that older people experience: a qualitative study.

OBJECTIVES: To identify the practical problems that older people experience with the daily use of their medicines and their management strategies to address these problems and to determine the potential clinical relevance thereof. DESIGN: Qualitative study with semistructured face-to-face interviews. SETTING: A community pharmacy and a geriatric outpatient ward. PARTICIPANTS: Community-dwelling people aged 70 and older (N = 59). MEASUREMENTS: Participants were interviewed at home. Two researchers coded the reported problems and management strategies independently according to a coding scheme. An expert panel classified the potential clinical relevance of every identified practical problem and associated management strategy using a 3-point scale. RESULTS: Two hundred eleven practical problems and 184 management strategies were identified. Ninety-five percent of the participants experienced one or more practical problems with the use of their medicines: problems reading and understanding the instructions for use, handling the outer packaging, handling the immediate packaging, completing preparation before use, and taking the medicine. For 10 participants, at least one of their problems, in combination with the applied management strategy, had potential clinical consequences and 11 cases (5% of the problems) had the potential to cause moderate or severe clinical deterioration. CONCLUSION: Older people experience a number of practical problems using their medicines, and their strategies to manage these problems are sometimes suboptimal. These problems can lead to incorrect medication use with clinically relevant consequences. The findings pose a challenge for healthcare professionals, drug developers, and regulators to diminish these problems.

Participation of older people in preauthorization trials of recently approved medicines.

OBJECTIVES: To investigate the inclusion of older people in clinical trials of recently authorized medicines, evaluating adherence to the 20-year-old International Conference of Harmonisation (ICH) guideline on geriatrics (E7). DESIGN: Observational. SETTING: European public assessment reports, published clinical trials, World Health Organization International Clinical Trials Registry Platform. PARTICIPANTS: Individuals aged 65 and older and 75 and older. MEASUREMENTS: Number and proportion of randomized participants and all exclusion criteria of studies involving diseases characteristically associated with aging (venous thromboembolism, osteoporosis, atrial fibrillation) and diseases not unique to older adults (type 2 diabetes mellitus, depression, bipolar disorder, epilepsy). RESULTS: In 114 Phase II and III trials of 12 medicines, 43.1% of participants were aged 65 and older, and 16.1% were aged 75 and older. In trials involving diseases characteristically associated with ageing, 57% were aged 65 and older; 22% were aged 75 and older. In trials involving diseases not unique to old age, 9% were aged 65 and older, and 1% were aged 75 and older. Upper age limits were applied in 30.7% of the trials; the frequency did not differ between larger (sample size ≥ 500) and smaller trials (P = .36), although it was significantly lower in trials involving diseases characteristically associated with aging (18.0%) than in trials of diseases not unique to old age (45.3%; P = .002). Age-sensitive exclusion criteria, based on comorbidity (75.4%), concomitant medication (71.9%), and other criteria correlated with age (60.5%) were applied more frequently in larger trials (P < .02). CONCLUSION: Studies of diseases not uniquely associated with old age included an unacceptably low proportion of older people, contrary to the recommendations of the ICH E7 guideline. Although the proportion of older participants in trials of diseases characteristically associated with aging was appropriate for certain medicines, the use of age-sensitive exclusion criteria limits the representativeness of the trial population for daily practice.

The views of healthcare professionals, drug developers and regulators on information about older people needed for rational drug prescription.

BACKGROUND: The ICH E7 guideline intends to improve the knowledge about medicines in geriatric patients. As a legislative document, it might not reflect the needs of healthcare professionals. This study investigated what information healthcare professionals, regulatory agencies and pharmaceutical industries consider necessary for rational drug prescribing to older individuals. METHODS AND FINDINGS: A 29-item-questionnaire was composed, considering the representation in trials, pharmacokinetics, efficacy, safety, and convenience of use in older individuals, with space for additions. Forty-three European professionals with an interest in medication for older individuals were included. In order to investigate their relevance, five items were included in a second questionnaire, with 11 control items. Median scores, differences between clinical and non-clinical respondents and response consistency were analysed. Consistency was present in 10 control items. Therefore, all items of the first questionnaire and the five additional items were analysed. Thirty-seven (86%) respondents returned the first questionnaire; 31/37 (84%) the second. Information about age-related differences in adverse events, locomotor effects, drug-disease interactions, dosing instructions, and information about the proportion of included 65+ patients was considered necessary by most respondents. Clinicians considered information significantly more important than the non-clinical respondents about the inclusion of 75+, time-until-benefit in older people, anticholinergic effects, drug-disease interactions, and convenience of use. Main study limitations are the focus on information for daily practice, while the ICH E7 guideline is a legislative document focused on market approval of a new medicine. Also, a questionnaire with a Likert scale has its limitations; this was addressed by providing space for comments. CONCLUSIONS: This study reveals that items considered necessary are currently not included in the ICH E7 guideline. Also, clinicians' and non-clinicians' opinions differed significantly in 15% of the items. Therefore, all stakeholders should collaborate to improve the availability of information for the rational prescribing to older individuals.

