Latest clinical recommendations on valproate use for migraine prophylaxis in women of childbearing age. Overview from European Medicines Agency and European Headache Federation

Migraine is a common and burdensome neurological condition which affects mainly female patients during their childbearing years. Valproate has been widely used for the prophylaxis of migraine attacks and is also included in the main European Guidelines. Previous (2014) European recommendations on limiting the use of valproate in women of childbearing age did not achieve their objective in terms of limiting the use of valproate in women of childbearing age and raising awareness regarding the hazardous effect of valproate to children exposed in utero. The teratogenic and foetotoxic effects of valproate are well documented, and more recent studies show that there is an even greater neurodevelopmental risk to children exposed to valproate in the womb. The latest 2018 European review from the European Medicines Agency, with the active participation of the European Headache Federation, concluded that not enough has been done to mitigate the risks associated with in utero exposure to valproate. The review called for more extensive restrictions to the conditions for prescribing, better public awareness, and a more effective education campaign in migrainous women

Drugs, QTc prolongation and sudden cardiac death

__Abstract__ The term sudden cardiac death pertains to an unexpected death from cardiac causes within a short time period and has been described throughout history. The ancient Egyptians inscribed on the tomb of a nobleman some 4500 years ago that he had died suddenly and without apparent cause. Another early case of sudden death was Phidippides, the young Greek messenger, who collapsed and died after he ran 26.2 miles from Marathon to Athens to deliver the news of the Greek victory over the Persians in 460 BC. It has been hypothesised that Hippocrates in his writings provided the first medical description (approximately 400 BC) of sudden cardiac death: "Those who are subject to frequent and severe fainting attacks without obvious cause die suddenly". Sudden (cardiac) death was originally ascribed to supernatural causes. In the bible Ananias and his wife Sapphira were punished for their deceit by sudden death "WhenAnanias heard this, he fell down and died. And great fear seized all who heard what had happened. About three hours later his wife came in, not knowing what had happened. Peter asked her, "Tell me, is this the price you and Ananias got for the land?" "Yes," she said, "that is the price." Peter said to her, "How could you agree to test the Spirit of the Lord? Look! 1he feet of the men who buried your husband are at the door, and they will carry you out also. " At that moment she fell down at his feet and died. 1hen the young men came in and, .finding her dead, carried her out and buried her beside her husband. (ACTS 4:32-5:II). Even when medical science advanced to a stage where autopsies became available many sudden cardiac deaths remained unexplained. Only recently, it has been hypothesized that Napoleon might have died due cardiac arrhythmias induced by drugs the Emperor was using at that time

Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021

Introduction:In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. Methods: We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012–December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. Results: We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8–32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. Conclusion: The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.</p

Healthcare professionals' self-reported experiences and preferences related to direct healthcare professional communications:a survey conducted in the Netherlands

Background: In Europe, Direct Healthcare Professional Communications (DHPCs) are important tools to inform healthcare professionals of serious, new drug safety issues. However, this tool has not always been successful in effectively communicating the desired actions to healthcare professionals. Objective: The aim of this study was to explore healthcare providers' experiences and their preferences for improvement of risk communication, comparing views of general practitioners (GPs), internists, community pharmacists and hospital pharmacists. Methods: A questionnaire was developed and pilot tested to assess experiences and preferences of Dutch healthcare professionals with DHPCs. The questionnaire and two reminders were sent to a random sample of 3488 GPs, internists and community and hospital pharmacists in the Netherlands. Descriptive statistics were used to describe demographic characteristics of the respondents. Chi squares, ANOVAs and the Wilcoxon signed rank test were used, when appropriate, to compare healthcare professional groups. Results: The overall response rate was 34% (N=1141, ranging from 24% for internists to 46% for community pharmacists). Healthcare providers trusted safety information more when provided by the Dutch Medicines Evaluation Board (MEB) than by the pharmaceutical industry. This was more the case for GPs than for the other healthcare professionals. Respondents preferred safety information to be issued by the MEB, the Dutch Pharmacovigilance Center or their own professional associations. The preferred alternative channels of drug safety information were e-mail, medical journals and electronic prescribing systems. Conclusions: Safety information of drugs does not always reach healthcare professionals through DHPCs. To improve current risk communication of drug safety issues, alternative and/or additional methods of risk communication should be developed using electronic methods and medical journals. Moreover, (additional) risk communication coming from an independent source such as the MEB should be considered. Special effort is needed to reach GPs

Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis

Background: At the time of approval of a new medicine, there are few long-term data on the medicine's benefit-risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations. Methods and Findings: All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968-3,195) for standard medicines and 438 (IQR 132-915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462-4,135) than medication for intermediate (878, IQR 513-1,559) or short-term use (1,315, IQR 609-2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among t

Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs

Introduction: Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation. Methods: Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes o