PRAC May 2018 – Recommendation to suspend hydroxyethyl-starch (HES) solutions for infusion, new measures for Esmya, end of the review of Zinbryta and precautionary advice on HIV medicine

During its meeting of May 2018, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has confirmed its recommendation to suspend hydroxyethyl-starch (HES) solutions for infusion, has recommended new measures for Esmya, has finalised the review of Zinbryta and has issued precautionary advice on HIV medicine.

Recommendation to suspend hydroxyethyl-starch (HES) solutions for infusion in the European Union (EU)

Following a request from the European Commission to look into certain aspects related to the suspension of the marketing authorisations (MAs)for hydroxyethyl starch (HES) solutions for infusion, the PRAC has confirmed its recommendation to suspend these products across the EU.

In January 2018, the PRAC has recommended suspending the MAs for HES solutions for infusion because they continued to be used in critically ill patients and patients with sepsis despite restrictions introduced in 2013 to reduce the risk of kidney injury and death in such patients.

This recommendation was endorsed by the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) and sent to the European Commission. In April 2018, the European Commission requested the PRAC to consider whether suspending the MAs could result in an unmet medical need. It also requested the PRAC to consider the feasibility and likely effectiveness of additional risk minimisation measures.

After having assessed the relevant data on these specific aspects, the PRAC has now confirmed its previous recommendation that HES solutions for infusion should be suspended. The PRAC recommendation will now be sent to the CMDh for consideration at its meeting on 23-25 May 2018.

In Belgium, medicinal products containing hydroxyethyl-starch (HES) are available under the following commercial names : TETRASPAN, VENOHES, VOLULYTE and VOLUVEN.

More information is available on the EMA website.

New measures to minimise risk of rare but serious liver injury with Esmya for fibroids - Regular liver function testing required during treatment

The PRAC has completed its review of Esmya (ulipristal acetate), following reports of serious liver injury. After considering all the evidence, the PRAC concluded that the medicinal product 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.

Esmya is used to treat moderate to severe symptoms of uterine fibroids (benign tumours of the womb). The medicinal product has been shown to be effective at reducing bleeding and anaemia, as well as the size of the fibroids.

The PRAC has concluded that Esmya may have contributed to the development of some cases of serious liver injury[1] and has therefore made the following recommendations to minimise this risk.

  • Esmya must not be used in women with known liver problems;
  • A liver function test should be performed before starting each treatment course and treatment must not be started if liver enzyme levels are more than two times the upper limit of normal.
  • Liver function tests should be performed once a month during the first 2 treatment courses and 2 to 4 weeks after stopping treatment. If the test is abnormal (liver enzyme levels more than three times the upper limit of normal), the medical doctor should stop treatment and closely monitor the patient.
  • Esmya should be used for more than one treatment course only in women who are not eligible for surgery. Women who are about to have surgery should continue to use only one course.
  • A card will be included in the box of the medicinal product to inform patients about the need for liver monitoring, and to contact their medical doctor should they develop symptoms of liver injury (such as tiredness, yellowing of the skin, darkening of the urine, nausea and vomiting).
  • Studies should be performed to determine the effects of Esmya on the liver and whether these measures are effectively minimising the risks.

In February 2018, while the review was ongoing, the PRAC had issued temporary recommendations that no new patients should be started on Esmya. Having finalised its review, the PRAC has now concluded that new patients can start treatment in line with the above recommendations to minimise the risk of liver injury.

These 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 European Commission decision is issued.

In Belgium, the medicinal product Esmya is authorised and commercialised.

More information is available on the EMA website.


EMA review of Zinbryta confirms medicine’s risks outweigh its benefits

Multiple sclerosis medicine no longer authorised and recalled from hospitals and retail pharmacies.

The PRAC has confirmed that the multiple sclerosis medicine Zinbryta (daclizumab beta) poses a risk of serious and potentially fatal immune reactions affecting the brain, liver and other organs.

