[Risk minimalisation measures for medications; are they incorporated in Dutch clinical guidelines?] / Risicominimalisatiemaatregelen voor geneesmiddelen.

OBJECTIVE: Risk minimisation measures (RMM) are put in place to ensure safe and effective use of medicines. This study assessed whether RMM for five medicines are implemented in Dutch clinical guidelines. DESIGN: Descriptive study. METHOD: Dutch clinical guidelines where treatment with valproate, fluoroquinolones, methotrexate, metformin or fluorouracil was recommended were identified. In those guidelines that had been updated after publication of the RMM, we determined whether RMM-information was included in the guideline. RESULTS: Out of 50 identified guidelines recommending treatment with one of the five medicines, only 21 (42%) were revised after RMM-implementation. Of these 21 guidelines, 12 (n = 57%) included RMM-related information. CONCLUSION: Uptake of RMM information in Dutch clinical guidelines is limited and RMM-publication does not prompt guideline updates. This suggests that guidelines alone are not an optimal way to inform health care professionals of new safety warnings.

Acute Valproate-Induced Encephalopathy in Status Epilepticus: A Registry-Based Assessment.

BACKGROUND: Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown. OBJECTIVE: The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients. METHODS: We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment. RESULTS: Patients had a mean valproate intravenous loading dose of 34.5 mg/kg and a mean maintenance dose of 15.3 mg/kg/d (1078 mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p = 0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone). CONCLUSION: Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.

Compliance with Prescribing and Dispensing Conditions for Valproate and Related Substances in Girls and Women of Childbearing Potential: A Survey of Community Pharmacists in France.

INTRODUCTION: Prenatal exposure to valproate and related substances is associated with a risk of malformations and/or neurodevelopmental disorders. In France, prescription and dispensing conditions of oral valproate forms are subject to risk minimization measures for girls and women of childbearing potential with the aim to limit pregnancy under this treatment. These risk minimization measures were issued in 2015 and were strengthened in 2018. OBJECTIVE: We aimed to evaluate compliance with prescription and dispensing conditions of valproate for oral administration: an annual prescription from a specialist and a signed risk acknowledgment form. METHODS: Two prospective observational surveys were carried out between 2018 and 2020 on a representative sample of French community pharmacies. Data were collected from female patients aged 2-49 years presenting to one of the participating pharmacies with a valproate prescription. RESULTS: In total, 1067 and 824 valproate prescriptions were analyzed in 2018 and 2020, respectively, the majority of which were for girls and women of childbearing potential (≥ 92%). The prescription and dispensing conditions for valproate were met in 42% of cases (95% confidence interval 39-45) in 2018 and in 47% of cases (95% confidence interval 43-50) in 2020. Compliance levels were higher for prescriptions from neurologists (≥ 60%) than from other prescribers (≤ 45%). CONCLUSIONS: In France, the implementation of specific risk minimization measures for girls and women of childbearing potential with respect to oral valproate forms and related substances requires a stronger involvement of stakeholders. Increased awareness and compliance among healthcare professionals regarding risk minimization measures could limit prenatal exposure to valproate.

Assessment of asymmetric dimethylarginine and homocysteine in epileptic children receiving antiepileptic drugs.

