Recommendation endorsed due to the difficulty in managing overdose
On December 15, 2017, the European Medicines Agency's (EMA), Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)1 has endorsed the recommendation to suspend marketing of products containing modified- or prolonged-release Paracetamol (designed to release Paracetamol slowly over a longer period than the usual immediate-release products). The recommendation was made by the Agency's experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC).
Earlier, the Agency's experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC) had recommended, that the advantages of a longer-acting product did not outweigh the complications of managing an overdose of the medicine, since the treatment procedures for immediate-release products are not appropriate for modified-release paracetamol products. In many cases, it may not be known whether an overdose of paracetamol involves immediate-release or modified-release products, making it difficult for caregivers to decide the overdose management.
CMDh noted the PRAC conclusion that practical measures to sufficiently reduce the risk to patients had not been identified. Furthermore, it had not proved possible to agree to a feasible and standardized way to adapt the management of overdose across the EU to cover both immediate- and modified-release paracetamol products. The CMDh therefore, endorsed the PRAC recommendation that the marketing authorizations for medicines containing modified-release paracetamol, alone or combined with the opioid medicine tramadol, should be suspended.
Because the CMDh's decision was agreed to by a majority vote, it will now be sent to the European Commission which will issue a final legally binding decision valid throughout the EU.
The review procedure of modified-release paracetamol by EMA:
*Article 31 referrals: In the European Union, this type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines4.
Background
The Agency's recommendations are based on a review of available data including a retrospective pharmacokinetic and clinical analysis of 53 cases of acute overdose with modified-release paracetamol by the Swedish Poison Information Centre, which found that the standard treatment protocol utilizing solely the Rumack-Matthew nomogram (or variations thereof) based on conventional paracetamol formulations may not be effective for overdoses with modified-release paracetamol formulations. The maximum plasma concentration may occur later, and high concentrations, in particular after large doses, may persist for several days. The usual protocols of sampling and treatment regimens used in the management of overdose with immediate-release formulations are therefore, not adequate. The dose of NAC may have to be increased and the optimal dosing has not been determined. These results confirm a similar Australian case series.
More about the medicine (Modified-release-paracetamol)
Products covered by this review contain paracetamol for modified-release and are intended to be taken by mouth and have a longer action. They are available in Belgium, Denmark, Finland, Greece, Iceland, Luxembourg, the Netherlands, Portugal, Romania, and Sweden under various names including Alvedon 665 mg, Panadol Artro, Panadol Extend, Panadol Retard 8 hours, Panodil 665 mg, Paratabs Retard and Pinex Retard.
Modified-release medicines containing paracetamol with the opioid painkiller tramadol are available under the names Diliban Retard or Doreta SR in Bulgaria, Czech Republic, Estonia, Hungary, Iceland, Latvia, Lithuania, Poland, Portugal, Romania, Slovakia, Slovenia and Spain, and these medicines are also covered by this review.
About CMDh & PRAC:
CMDh: Coordination Group for Mutual Recognition and Decentralised Procedures - Human - the group responsible for the examination and coordination of questions relating to the marketing authorisation of medicines for human use in two or more Member States in accordance with the mutual recognition or decentralised procedure.
PRAC: Pharmacovigilance Risk Assessment Committee - the committee that is responsible for assessing all aspects of the risk management of medicines for human use.
Conclusion:
The targeted medicines will remain suspended unless the companies that hold the marketing authorisations can provide evidence of appropriate and practical EU-wide measures to help prevent overdose with these products and adequately reduce its risks. However, immediate-release paracetamol products, which are not affected by this review, will continue to be available as before.
Footnotes
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