Patients could be at risk from the start of treatment and for several months after stopping treatment, and it is not possible to predict which patients will be affected. The PRAC therefore confirmed its previous conclusions that risks of Zinbryta outweigh its benefits for patients with multiple sclerosis.

Healthcare professionals should continue monitoring patients who have been treated with Zinbryta in line with recommendations issued in March 2018.

There are no immediate consequences of the PRAC’s review as Zinbryta is no longer authorised in the EU. On 27 March 2018, the MA was withdrawn at the request of Biogen Idec Ltd, the company that marketed the medicine. Zinbryta is no longer available in hospitals and retail pharmacies in the EU.

A full assessment report on the review will be published shortly.

Zinbryta is no longer authorised in Belgium.

More information is available on the EMA website.

Dolutegravir should not be used in women seeking to become pregnant while EMA review is ongoing

The EMA is evaluating preliminary results from a study which found four cases of birth defects such as spina bifida (malformed spinal cord) in babies born to mothers who became pregnant while taking a HIV medicinal product containing dolutegravir. While EMA is assessing the new evidence it has issued the following precautionary advice:

  • HIV medicinal products containing dolutegravir should not be prescribed to women seeking to become pregnant;
  • women who can become pregnant should use effective contraception while taking medicinal products containing dolutegravir.

The study, which looked at babies born to 11,558 HIV-infected women in Botswana, showed that 0.9 % of babies (4 of 426) whose mothers became pregnant while taking dolutegravir had a neural tube defect, compared with 0.1 % of babies (14 of 11,173) whose mothers took other HIV medicines. Final results are expected in about a year.

Women who have been prescribed dolutegravir should not stop taking their medicine without first consulting their medical doctor.

The EMA will update the recommendations as necessary when it concludes its assessment.

Information for patients

  • Preliminary data show that taking dolutegravir for HIV before pregnancy may increase the risk of birth defects such as spina bifida (malformed spinal cord).
  • If you are taking dolutegravir and you can become pregnant you should use an effective contraception.
  • If you are taking dolutegravir and wish to become pregnant please talk to your medical doctor about whether dolutegravir remains the most appropriate treatment.
  • If you are pregnant and using dolutegravir, you should consult your medical doctor. Do not discontinue dolutegravir without consulting your medical doctor, as this may harm you and your unborn child.
  • Tell your medical doctor if you become pregnant, think you might be pregnant or are planning to become pregnant. Your medical doctor will review your treatment.
  • If you have any questions about your treatment or contraception, speak to your medical doctor or pharmacist.

Information for healthcare professionals

  • Preliminary results from an observational study revealed an increased risk of neural tube defects in infants born to women who took dolutegravir at the time of conception. No cases were reported in infants born to women who started dolutegravir later during pregnancy.
  • Reproductive toxicology studies have not shown any relevant findings. Likewise, other data on the use of dolutegravir in pregnancy, including data from the Antiretroviral Pregnancy Registry (APR), clinical trials and post-marketing use have not indicated a risk of neural tube defects.
  • As a precaution, healthcare professionals in the EU are advised of the following:
    • do not prescribe dolutegravir for women of child bearing potential who are trying to become pregnant;
    • exclude pregnancy in women of child bearing potential before starting dolutegravir;
    • advise women of child bearing potential who are taking dolutegravir to use effective contraception throughout treatment;
    • if pregnancy is confirmed in the first trimester while a woman is taking dolutegravir, switch to an alternative treatment unless there is no suitable alternative.
    • Healthcare professionals in the EU will be sent a dear healthcare professional letter concerning (DHPC) these recommendations.

In Belgium, medicinal products containing dolutegravir are available under the following commercial names : Tivicay, Triumeq.

More information is available on the EMA website.

[1] In eight cases of serious liver injury, a role of Esmya in contributing to these cases is possible. It is estimated that around 765,000 patients have been treated with Esmya to date.
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