BACKGROUND: Epilepsy is a neurological disease that requires long-term antiepileptic drugs (AEDs). The old generation of AEDs may affect serum homocysteine and asymmetric dimethylarginine (ADMA) and disturb lipid levels. The aim of the study was to evaluate serum ADMA, homocysteine, lipid profile, and carotid intima-media thickness (CIMT) in epileptic children. METHODS: This study was implemented on 159 epileptic children who were subdivided into 3 subgroups, with 53 receiving sodium valproate, 53 receiving levetiracetam, and 53 receiving polytherapy, for over 6 months and 53 healthy children. RESULTS: Low-density lipoprotein, triglycerides, and cholesterol levels were increased in epileptic children (p < 0.001), which were higher in those receiving multidrug followed by a valproate receiver. While high-density lipoprotein was lower in those receiving multidrug more than those receiving valproate. ADMA and homocysteine levels increased in epileptic patients than in controls (p < 0.001). Higher ADMA was also observed in the multidrug receiver (5.78 ± 0.62), followed by the levetiracetam group (5.56 ± 0.61). Homocysteine levels were significantly higher in multidrug and valproate-treated children than those treated with levetiracetam. CIMT was significantly higher in multidrug and valproate-treated patients (p < 0.001). CONCLUSIONS: Long-term use of AEDs, especially old-generation polytherapy, can elevate lipid profiles, homocysteine, ADMA levels, and carotid intima-media thickness compared to the minimal effect of new AEDs. IMPACT: The long-term use of antiepileptic drugs, especially old-generation polytherapy, can increase lipid profiles, homocysteine levels, ADMA, and carotid intima thickness compared to the minimal effect of new antiepileptic generation. A routine follow-up of these markers and a lifestyle modification are recommended to avoid cerebrovascular events as much as possible.

Assessment of need for hemostatic evaluation in patients taking valproic acid: A retrospective cross-sectional study.

INTRODUCTION: Valproic acid (VPA) is a frequently prescribed anti-epileptic drug. Since its introduction side effects on hemostasis are reported. However, studies show conflicting results, and the clinical relevance is questioned. We aimed to determine the coagulopathies induced by VPA in patients who undergo high-risk surgery. The study results warrant attention to this issue, which might contribute to reducing bleeding complications in future patients. METHODS: Between January 2012 and August 2020, 73 consecutive patients using VPA were retrospectively included. Extensive laboratory hemostatic assessment (including platelet function tests) was performed before elective high-risk surgery. Patient characteristics, details of VPA treatment, and laboratory results were extracted from medical records. RESULTS: 46.6% of the patients using VPA (n = 73) showed coagulopathy. Mainly, platelet function disorder was found (36.4%). Thrombocytopenia was seen in 9.6% of the patients. Data suggested that the incidence of coagulopathies was almost twice as high in children as compared to adults and hypofibrinogenemia was only demonstrated in children. No association was found between the incidence of coagulopathies and VPA dosage (mg/kg/day). CONCLUSION: A considerable number of patients using VPA were diagnosed with coagulopathy, especially platelet function disorder. Further prospective studies are needed to confirm the need for comprehensive laboratory testing before elective high-risk surgery in these patients.

Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder.

Autism spectrum disorders (ASD) are neurodevelopmental disorders, that are characterized by core symptoms, such as alterations of social communication and restrictive or repetitive behavior. The etiology and pathophysiology of disease is still unknown, however, there is a strong interaction between genetic and environmental factors. An intriguing point in autism research is identification the vulnerable time periods of brain development that lack compensatory homeostatic corrections. Valproic acid (VPA) is an antiepileptic drug with a pronounced teratogenic effect associated with a high risk of ASD, and its administration to rats during the gestation is used for autism modeling. It has been hypothesized that valproate induced damage and functional alterations of autism target structures may occur and evolve during early postnatal life. Here, we used prenatal and postnatal administrations of VPA to investigate the main behavioral features which are associated with autism spectrum disorders core symptoms were tested in early juvenile and adult rats. Neuroanatomical lesion of autism target structures and electrophysiological studies in specific neural circuits. Our results showed that prenatal and early postnatal administration of valproate led to the behavioral alterations that were similar to ASD. Postnatally treated group showed tendency to normalize in adulthood. We found pronounced structural changes in the brain target regions of prenatally VPA-treated groups, and an absence of abnormalities in postnatally VPA-treated groups, which confirmed the different severity of VPA across different stages of brain development. The results of this study clearly show time dependent effect of VPA on neurodevelopment, which might be explained by temporal differences of brain regions' development process. Presumably, postnatal administration of valproate leads to the dysfunction of synaptic networks that is recovered during the lifespan, due to the brain plasticity and compensatory ability of circuit refinement. Therefore, investigations of compensatory homeostatic mechanisms activated after VPA administration and directed to eliminate the defects in postnatal brain, may elucidate strategies to improve the course of disease.

Active Surveillance of the Safety of Medications Used During Pregnancy.

