N-methyl pyrrolidone (NMP) is an excipient (solvent) in a number of veterinary medicines that are given by injection, applied topically or given orally.
Given the potential of NMP to be toxic to the developing foetus, the European Medicines Agency (EMA) conducted a review in 2022 to determine whether the user and target animal safety warnings on veterinary medicines needed to be strengthened.
The outcome of the review recommended new safety warnings to highlight potential risks to pregnant women who might come in contact with the solvent.
In the case of injectables containing NMP, the EMA advised that:
‘Women of childbearing age, pregnant women or women suspected of being pregnant should use the veterinary medicinal product with serious caution to avoid accidental self-injection.’
For other scenarios, such as dermal exposure, the risk to users was negligible. This was on the basis that women of childbearing age use gloves and other appropriate personal protective equipment (PPE).
The EMA also concluded that unless reproductive toxicity studies were conducted in target species which confirmed no foetotoxic effects, the warnings of veterinary medicines concerned should be amended to advise:
‘The safety of the veterinary medicinal product has not been established in <target species> intended for breeding. Laboratory studies in rabbits and rats with the excipient N-methyl pyrrolidone have shown evidence of foetotoxic effects. Use only according to the benefit-risk assessment by the responsible veterinarian.’
Manufacturer Or Supplier:
Over 60 different products were concerned, including two centrally authorised veterinary medicines. The products are mainly antiparasitic drugs, antibacterials and an anti-inflammatory drug for a wide variety of species, including companion animals, livestock, horses, poultry and fish. The products are presented in various forms: injectables, spot-on or pour-on products, shampoos, sheep dips, sprays, and oral solutions.
Veterinary Practitioners, Pharmacists, Licensed Merchants and retailers of veterinary medicines in Ireland.
Problem Or Issue:
In May 2022 the German regulatory authority referred an issue over potential risks of developmental toxicity to users and target animals to the EMA. The specific concern was that in view of the teratogenic potential of NMP, the user and target animal safety warnings on veterinary medicines needed to be strengthened. Many of the medicines have been supplied in the EU for decades.
In its review in 2022, the EMA that:
- Concluded that NMP is an established teratogen in laboratory animals following various routes of exposure.
- Noted that the European Chemicals Agency (ECHA) has classified NMP as in the ‘reproductive toxicant category’ (may cause harm to the unborn child).
- Found that while for some veterinary medicines the current warnings are adequate, for the majority of the veterinary medicines concerned new user and target animal safety warnings are needed.
Following the review, the EMA concluded that in all cases the benefit-risk balance for the ongoing availability of the medicines remained favourable, so all the products remain as authorised veterinary medicines.
However, in accordance with the outcome of the referral procedure, the marketing authorisations of the affected products are being updated.
The process to update the marketing authorisations is in progress. However, changes to the product information for the products concerned may take several months as these changes can only be applied once the HPRA has received and approved the new text.
Actions To Be Taken:
Veterinary Practitioners, Pharmacists, Licensed Merchants and Companion Animal Medicines retailers should familiarise themselves with the risks so that they can advise animal owners accordingly.
Whilst the package leaflets of the products concerned are being updated, the new instructions for use should be followed from now on.
There are no implications for the safety of food produced from treated animals. The EMA risk assessment on residues of NMP remains as was; NMP is rapidly and extensively metabolised following administration to animals and the EMA concluded that there is not a need for a maximum residue limit for the substance in any animal species.