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Regular liver function testing required during treatment

The PRAC has completed its review of Esmya (ulipristal acetate), used to treat moderate to severe symptoms of uterine fibroids (benign tumours of the womb), following reports of serious liver injury.

After considering all the evidence, the PRAC concluded that the medicine must not be used in women with liver problems and that certain other patients may start new treatment courses provided they have regular liver tests. In addition, PRAC recommended that Esmya should be used for more than one treatment course only in women who are not eligible for surgery.

The PRAC’s recommendations will now be forwarded to the Committee for Medicinal Products for Human Use (CHMP) for the adoption of EMA’s final opinion, and this will then go to the European Commission for a final legal decision. A letter will be sent to doctors to inform them of the new restrictions of use, which will become applicable after a Commission decision is issued.

More information:

PRAC recommends new measures to minimise risk of rare but serious liver injury with Esmya for fibroids

The European Medicines Agency (EMA) has started a review of the risk of dosing errors with methotrexate medicines. When used for inflammatory diseases, such as arthritis and psoriasis, methotrexate is taken once a week whereas for some types of cancer, the dose is higher and the medicine is used more frequently. Mistakes have led to some patients incorrectly receiving a dose every day instead of every week. As a result, patients have received too much of the medicine, with serious consequences in some cases.

More information:

Methotrexate containing medicinal products

The European Medicines Agency (EMA) has recommended contraindicating the use of the prostate cancer medicine Xofigo (radium-223 dichloride) with Zytiga (abiraterone acetate) and prednisone/prednisolone, due to an increased risk of death and fractures with this combination.

More information:

Prostate cancer medicine Xofigo must not be used with Zytiga and prednisone/prednisolone

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EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has concluded its review of retinoid1 medicines and has recommended updating the measures for pregnancy prevention and including a warning on the possible risk of neuropsychiatric disorders (such as depression, anxiety and mood changes).

During its review, the PRAC assessed the available data including published literature and post-marketing reports of side effects, and also sought the views of patients and healthcare professionals in a dedicated stakeholder meeting and a successive written consultation.

More information

The PRAC recommendations are summarised below:

Retinoid-containing medicinal products

The European Medicines Agency’s experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC) are recommending new measures to avoid exposure of babies to valproate medicines in the womb. Babies exposed are at risk of malformations and developmental problems.

More information:

PRAC recommends new measures to avoid valproate exposure in pregnancy

No new patients should start treatment for the time being.

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) is currently reviewing the benefits and risks with Esmya, following reports of serious liver injury, including liver failure leading to transplantation.

As a temporary measure while the review is ongoing, the PRAC has recommended regular liver monitoring for women taking Esmya for uterine fibroids.

All women taking Esmya should have a liver function test at least once a month during treatment. If the test is abnormal (liver enzyme levels more than 2 times the upper limit of normal), the healthcare professional should stop treatment and closely monitor the patient. Liver tests should be repeated 2 to 4 weeks after stopping treatment.

The PRAC is also recommending that no new patients should be started on Esmya and no patients who have completed a course of treatment should start another one for the time being.

A link between Esmya and cases of serious liver injury is under review. These recommendations are temporary measures to protect patients’ health, pending the conclusion of the review of Esmya which started in December 2017.

More information:

Women taking Esmya for uterine fibroids to have regular liver tests while EMA review is ongoing

Review finds measures to protect patients have not been sufficiently effective

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorisations for hydroxyethyl-starch (HES) solutions for infusion across the European Union. These products are used as plasma volume replacement following acute (sudden) blood loss, where treatment with alternative products known as ‘crystalloids’ alone is not considered to be sufficient.

The review was triggered by results from two drug utilisation studies indicating that HES solutions are being used in critically ill patients and those with sepsis and kidney injury despite restrictions introduced in 2013 to reduce the risks of kidney problems and deaths in these patient populations.

