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During its July meeting, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded two referrals and continued its evaluation of six referrals. The PRAC also issued provisional measures for treatment of multiple sclerosis and noted a contraindication to be added for valproate in France.

EU referral procedures for safety reasons – urgent EU procedures:

• Newly triggered procedures – None

• Ongoing procedures – None

• Procedures for Finalisation – None

• Planned public hearings – None

EU referral procedures for safety reasons – other EU referral procedures:

• Newly triggered procedures: None

• Ongoing procedures: The PRAC continued to evaluate the following referrals:

• Article-31 referral-Factor VIII: As per update of 09 June 2017, following the PRAC’s May 2017 recommendation, a MAH has requested a re-examination. Upon receipt of the grounds for their request, the PRAC will commence a re-examination, expected to conclude at the PRAC meeting on 29 August – 01 September 2017.

• Article-31 referral-paracetamol modified release. • Article-31 referral-retinoid containing medicinal products.

• Article-31 referral-systemic and inhaled quinolones and fluoroquinolone antibiotics.

• Article-20 referral-Zinbryta: PRAC has issued provisional measures to ensure that Zinbryta continues to be used as safely as possible while a review of its safety on the liver is ongoing. It has provisionally restricted the use of zinbryta in patients with highly active relapsing multiple sclerosis that failed to respond to certain other treatments, and for patients with rapidly evolving relapsing disease who cannot be treated by other medicines. Patients with liver injury must not be given zinbryta. Patients who are taking the medicine should have their liver function monitored by doctors and be closely checked for signs and symptoms of liver injury.

Healthcare professionals and doctors will be informed in writing about these provisional measures. Once the review is completed, the EMA will provide updated guidance to patients and HCPs.

Article-31 referral-valproate and related substances: PRAC noted that a contraindication is to be implemented in France for the drug. It applies to women using valproate for bipolar disorder during pregnancy and also for use in women of childbearing potential not using effective contraception. PRAC’s most recent recommendation has been to prohibit the use of valproate in pregnancy or for women of childbearing potential not using effective contraception, unless there is no other alternative. Once PRAC completes its evaluation, more EU-wide guidance will be issued in the next few months, on the precautions of using valproate for all its indications.

This ongoing review includes a planned public hearing scheduled for 26 September 2017 and registration to attend the public hearing opened on 11 July 2017. The hearing will involve patients, prescribers and other stakeholders and further details are now available from the EMA website.

In the interim period, patients with any questions about valproate should discuss them with their healthcare provider and should not stop using it without consultation with their HCP.

• Procedures for finalisation:

• Article-31 referral – Gadolinium-containing contrast agents: The PRAC has confirmed that there is convincing evidence of gadolinium deposits in brain tissue following the use of gadolinium contrast agents. No conditions have been linked with these deposits however, the clinical consequences are unknown. The PRAC have recommended that the IV linear agents gadoxetic acid and gadobenic acid should only be used for liver scans when there is an important diagnostic need. In addition, the contrast agent gadopentetic acid should only be used for joint scans as the gadolinium content is very low.

All other IV linear agents (gadodiamide, gadopentetic acid and gadoversetamide) should be suspended from use, as per PRAC’s March 2017 recommendation.
Another class of gadolinium agents known as macrocyclic agents (gadobutrol, gadoteric acid and gadoteridol) are more stable and release less gadolinium than linear agents. PRAC recommends these may continue to be used at the lowest doses and only when unenhanced body scans are not suitable.

Article-31 referral- Medicinal products containing lactose of bovine origin for IV/IM use in acute allergic reactions: PRAC has recommended that injectable methylprednisolone products containing lactose must not be given to patients allergic to cow’s milk proteins. Companies must replace all current formulations containing lactose with lactose-free formulations. Patients being treated for an allergic reaction with methylprednisolone should have their treatment stopped if their symptoms worsen or they develop new symptoms.

The PRAC issued these recommendations following a review which found that lactose derived from cow’s milk may introduce traces of cow’s milk proteins into the medicine which can trigger a reaction in patients allergic to these proteins. This is particularly important for patients already being treated for allergic reactions as it may trigger new allergic reactions. It may then be difficult to determine whether the patient’s symptoms are due to a new allergic reaction caused by methylprednisolone products containing lactose or due to a worsening of the original allergic reaction.
The PRAC have concluded no level of cow milk proteins can be considered safe for these medicines when used to treat severe allergic reactions. The most effective away of minimising any risks is to remove cow’s milk proteins from the preparation. All MAHs should now replace current formulations containing cow’s milk proteins with formulations free of these proteins. The deadline for completion is the middle of 2019.

In the meantime, the MAHs are to update their product information to show that injectable methylprednisolone products containing lactose must not be given to patients allergic to cow’s milk proteins.

The MAHs must also ensure the packaging of these products are clearly marked with a warning against use in patients with an allergy to cow’s milk proteins. Healthcare professionals will be informed of this risk in writing.

• Planned Public Hearings: a planned public hearing is scheduled to review Article-31 referral-valproate and related substances, on 26 September 2017.

• Article 5(3) of Regulation (EC) No 726/2004: None