Information for adequate prescribing to older patients : an evaluation of the product information of 53 recently approved medicines.

BACKGROUND: Historically, older patients have been frequently excluded from clinical trials. This has a knock-on effect on the availability of relevant information from trials for health-care professionals prescribing medicines to older individuals in daily clinical practice. OBJECTIVE: To investigate the availability of information relevant to appropriate prescribing for older people in the summaries of product characteristics (SmPCs) of recently approved medicines. METHODS: An analysis was undertaken of the SmPCs and European public assessment reports (EPARs) of all non-generic medicines indicated for diseases that are common in older individuals and that were approved by the European Medicines Agency between January 2008 and December 2010. The EPARs were considered the second most complete, publicly available document after the pre-authorization dossier. The availability of information was evaluated for 19 items on the representation of and clinical experience in older people, as well as pharmacokinetic and drug-drug interaction studies. These items were derived from the ICH E7 guideline for studies involving geriatric populations in the SmPCs and EPARs. Information not included was classified as being essential or non-essential, based on the product characteristics. RESULTS: Fifty-three medicines were investigated. Overall, information on the ICH E7 items was available in 56 % of the SmPCs (EPARs 79 %); 41 % of the SmPCs (EPARs 24 %) did not provide information that should have been included. Twenty-seven percent of the SmPCs, but 78 % of the EPARs, provided information about the number of patients included. Moreover, 2 % of the SmPCs (EPARs 51 %) provided information about the exclusion of patients with common comorbidities, and 14 % of the SmPCs, but 81 % of the EPARs, provided information about exclusion based on age. CONCLUSIONS: SmPCs, unlike EPARs, do not sufficiently provide adequate information about older individuals. Consequently, it is not clear whether the information about efficacy and safety applies to the frail older patients often seen in daily practice. The SmPC is intended for use by health-care professionals in daily clinical practice and provides basic information for safe and effective prescribing. As the EPAR describes regulatory considerations relevant to drug approval and is too long for daily use, the information about older individuals included in the SmPCs should be improved.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatraemia associated with valproic Acid: four case reports from the Netherlands and a case/non-case analysis of vigibase.

The Netherlands Pharmacovigilance Centre Lareb received four cases of severe symptomatic hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) in association with valproic acid use, in which a causal relationship was suspected. This study describes these cases and gives support for this association from Vigibase, the adverse drug reaction (ADR) database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. Cases of hyponatraemia in valproic acid users are described. In a case/non-case analysis, the strength of the association between reported cases of hyponatraemia and the use of valproic acid in Vigibase was established by calculating a reporting odds ratio, adjusted for possible confounding by concomitant medication. Four females aged 57, 67, 71 and 88 years developed symptomatic hyponatraemia or SIADH after starting valproic acid. Despite concomitant medication or co-morbidity, a causal relationship was plausible. In Vigibase, valproic acid is disproportionally associated with hyponatraemia and SIADH (corrected reporting odds ratio 1.83 [95% CI 1.61, 2.08]). Based on the described cases and the reports from Vigibase, a causal relationship between valproic acid use and hyponatraemia or SIADH can be suspected. The mechanism by which valproic acid could cause hyponatraemia or SIADH has not been fully elucidated. Valproic acid use could lead to reduced sensitivity of hypothalamic osmoreceptors. It also might directly affect tubular cell function, thereby leading to SIADH. It might be expected that a combination of effects on the osmoreceptors and a lack of compensation of the salt-water unbalance by the nephrons causes SIADH in some patients using valproic acid. It could be a dose- or concentration-related adverse effect. In this report, severe symptomatic hyponatraemia and SIADH have been associated with the use of valproic acid. With this study, not only is the number of published cases doubled, but also the data from Vigibase strongly support the association. Since hyponatraemia and SIADH have a high morbidity, health professionals should be aware of this potential ADR.

Hypothermia following antipsychotic drug use.

OBJECTIVE: Hypothermia is an adverse drug reaction (ADR) of antipsychotic drug (APD) use. Risk factors for hypothermia in ADP users are unknown. We studied which risk factors for hypothermia can be identified based on case reports. METHOD: Case reports of hypothermia in APD-users found in PUBMED or EMBASE were searched for risk factors. The WHO international database for Adverse Drug Reactions was searched for reports of hypothermia and APD use. RESULTS: The literature search resulted in 32 articles containing 43 case reports. In the WHO database, 480 reports were registered of patients developing hypothermia during the use of APDs which almost equals the number of reports for hyperthermia associated with APD use (n = 524). Hypothermia risk seems to be increased in the first days following start or dose increase of APs. APs with strong 5-HT2 antagonism seem to be more involved in hypothermia; 55% of hypothermia reports are for atypical antipsychotics. Schizophrenia was the most prevalent diagnosis in the case reports. CONCLUSION: Especially in admitted patients who are not able to control their own environment or physical status, frequent measurements of body temperature (with a thermometer that can measure low body temperatures) must be performed in order to detect developing hypothermia.