In 2013, the PRAC had recommended restrictions on the use of HES solutions, including that they must no longer be used to treat critically ill patients or patients with sepsis, because of an increased risk of kidney injury and mortality seen in clinical trials. The Committee requested that further studies be carried out to verify adherence to these restrictions.

The PRAC has reviewed the results from the drug utilisation studies of HES solutions for infusion together with the currently available data on benefits and risks from clinical trials and observational studies and feedback received from stakeholders and experts. Based on this review, the PRAC has concluded that the restrictions introduced in 2013 have not been sufficiently effective. The Committee explored the possibility of introducing additional measures but concluded that such measures would be ineffective or insufficient.

In view of the serious risks that certain patient populations are exposed to, the PRAC has recommended the suspension of the marketing authorisations for HES solutions. Alternative treatment options are available.

The PRAC recommendation will now be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)1 for consideration at its meeting on 22-25 January 2018.

For more information:

Hydroxyethyl starch (HES) containing medicinal products


1 The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Ongoing clinical trial shows an increased risk of death and fractures

The European Medicines Agency (EMA) is investigating an increased risk of death and fractures reported in an ongoing clinical trial with the prostate cancer medicine Xofigo (radium-223 dichloride). The clinical trial is comparing Xofigo with placebo (a dummy treatment), both given in combination with Zytiga (abiraterone acetate) and prednisone/prednisolone. It includes prostate cancer patients with no symptoms or only mild symptoms, such as pain.

EMA will review the full results of this study as well as other available data to evaluate their impact on the authorised use of Xofigo. While a full investigation is ongoing, doctors are asked not to use Xofigo in combination with Zytiga and prednisone/prednisolone to treat metastatic castration-resistant prostate cancer patients. Patients who are currently being treated with Xofigo and have any questions about their treatment should contact their doctor.

For more information:

Warning about use of prostate cancer medicine Xofigo

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The European Medicines Agency (EMA) has started a new review of medicines containing hydroxyethyl-starch (HES). These products are used for the management of hypovolaemia (low blood volume) caused by acute (sudden) blood loss, where treatment with alternative infusion solutions known as ‘crystalloids’ alone is not considered to be sufficient. HES medicines are given by infusion (drip) into a vein and are used as blood volume expanders to prevent shock following acute bleeding.

The review is triggered by results from two drug utilisation studies indicating that HES-containing medicines were being used outside their authorised uses, including in critically ill patients and those with sepsis and kidney injury despite restrictions introduced in 2013 to reduce the risks of kidney problems and deaths.

For more information:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/10/news_detail_002836.jsp&mid=WC0b01ac058004d5c1

No clear and consistent evidence exists of a difference in risk between plasma-derived and recombinant factor VIII medicines

Following a re-examination procedure, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has confirmed its previous conclusion of May 2017 that there is no clear and consistent evidence of a difference in the incidence of inhibitor development between the two classes of factor VIII medicines: those derived from plasma and those made by recombinant DNA technology.

Factor VIII is needed for blood to clot normally and is lacking in patients with haemophilia A. Factor VIII medicines replace the missing factor VIII and help control and prevent bleeding. However the body may develop inhibitors as a reaction to these medicines, particularly in patients starting treatment for the first time. This can block the medicines’ effect, so bleeding is no longer controlled.

Due to the different characteristics of individual products within the two classes, the PRAC reaffirmed that the risk of inhibitor development should be evaluated individually for each medicine, regardless of class. The risk for each product will continue to be assessed as more evidence becomes available.

To reflect the evidence currently available, the PRAC confirmed its recommendations that the prescribing information should be updated to include, as appropriate, inhibitor development as a very common side effect in previously untreated patients, and as an uncommon side effect in previously treated patients. The warning on inhibitor development should be amended to highlight that low levels of inhibitors pose less risk of severe bleeding than high levels.

The PRAC’s final recommendation will now be sent to EMA’s Committee for Medicinal Products for Human Use (CHMP) for the adoption of EMA’s opinion. Further details and information for patients and healthcare professionals will be published at that time.

More detailed information:

Factor VIII

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