Regulatory News - July 2019

EMA’s human medicines committee (CHMP) has recommended granting a marketing authorisation in the European Union (EU) for Sixmo (buprenorphine) as a substitution treatment for opioid dependence. Sixmo is an implant that releases low levels of buprenorphine into the patient’s body for six months. It is indicated in clinically stable adult patients who require no more than 8 mg per day of sublingual (i.e. administered under the tongue) buprenorphine, within a framework of medical, social and psychological treatment.

The active substance of Sixmo is buprenorphine. It consists of four small rods that are implanted in the patient’s upper arm by a trained physician under local anaesthetic and continuously deliver buprenorphine for six months. This new method of administration could enhance adherence to the treatment and reduce the potential for misuse or accidental overdoses in the home, as well as the risk of accidental ingestion of buprenorphine by others, especially children.

 The safety and efficacy of Sixmo were studied in three pivotal trials, in a total of 626 adult patients. One of the trials enrolled OUD adults who were considered clinically stable by their treating physician. The results demonstrated that 96.4% of patients in the Sixmo group responded to treatment, compared to 87.6% of patients treated with sublingual buprenorphine. The applicant is required to perform an additional study in patients in Europe to further evaluate the risks associated with the insertion and removal of the implants.

EMA has started a review of medicines containing fluorouracil (also known as 5-fluorouracil or 5-FU) and the related medicines capecitabine, tegafur and flucytosine, which are converted to fluorouracil in the body. These compounds are used for the treatment of cancer, various skin conditions, and fungal infections. The review examines existing screening methods and their value in identifying patients at inc-increased risk of severe side effects (neutropenia, neurotoxicity, severe diarrhoea, and stomatitis).

EMA has started a new review of high-strength estradiol-containing creams (0.01% w/w) that are used inside the vagina for treating women with vaginal atrophy who have been through menopause. The review will assess the risk of estradiol being absorbed systemically (throughout the body) from these creams. Systemic absorption is of concern because it may result in similar side effects to those associated with the use of estradiol in systemic hormone replacement therapy (HRT), which include venous thromboembolism (formation of blood clots in the veins), stroke and endometrial cancer (cancer of the lining of the womb).

EMA has started a review of medicines containing the antibiotic fosfomycin, which has been used in a number of EU Member States to treat a range of bacterial infections for many decades. Fosfomycin works in a unique way and bacteria resistant to other antibiotics are less likely to be resistant to fosfomycin. There are significant differences between the Member States in the authorised uses and doses of fosfomycin medicines. The German medicines authority has requested the reappraisal of the role of fosfomycin in the context of increasing resistance to antibiotics. The indications and dosage of fosfomycin and the adequacy of information on its safety and pharmacological properties will be re-evaluated in the light of up-to-date knowledge on antibacterial therapy. EMA’s human medicines committee (CHMP) will consider the available evidence and make recommendations as to whether the marketing authorisations for fosfomycin-containing medicines should be amended across the EU.

EMA has started a review of the multiple sclerosis medicine Lemtrada (alemtuzumab) following new reports of immune-mediated conditions (caused by the body’s defence system not working properly) and problems with the heart and blood vessels with the medicine, including fatal cases.

As a temporary measure, while the review is ongoing, Lemtrada should only be started in adults with relapsing-remitting multiple sclerosis that is highly active despite treatment with at least two disease-modifying therapies (a type of multiple sclerosis medicine) or where other disease-modifying therapies cannot be used. Patients being treated with Lemtrada who are benefitting from it may continue treatment in consultation with their doctor.

In addition to the restriction, EMA’s safety committee (PRAC) has recommended an update of the product information for Lemtrada to inform patients and healthcare professionals about cases of:

• immune-mediated conditions, including autoimmune hepatitis (with damage to the liver) and haemophagocytic lymphohistiocytosis (overactivation of the immune system which may affect different parts of the body);
• problems with the heart and blood vessels occurring within 1–3 days of receiving the medicine, including bleeding in the lungs, heart attack, stroke, cervicocephalic arterial dissection (tears in the lining of the arteries in the head and neck);
• severe neutropenia (low levels of neutrophils, a type of white blood cell that fights infections).

Healthcare professionals should consider stopping treatment in patients who develop signs of these conditions and patients should immediately seek medical help if they experience symptoms.

EMA will now evaluate all available data on the safety concerns with the medicine and consider any additional measures necessary to protect patients and whether there should be changes in the authorised use.

EMA’s safety committee (PRAC) is recommending that doctors must not prescribe the 10 mg twice daily dose of Xeljanz (tofacitinib) in patients who are at high risk of blood clots in the lungs. These include patients who have heart failure, cancer, inherited blood clotting disorders or a history of blood clots, as well as patients who take combined hormonal contraceptives, are receiving hormone replacement therapy or are undergoing major surgery.  In addition, doctors should consider other factors that may increase the risk of blood clots in the lungs including age, obesity, smoking or immobilisation.

Xeljanz is currently authorised for the treatment of rheumatoid arthritis, psoriatic arthritis, and severe ulcerative colitis. The PRAC’s recommendation follows results from an ongoing study (study A3921133) in patients with rheumatoid arthritis. This study showed an increased risk of blood clots in the lungs and death when the 10 mg twice daily dose was used, which is double the recommended dose for rheumatoid arthritis. The new advice means that, since 10 mg is the only recommended starting dose for ulcerative colitis, patients with this condition who are at high risk of blood clots must not be started on Xeljanz.

