EU Regulatory Roundup: Neuropsychiatric disorders prompt safety probe of hydroxychloroquine

RoundupsRoundups | 21 May 2020 |  By 

Cases of neuropsychiatric disorders in Spanish patients taking hydroxychloroquine for the treatment of COVID-19 have triggered a Europe-level review of the safety of the treatment.
Concerns about the risks posed by administering hydroxychloroquine to COVID-19 patients have so far primarily focused on the link between the drug and cardiac arrhythmia. However, the history of use of hydroxychloroquine in the treatment of conditions including lupus and malaria shows the drug is associated with other adverse events, some of which are now being seen in COVID-19 patients.
The Spanish Agency of Medicines and Medical Devices (AEMPS) has received reports of severe neuropsychiatric events including psychosis and suicidal ideation in patients taking the drug for the treatment of COVID-19.
In most cases, the neuropsychiatric disorders emerged shortly after the start of treatment with the drug, initially at an 800mg dose that was subsequently reduced to 400mg a day. Sanofi, which sells hydroxychloroquine as Plaquenil, has previously advised physicians to use the lowest dose possible in COVID-19 patients in light of reports of serious and life-threatening cases of QT prolongation.
AEMPS provided details of the neuropsychiatric adverse events linked to hydroxychloroquine to other regulatory agencies. The French National Agency for Medicines and Health Products Safety (ANSM) shared details of the AEMPS communication, adding that a Europe-level review is underway.
ANSM has asked sponsors and investigators involved in clinical trials of hydroxychloroquine and the related molecule chloroquine to take the risk into account. The agency thinks the neuropsychiatric risks of the drugs may be aggravated by confinement and other aspects of the pandemic that could put strains on mental health.
AEMPS Notice (Spanish), ANSM Notice (French)
EMA’s PRAC calls for changes to hormone replacement therapy safety information
EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has recommended changing the safety information for the use of hormone replacement therapy (HRT) in the management of symptoms of menopause.
PRAC reviewed the evidence after seeing the findings from a paper published in The Lancet last year. The paper found the likelihood of developing breast cancer, a known risk associated with HRT, may remain elevated for 10 years or more after stopping treatment in patients who took the therapy for upward of five years.
The findings led PRAC to recommend changes to the product information for multiple products. The Lancet paper had the biggest direct effect on combined estrogen-progestogen and estrogen-only HRT, which PRAC wants to carry a warning about the persistent risks of long-term use.
PRAC is advocating a different approach for other products. The risk Pfizer’s Duavive, which contains conjugated estrogens and bazedoxifene, poses are unknown, but PRAC wants to update the label to reflect the new information about estrogen-only HRT. PRAC also recommended updates to the labels of tibolone-containing HRT and low-dose vaginally applied oestrogen.
EMA’s pharmacovigilance body made the recommendations at a meeting at which it also proposed changes relating to leuprorelin depot medicines, which are used to treat conditions including prostate cancer.  A PRAC review found errors including incorrect needle use have caused some patients to receive too little of the medicine, leading it to call for changes to the content and placement of usage instructions.
The changes will limit the preparation and administration of the products to healthcare professionals who are familiar with their use. In the case of one leuprorelin depot medicine, Eligard, PRAC also wants the manufacturer to switch to a device that is easier to handle.
PRAC Notice, More
EMA doubles target timeline for responding to pre-submission queries
EMA has increased the target timeline for responding to pre-submission queries from five to 10 days. The agency may take more than 10 days to respond to complex queries from marketing authorization holders (MAHs) in relation to post-authorization procedures.
European officials disclosed the target timeline in an update to the post-authorization procedural advice for users of the centralized procedure. EMA revised its responses to tens of questions as part of the update, changing some other timelines in the process.
The revised timelines include the shortening of the deadline for filing Annex 1 of a risk-management plan to EudraVigilance. Under the revised rules, companies have 15 days to submit the annex if an immediate Commission Decision is applicable. The old deadline of 30 days still applies outside that situation.
Elsewhere, EMA updated the submission process for type IA and IAIN variations. EMA is now advising MAHs to use the eSubmission delivery file user interface to file all the required attributes, rather than include a template table in their cover letter. The move to eSubmission led EMA to update its responses to multiple questions.
EMA also provided new advice about when companies can request the re-examination of Committee for Medicinal Products for Human Use opinions regarding type II variations. In the new text, EMA explains that applicants can ask for positive opinions to be re-examined, provided the request relates
“to aspects of the opinion for which there had been objections by the Committee, further to which the applicant opted to amend the application.”
Ireland’s HPRA gives manufacturers more time to change leaflets and labels
Ireland’s Health Products Regulatory Authority (HPRA) has extended the deadline for implementing changes to labeling and package leaflets following the approval of a variation. HPRA granted the extension to help maintain the availability of medicines in Ireland during the COVID-19 pandemic.
Under normal circumstances, HPRA expects manufacturers to implement changes to their leaflets and labels within six months. HPRA temporarily increased the deadline to nine months this week.
Manufacturers can adopt the nine-month implementation deadline without making a batch-specific request, provided their variation is covered by the new target. HPRA is continuing to give companies six months to implement significant safety updates. The agency is advising manufacturers to evaluate the “specific nature” of their updates before switching to the nine-month deadline.
Typically, HPRA thinks significant safety updates affecting the section of the summary of product characteristics about indications, administration, contraindications and special warnings will continue to be subject to the six-month timeline. The six-month deadline also applies to the addition of safety information to other sections, such as the one providing pregnancy and breastfeeding advice.
HPRA will keep the measure under review with a view to reverting to the old timeline for all updates at some point in the future.
HPRA Notice
Other News:
EMA has shared a checklist companies should complete before submitting initial notifications for parallel distribution. The checklist is designed to ensure applicants cover details such as the method of re-packaging in their submissions. EMA does not want applicants to include the checklist in their submissions, but thinks it could help companies check filings cover the required details. Checklist
The European Directorate for the Quality of Medicines (EDQM) has released an updated technical guide covering the use of monographs for veterinary vaccines and other immunological animal medicines. EDQM thinks the guide will help manufacturers understand new requirements covering extraneous agent testing that come into force in July. EDQM Notice
Finland has extended the emergency provisions intended to ensure the supply of medicines during the coronavirus crisis until the end of June. The Ministry of Social Affairs and Health has used the powers to prevent the stockpiling of medicines and supply chain disruptions. Fimea Notice (Finnish)


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