Erna Beers

Practical Problems with Medication Use that Older People Experience: A Qualitative Study

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.

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

AbstractBackground: 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. Methods: 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. Results: 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]). Discussion: 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. Conclusion: 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.

Participation of Older People in Preauthorization Trials of Recently Approved Medicines

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).

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.

O2.21: Practical problems with medication use experienced by older people: a qualitative study

1 Dept of Public Health Effects, National Institute for Public Health and the Environment (RIVM), Bilthoven; 2 Dept of Geriatric Medicine&Expertise Centre Pharmacotherapy in Old Persons, UMC Utrecht; 3 Dutch Medicines Evaluation Board, Utrecht; 4 Dept of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharma ceutical Sciences (UIPS), Utrecht University, Utrecht; 5 Dept of Clinical Pharmacy, UMC Utrecht

Symptomatic hyponatremia due to the use of valproic acid - four cases and support from the WHO database

Introduction: The Netherlands Pharmacovigilance Centre Lareb received four cases of symptomatic hyponatremia during valproic acid (VPA) use. A causal relationship was suspected. This amount of reports doubles the described cases in worldwide literature. Almost 240 reports of hyponatremia and SIADH (syndrome of inappropriate ADH secretion) due to VPA were received by the WHO collaborating centre for international drug monitoring. We studied the strength of this association. Methods: The reported cases are described. In a case/non-case analysis, the strength of the association in the WHO database was established by calculating a reporting odds ratio, adjusted for possible confounding by concomitant medication. Results: The reported cases considered four females aged between 57 and 88 years. Sodium levels ranged from 116 to 125 mmol/l. Other possible causes for hyponatremia, like concomitant medication or co-morbidity, were ruled out or were considered not to be the primary causal factor. In the WHO database VPA was disproportionally associated with hyponatremia and SIADH (adjusted ROR 1.83 [95%CI 1.61-2.08]). Discussion: Hyponatremia may be caused by the use of VPA. The mechanism by which valproic acid could cause hyponatremia has not been fully elucidated. Possibly a combination of effects on the osmoreceptors and a lack of compensation of the salt-water unbalance by the nephrons causes hyponatremia or SIADH in some patients using valproic acid. Since hyponatremia has a high morbidity, health professionals should be aware of this adverse drug reaction. Electrolytes should be monitored closely during treatment with valproic acid in patients with risk factors for hyponatremia or SIADH.Introduction: PDE5i-related arterial thromboembolism is described in literature. Published venous thrombotic events are limited to one case of pulmonary embolism (tadalafil) and of recurrent deep venous thrombosis (DVT) related to sildenafil. Aim of the study: Presentation of two cases of vardenafil associated pulmonary embolisms and of PDE5i related pulmonary embolisms reported to international databases. Methods: Analysis of reports received by the Netherlands Pharmacovigilance Centre and international databases. Results: In the Netherlands, two recent cases of pulmonary embolism in vardenafil users have been reported. A 57-year-old male experienced dyspnoea after start and chest pain 30 min after each ingestion of vardenafil, which was three times used. CT-scan angiography showed a pulmonary embolus of the right lobe. A 62-year-old male experienced DVT in 2006, and pulmonary embolism in 2008, both shortly after vardenafil use. Seventeen cases of pulmonary embolism associated with PDE5i use were reported to the WHO and Eudravigilance ADR databases. Phosphodiestarase is an important regulator of AMP and cGMP mediated signal transduction and is involved in pulmonary vasodilatation. Proposed mechanisms include local pulmonary hypoperfusion due to vasodilatory properties of PDE5i and an interaction of PDE5i-induced raised cGMP may interfere with endothelial function. Also stimulation of phosphodiesterase E2 and E4 may result in increased endothelial adhesion and finally interaction of PDE5is with ions may influence the coagulation cascade. Conclusion: The cases are suggestive for a possible effect of PDE5is leading to pulmonary embolism. Short latencies are in line with vardenafils pharmacokinetic profile and fit in local vasodilatory effects of PDE5is.