The scientific community relies on postmarketing approaches to define the risk of using medications in pregnancy because information available at the time of drug approval is limited. Most studies carried out in pregnancy focus on a single outcome or selected outcomes. However, women must balance the benefit of treatment against all possible adverse effects. We aimed to apply and evaluate a tree-based scan statistic data-mining method (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) as a safety surveillance approach that allows for simultaneous evaluation of a comprehensive range of adverse pregnancy outcomes, while preserving the overall rate of false-positive alerts. We evaluated TreeScan with a cohort design and adjustment via propensity score techniques, using 2 test cases: 1) opioids and neonatal opioid withdrawal syndrome and 2) valproate and congenital malformations, implemented in pregnancy cohorts nested within the Medicaid Analytic eXtract (January 1, 2000-December 31, 2014) and the IBM MarketScan Research Database (IBM, Armonk, New York) (January 1, 2003-September 30, 2015). In both cases, we identified known safety concerns, with only 1 previously unreported alert at the preset statistical alerting threshold. This evaluation shows the promise of TreeScan-based approaches for systematic drug safety monitoring in pregnancy. A targeted screening approach followed by deeper investigation to refine understanding of potential signals will ensure that pregnant women and their physicians have access to the best available evidence to inform treatment decisions.

Valproate prescribing practices for women with intellectual disability across Europe.

BACKGROUND: Valproate (VPA) is a known teratogen associated with greater risk of major congenital malformations and other neurodevelopmental sequelae than all other licensed antiepileptic medicines. To reduce the potential for VPA-related teratogenicity, the European Medicines Agency issued recommendations in 2018. Over two-thirds of women/girls with intellectual disability (ID) may have treatment-resistant epilepsy that could benefit from VPA treatment. AIMS: This investigation compared VPA prescribing practice for women/girls with ID between European countries, specifically evaluating the practice in the UK with that in other countries. METHODS: An expert working group with representation from key stake-holding organizations developed a survey for dissemination to relevant professionals across Europe. RESULTS: Seventy one responses were received (27 UK, 44 Europe). Clinicians in the UK were more likely to report that they are working to mandatory regulations compared with European respondents (P = .015). European respondents were less likely to be aware of user-independent contraception options (P = .06). In The UK, VPA regulations were more likely to be applied to women with ID than in Europe (P = .024). CONCLUSION: There is heterogeneity in the application of VPA regulations across Europe for women/girls with ID. In both the UK and Europe, the regulations lack suitable adjustments for specific ID-related factors.

Proposals for Engaging Patients and Healthcare Professionals in Risk Minimisation from an Analysis of Stakeholder Input to the EU Valproate Assessment Using the Novel Analysing Stakeholder Safety Engagement Tool (ASSET).

INTRODUCTION: Understanding the impact of regulatory actions for medicines and enablers/barriers for positive health outcomes is fundamental to effective risk minimisation measures (RMM). Therefore, the Impact Strategy of the European Union (EU) Pharmacovigilance Risk Assessment Committee (PRAC) includes engagement with patient communities and healthcare professional (HCP) bodies regarding RMM. However, there is uncertainty on how best to obtain stakeholder input. OBJECTIVES: The objectives of this study were to (1) analyse stakeholder input at a public hearing and dedicated meeting for the 2017-18 EU procedure on valproate teratogenicity and (2) draw proposals for enhancing PRAC engagement. METHODS: For the content analysis, the novel 'Analysing Stakeholder Safety Engagement Tool' (ASSET) was developed with 21 themes in six domains (appropriateness, access, audience, compatibility, integrability, time), based on implementation theories. RESULTS: Stakeholders provided a wide range of RMM proposals, some beyond the regulatory remit. Patients and most HCPs converged remarkably, but there was some divergence among HCPs on the informed choice objective, the therapeutic place of valproate, the RMM appropriateness, and RMM delivery to HCPs and patients. Ethical aspects emerged as relevant for regulatory decision making, and crucial input gaps were identified from an RMM implementation perspective. Nine pilotable proposals for PRAC were made regarding: (A) Agreeing on appropriate RMM with stakeholders and catalysing healthcare leadership for implementation; (B) Building-up stakeholder input on all elements critical to RMM implementation guided by the ASSET; and (C) Collaborating with all stakeholders for monitoring implementation and evaluating RMM. CONCLUSIONS: New implementation theory-based approaches are promising for enhancing the valuable dialogue between regulators, patients and HCPs and achieving patient safety. EU PAS REGISTER NUMBER: EUPAS35947.

