Veterinary medicines product information is not always as helpful as is needed

Every licensed veterinary medicine comes with a summary of product characteristics (SPC), which is a legal document containing factual information about the medicine based on data generated during the development of the product. The company applying for the marketing authorisation drafts the SPC and the veterinary medicines regulator may require modifications to the text, and approves the final wording. The SPC forms the basis for the package leaflet (commonly referred to as the ‘data sheet’) and most veterinary SPCs are published as ‘data sheets’ in the NOAH Compendium. Objectives of the SPC include helping the prescribing vet to anticipate and minimise the risk of preventable unwanted effects. But sometimes advice in SPCs is too vague, or less helpful than is needed.

NexGard Combo’s SPC recommendation on duration of use

One example is the product information that accompanies NexGard Combo, a relatively new broad-spectrum spot-on parasiticide for cats containing esafoxolaner (a new drug for cats that provides cover against ectoparasites), eprinomectin (nematodes) and praziquantel (tapeworm). As for all parasiticides, the choice and duration of treatment should be based on risk (and this is spelled out in NexGard Combo’s SPC: the product is “exclusively indicated” when all three groups [ectoparasites, nematodes and cestodes] are targeted at the same time; and the rationale for prescription and frequency of use should be tailored to the individual needs of the cat, based on clinical assessment, the animal’s lifestyle and on the local epidemiological situation; in the absence of risk of co-infestation, the use of a narrow spectrum parasiticide should be considered as a first line therapy (NexGard Combo SPC). So far so good.

Much further down in the document under “special precautions” is the statement that “The safety was not evaluated beyond 6 months; therefore, no more than 6 consecutive treatments are recommended to be given within a 12-month period”.

It’s not unusual for safety studies of a new veterinary medicine to be limited to 6 months' duration (EMA 2008), so this information alone seems an insufficient explanation for the recommendation. The SPC does offer clues to a fuller explanation by referring to other sections of the document: section 4.4 (special warnings) that contains advice to base treatment on a risk assessment in order to prevent the development of resistance through repeated use over a long period; section 4.10 (overdose) that summarises the results of safety studies involving overdoses; and section 5.5 (pharmacokinetics) that describes the drugs’ pharmacokinetics, including information about drug accumulation. But it’s not easy to make sense of this disjointed information.

More helpful detail in the regulator’s report

You need to read the Public Assessment Report (EPAR) (the publicly-available summary of the regulatory assessors’ scientific discussion) to find a more meaningful explanation and insight into the thought process of the regulator (EPAR 2020). The EPAR explains that in pre-marketing pharmacokinetic studies of NexGard Combo, two of the active ingredients (esafoxolaner and eprinomectin) were found to accumulate with repeated use, reaching steady state (the point at which drug administration is balanced by elimination) by month 5 (although there is a statement in the EPAR that this figure was an estimate for esafoxolaner). In the absence of longer-term data, the regulator could not be certain that accumulation of esafoxolaner would not continue beyond 6 months. In separate safety studies there was an episode of serious adverse neurological effects in one kitten after treatment with a 5x overdose of the product (including ataxia, inability to stand, slight tremors, pupil dilation and hypothermia, that were reversible following washing of the application site, emergency measures and symptomatic treatment). On the basis of these pieces of information, the regulator (whose role it is to protect animal health) was concerned that if NexGard Combo is used more often than 4-weekly or for longer than the duration for which it has been studied (6 months), there is a potential for drug accumulation, which could potentially lead to adverse effects in the treated cat. This is the basis for the SPC recommendation.

Dealing with uncertainty

When deciding on medical treatment, every effort should be made to minimise risk. To this end, the SPCs for medicines list unwanted effects and advise on how they may be avoided. While product information can never be complete enough to cover all eventualities, it should be detailed and explicit enough to enable the prescribing vet to navigate the uncertainties.

Written by

Andrea Tarr, Founder and Director

Veterinary Prescriber

References

EMA. (2008). VICH Topic GL43. Guideline on target animal safety for veterinary pharmaceutical products. https://www.ema.europa.eu/en/vich-gl43-target-animal-safety-pharmaceuticals

EMA. (2020) CVMP assessment report for NexGard Combo. https://www.ema.europa.eu/en/documents/assessment-report/nexgard-combo-epar-public-assessment-report_en.pdf

NexGard Combo.(2021) Summary of product characteristics. https://www.vmd.defra.gov.uk/ProductInformationDatabase