Dr. Joan Gilvarry:

Good morning Chairman and committee members. My name is Joan Gilvarry and I am the director of human medicines at the HPRA and I am joined by my colleague Dr. Almath Spooner, the pharmacovigilance and risk-management lead at the HPRA. Dr. Spooner is also the Irish delegate on the European Medicines Agency pharmacovigilance risk assessment committee, PRAC, which has been referred to already this morning.

The PRAC is the committee at the EMA responsible for assessing and monitoring safety issues for human medicines. It is composed of experts such as doctors, pharmacists, scientists and patient organisation representatives from all EU member states. We are grateful for the opportunity to talk to the committee this morning about the regulation of this medicine, which is known in Ireland under the brand name Epilim. We will discuss the recent European reviews in which we have been actively involved and our collaboration with national colleagues, namely, the Department of Health, the HSE, the clinical leads in neurology, psychiatry and primary care, the Pharmaceutical Society of Ireland, PSI, and patient representatives from Epilepsy Ireland and the Organisation for Anti-Convulsant Syndrome, OACS. I would particularly like to thank the patients and their representatives for their collaboration with us over the past number of years.

Valproate-containing medicines have been licensed across the EU and in many countries worldwide since the 1960s and in Ireland since 1975. It is an effective treatment for epilepsy and bipolar disorder and for some patients may be the only treatment option. When the medicine was first approved, the prescribing information included a warning about the risk of congenital abnormalities if taken during pregnancy. These warnings were strengthened on many occasions in subsequent years as new information became available. More recently, new studies were published internationally which showed a higher than expected risk of congenital abnormalities, together with a risk of neurodevelopmental disorders in children born to mothers who had taken valproate during their pregnancy. This prompted a European-wide safety review of all the available data by the PRAC. This review was commenced in 2013 and was finalised in 2014 concluding that children exposed in uteroto valproate were at a high risk of serious developmental disorders, in up to 30% to 40% of cases, and-or congenital malformations, in approximately 10% of cases. In the interests of patient safety, the PRAC recommended that valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments were not effective or not tolerated. The prescribing information and package leaflet for patients were updated with new recommendations around supervision of treatment by a specialist, the importance of using effective contraception and the need for regular treatment reviews. In addition, warnings around use in female children, adolescents and women of childbearing potential, and the need for discussion of such issues with the patient, were highlighted.

Following that European review, the HPRA communicated extensively with neurologists, psychiatrists, paediatricians, obstetricians, GPs, specialist nurses, pharmacists and the HSE to emphasise the new warnings and recommendations. These communications included letters from the pharmaceutical company that was mandated by us to doctors and pharmacists, following approval by the HPRA. It appeared in several editions of our Drug Safety Newsletter, warnings in national prescribing formularies and on our website. Additionally, materials designed to minimise the risks with the medicine, for example, a guide for patients and a patient alert card, a healthcare professional guide and a prescribing checklist were developed and distributed. We also met with patient representatives at that time and discussed it with them.

In 2017, following concerns across Europe that the measures taken in 2014 and relayed over a number of years were not sufficiently effective in increasing awareness and reducing exposure to valproate use during pregnancy, a second European-wide safety review was initiated. This review was again conducted by the PRAC which considered that these concerns were well founded. During the review, the first ever public hearing was held at the European Medicines Agency where the views and experiences of patients, including our Irish colleagues who are present today, were heard and this proved to be invaluable in the development of the latest safety recommendations. The outcome of this review has led to the introduction of new contraindications, essentially a ban on the use of valproate during pregnancy, strengthened warnings and further measures to prevent exposure during pregnancy, including a pregnancy prevention programme. The programme will incorporate measures such as assessment of individual patients regarding their likelihood of becoming pregnant, pregnancy tests before and during treatment as needed, the need for effective contraception while on treatment, and carrying out reviews of treatment by the prescribing specialist at least once a year. Most important is the requirement for the doctor to involve the patient in evaluating her own individual circumstances, to have a discussion with her on treatment and therapeutic options, to inform her of the risks and how to minimise the risks, and counselling around pregnancy prevention.

Additionally, the HPRA has mandated that the outer packaging of all valproate-containing medicines must include a visual symbol warning about the risks in pregnancy in addition to the boxed text that is already approved. The blister packs inside the outer packs will also carry a visual warning symbol. The patient reminder card will be attached to every treatment pack for pharmacists to discuss with the patient each time the medicine is dispensed. As an interim measure, pending the production of the new cartons, stickers with the warning and pictographs are being made available to pharmacies. Updated versions of the healthcare professional and patient guides and of the patient alert cards are being distributed to help support healthcare professionals and patients in their discussions on the minimisation of risk and to further ensure that all affected patients receive full and accurate information. Also, based on specific feedback from patients, the pack sizes are being reduced to packs of 30. All of these recommendations are currently being implemented in Ireland with significant progress already achieved.

Last week we published and distributed a special edition of our Drug Safety Newsletterto all registered doctors and pharmacists in the country and a letter was sent to relevant healthcare professionals by the company following approval by the HPRA. Over the years the HPRA has worked closely with our national colleagues, including the patient groups, the HSE, the clinical leads, the PSI and the Department of Health. Our priority at the HPRA is patient safety, and to ensure that women and girls are aware of the very real risks of taking valproate during pregnancy. We will continue working together to facilitate timely and effective implementation of the new recommendations nationally and, crucially, to support their successful introduction into everyday clinical practice. I thank members for their time. Dr. Spooner and I are very happy to take any questions members may have.