Risk-benefit assessment of treatment of epileptic women of childbearing age with valproic acid.

AIM: Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude. METHODS: We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient's willingness to their change treatment were analysed. RESULTS: A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA. CONCLUSIONS: Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.

Assessment of atherosclerotic risk among patients with epilepsy on valproic acid, lamotrigine, and carbamazepine treatment.

OBJECTIVE: To compare the long-term effects of carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) as monotherapy on the markers of vascular risk. METHODS: The present cross-sectional study was carried out at the Department of Neurology, Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan, from 2012 to 2013. We selected 120 adult patients with epilepsy and 40 control subjects. The patients with epilepsy were divided into 3 groups according to the use of antiepileptic drugs (AEDs) (CBZ, n = 40; VPA, n = 40; and LTG, n = 40). All participants` total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), high-density lipoprotein cholesterol (HDL-c), ratio of TC/HDL-c, ratio of LDL-c/HDL-c, body mass index (BMI), and blood pressure was determined. RESULTS: In patients with epilepsy, CBZ and VPA treatment caused a noteworthy increase in the concentrations of TG, TC, and LDL-c compared with LTG treatment and the control group (p<0.001). The HDL-c significantly decreased in CBZ, VPA, and LTG-treated patients as compared with controls (p<0.001). The ratio of LDL-c/HDL-c and TC/HDL-c significantly increased in VPA- and CBZ-treated groups compared with the LTG-treated, and control group, while the ratio was also considerably elevated in patients treated with CBZ as compared with the patients treated with VPA. The weight and BMI of the patients treated with AEDs were higher (p<0.01). CONCLUSION: Patients with epilepsy on CBZ or VPA have changed vascular risk markers that may lead to atherosclerosis, while LTG-treated patients have less alteration in lipid profile.

Evaluating executive function in patients with temporal lobe epilepsy using the frontal assessment battery.

Previous studies have demonstrated executive dysfunction in patients with temporal lobe epilepsy (TLE). Frontal assessment battery (FAB) is a short neuropsychological tool that was developed for assessment of frontal lobe function in a clinical setting. The aim of the present study is to evaluate the clinical utility of FAB for detection of executive dysfunction in TLE patients. Forty-eight TLE patients and 48 sex and age-matched healthy controls participated in this study. Compared to healthy participants, the total FAB score was significantly lower among the TLE patients. TLE patients performed significantly worse at the mental flexibility, motor programming, sensitivity to interference and inhibitory control tasks. The duration of time has been passed since the last seizure was the only significant predictor of FAB score and patients who had a seizure less than a week before the evaluation time, had significantly lower FAB scores. The number of antiepileptic drugs (AEDs) did not influence the executive function in this study; however, sodium valproate was found to affect the mental flexibility. In conclusion, impaired executive function is common in TLE patients, and we suggest that FAB is a clinically applicable tool to monitor it. Moreover, we found that the time of the last seizure is a significant predictor of executive functioning and patients' performance may become worse up to seven days after a seizure. We also recommend that clinicians evaluate the cognitive adverse effects of AEDs especially sodium valproate, which was found to affect the mental flexibility in this study.

A population-based study of the comparative effectiveness of second-generation antipsychotics vs older antimanic agents in bipolar disorder.