Patients at high risk currently taking this dose for any condition must be switched to alternative treatments. Patients should not stop or change their dose of Xeljanz without talking to their doctor. They should seek medical attention immediately if they experience symptoms such as difficulty breathing, pain in the chest or upper back and coughing up blood, which could indicate the presence of a blood clot in the lungs.

The new recommendations are temporary and follow previous PRAC advice not to exceed the recommended 5 mg twice daily dose when treating rheumatoid arthritis. The PRAC will now carry out a review of all available evidence, and updated guidance will be provided to patients and healthcare professionals once the review is concluded.

EMA is advising healthcare professionals and patients not to exceed the recommended dose of Xeljanz (tofacitinib) when treating rheumatoid arthritis. The advice follows early results from an ongoing study (study A3921133) in patients with rheumatoid arthritis, which showed an increased risk of blood clots in the lungs and death when the normal dose of 5 mg twice daily was doubled. In the EU, 5 mg twice daily is the authorised dose for rheumatoid arthritis and psoriatic arthritis. The higher dose of 10 mg twice daily is approved for the initial treatment of patients with ulcerative colitis. EMA is assessing the early results and will consider if any regulatory action is needed.

 In the meantime, patients with rheumatoid arthritis who are receiving Xeljanz at 10 mg twice daily in study A3921133 will have their dose reduced to 5 mg twice daily for the remaining duration of the study. The aim of the study was to look at the risks of heart and circulatory problems with Xeljanz in patients 50 years of age or older who were already at higher risk of these and to compare its safety with that of another medicine called a TNF inhibitor.

EMA’s safety committee (PRAC) has recommended that the marketing authorisations for fenspiride medicines be revoked, so the medicines can no longer be marketed in the EU. This follows a review that confirmed that these cough medicines could cause heart rhythm problems. The PRAC considered all the available evidence in its review. This included cases of QT prolongation and torsades de pointes (abnormalities of the heart’s electrical activity that may lead to heart rhythm disturbances) in patients using these medicines, results of laboratory studies, data from published literature and stakeholder input. Heart rhythm problems can be serious and occur suddenly, and it is not feasible to identify in advance the patients who may be at risk of these problems with fenspiride. In contrast, fenspiride medicines are used to treat non-serious cough. Therefore, the PRAC considered that these medicines should no longer be marketed. The PRAC recommendation was adopted by the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) by consensus and will be implemented directly at the national level.

An improved version of the EudraVigilance system in November 2017 simplified the reporting of suspected adverse reactions, enabled better analysis of data for the benefit of patient safety in Europe and increased the transparency and accessibility of these case reports. The new and improved EudraVigilance, the European system for managing and analysing information on suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the EU, received more than 2 million reports of suspected side effects in 2018. This is an increase of 37% compared to 2017 which largely reflects that from November 2017 the national competent authorities and the marketing authorisation holders were required to report non-serious cases of suspected adverse reactions to EudraVigilance, having previously only reported serious cases.

This was also a key driver for the increase in the number of reports received from European patients and consumers through national authorities and marketing authorisation holders, which almost doubled between 2017 and 2018. Improvements in patient reporting also reflect efforts at the national level to encourage patients to share information on side effects through information campaigns. These and other findings are summarised in EMA’s annual report on Eudravigilance.

According to the report, EMA reviewed more than 2,200 potential signals. This is information on a new adverse reaction or a new aspect of a known adverse reaction that is potentially caused by a medicine and warrants further investigation. Almost 80% of these signals originated from monitoring the EudraVigilance database. Other signals were generated from clinical studies and scientific literature.

The Agency’s safety committee (PRAC) assessed 114 safety signals in 2018, 40% more than in 2017. 44% of the signals assessed by PRAC resulted directly in a recommendation to change the product information for patients and healthcare professionals, thus ensuring the safe and effective use of medicines.

The EMA has released a document that provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 13-16 May 2019 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT] reference numbers). PRAC recommendations to provide supplementary information are directly actionable by the concerned marketing authorisation holders (MAHs).

PRAC recommendations for regulatory action (e.g. amendment of the product information) are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs), and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for information in the case of Nationally Authorised Products (NAPs). Thereafter, MAHs are expected to take action according to the PRAC recommendations. When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency or the Member States. MAHs are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with the current scientific knowledge including the conclusions of the assessment and recommendations published on the European Medicines Agency (EMA) website (currently acting as the EU medicines web portal). 

For CAPs, at the time of publication, PRAC recommendations for the update of product information have been agreed by the CHMP at their plenary meeting (27-29 May 2019) and corresponding variations will be assessed by the CHMP. For nationally authorised medicinal products, it is the responsibility of the National Competent Authorities (NCAs) of the Member States to oversee that PRAC recommendations on signals are adhered to. Variations for CAPs are handled according to established EMA procedures. MAHs are referred to as the available guidance. Variations for NAPs (including via mutual recognition and decentralised procedures) are handled at the national level in accordance with the provisions of the Member States). The timeline recommended by PRAC for submission of variations following signal assessment is applicable to both innovator and generic medicinal products unless otherwise specified.