OBJECTIVES: Numerous antimanic treatments have been introduced over the past two decades, particularly second-generation antipsychotics (SGAs). However, it is not clear whether such newer agents provide any advantage over older treatments. METHODS: A historical cohort design investigated the nationwide population of outpatients with bipolar disorder treated in the Department of Veterans Affairs who were newly initiated on an antimanic agent between 2003 and 2010 (N=27 727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation, controlling for numerous demographic, clinical, and treatment characteristics. Potential correlates of effect were explored by investigating time to initiation of a second antimanic agent or antidepressant. RESULTS: After control for covariates, those initiated on lithium or valproate monotherapy, compared to those beginning SGA monotherapy, were significantly less likely to be hospitalized, had a longer time to hospitalization, and had fewer hospitalizations in the subsequent year. Those on combination treatment had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of an additional antimanic agent or antidepressant. CONCLUSIONS: The present analysis of a large and unselected nationwide population provides important complementary data to that from controlled trials. Although various mechanisms may be responsible for the results, the data support the utilization of lithium or valproate, rather than SGAs, as the initial antimanic treatment in bipolar disorder. A large-scale, prospective, randomized, pragmatic clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.

Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK electronic primary care health records.

BACKGROUND: Although many women treated with psychotropic medication become pregnant, no psychotropic medication has been licensed for use in pregnancy. This leaves women and their health-care professionals in a treatment dilemma, as they need to balance the health of the woman with that of the unborn child. The aim of this project was to investigate the risks and benefits of psychotropic medication in women treated for psychosis who become pregnant. OBJECTIVE(S): (1) To provide a descriptive account of psychotropic medication prescribed before pregnancy, during pregnancy and up to 15 months after delivery in UK primary care from 1995 to 2012; (2) to identify risk factors predictive of discontinuation and restarting of lithium (multiple manufacturers), anticonvulsant mood stabilisers and antipsychotic medication; (3) to examine the extent to which pregnancy is a determinant for discontinuation of psychotropic medication; (4) to examine prevalence of records suggestive of adverse mental health, deterioration or relapse 18 months before and during pregnancy, and up to 15 months after delivery; and (5) to estimate absolute and relative risks of adverse maternal and child outcomes of psychotropic treatment in pregnancy. DESIGN: Retrospective cohort studies. SETTING: Primary care. PARTICIPANTS: Women treated for psychosis who became pregnant, and their children. INTERVENTIONS: Treatment with antipsychotics, lithium or anticonvulsant mood stabilisers. MAIN OUTCOME MEASURES: Discontinuation and restarting of treatment; worsening of mental health; acute pre-eclampsia/gestational hypertension; gestational diabetes; caesarean section; perinatal death; major congenital malformations; poor birth outcome (low birthweight, preterm birth, small for gestational age, low Apgar score); transient poor birth outcomes (tremor, agitation, breathing and muscle tone problems); and neurodevelopmental and behavioural disorders. DATA SOURCES: Clinical Practice Research Datalink database and The Health Improvement Network primary care database. RESULTS: Prescribing of psychotropic medication was relatively constant before pregnancy, decreased sharply in early pregnancy and peaked after delivery. Antipsychotic and anticonvulsant treatment increased over the study period. The recording of markers of worsening mental health peaked after delivery. Pregnancy was a strong determinant for discontinuation of psychotropic medication. However, between 40% and 76% of women who discontinued psychotropic medication before or in early pregnancy restarted treatment by 15 months after delivery. The risk of major congenital malformations, and neurodevelopmental and behavioural outcomes in valproate (multiple manufacturers) users was twice that in users of other anticonvulsants. The risks of adverse maternal and child outcomes in women who continued antipsychotic use in pregnancy were not greater than in those who discontinued treatment before pregnancy. LIMITATIONS: A few women would have received parts of their care outside primary care, which may not be captured in this analysis. Likewise, the analyses were based on prescribing data, which may differ from usage. CONCLUSIONS: Psychotropic medication is prescribed before, during and after pregnancy. Many women discontinue treatment before or during early pregnancy and then restart again in late pregnancy or after delivery. Our results support previous associations between valproate and adverse child outcomes but we found no evidence of such an association for antipsychotics. FUTURE WORK: Future research should focus on (1) curtailing the use of sodium valproate; (2) estimating the benefits of psychotropic drug use in pregnancy; and (3) investigating the risks associated with lifestyle choices that are more prevalent among women using psychotropic drugs. FUNDING DETAILS: The National Institute for Health Research Health Technology Assessment programme.