Recent changes to penicillin withholding periods
We are grateful to the ACVM Group for preparing this guidance
New Zealand Food Safety (NZFS) registers trade name products under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997 after conducting a risk assessment on that product to confirm the benefits of its registration and use and all associated risks can be appropriately managed. Once a product is registered, NZFS can decide to reassess a registered product if significant new information comes to light that draws that original risk assessment or the applied risk management controls into question. Reassessment can also be triggered if there has been a significant change in the use of any or all registered trade name products that can alter the risk assessment associated with the approved use.
In 2020, NZFS began a programme of reassessing all antibiotic-based agricultural compounds. The first step in this work was to classify all antibiotic compounds as ‘Important’, ‘Highly Important’, and ‘Critically Important’ with respect to each compound’s risk of developing antimicrobial resistance (AMR) and its clinical need as a veterinary or horticultural treatment. The classification would also trigger the application of a mandatory classification label for each product, as well as a standardised statement advising veterinarians and end users of the expectations of prudent use and AMR risks.
More information on the classification process and the outcomes of classification of the first tranche of antibiotic compounds to be reviewed can be found on the MPI website in the paper AMR Reassessment Review: Macrolides, Later-Generation Cephalosporins and Penicillins.
Once the classification of an agricultural compound is complete, individual trade name products are reassessed to review all existing claims, dose rates, and use patterns to ensure that the efficacy and safety of the approved uses were still supported. If the existing label information is found not to conform to the expectations of prudent antibiotic use, such as having a dose rate that is too low to be efficacious against modern disease profiles or having claims against organisms known to now be resistant to the active ingredient, the product label information and approval is updated to address these risks. For products used in food producing animals or crops, this work includes a review and adjustments to the maximum residue levels (MRLs) and withholding periods where needed to manage food safety and trade risks.
Penicillins were included in the first tranche of antibiotic reassessment work, with amoxicillin, ampicillin, cloxacillin, penethamate hydriodide, penicillin G benzathine, and penicillin G procaine all being classed as Highly Important Antibiotics. This triggered the reassessment of all 69 individual trade name veterinary medicine products, as well as the MRLs associated with each compound.
For some products, the post-reassessment changes involve minor adjustments to label information and the addition of the mandatory classification and prudent use statements.
For others, however, target species, diseases, dose rates, dosing intervals or withholding periods required an update to bring this information in line with current practice and AMR risk management. What, and how much, change is required depends on each product’s individual risk profile, the age of the product, and the time since its last review and update.
The most common change actioned for the penicillin products was an increase in dose rate. Available data and recent literature evaluating the efficacy and AMR risk place most best-practice use of penicillins at a dose rate between 15 mg_kg and 30 mg_kg or higher, with narrower dose rates and ranges dependent on the specifics of product formulation, penicillin identity, and target species. For some older products, approved dose rates were as low as 6 mg/kg, requiring many products to increase in the minimum dose rate or range previously approved for their products. These changes to the approved dose rates, and in some cases a reconsideration of historic data and information, has led to meat and milk withholding period changes for some products.
Once the reassessment of a particular product has been finalised, the new dose rates, withholding period, and other label information is included on a new approved product label that is published to the ACVM Register . But because these products are actively used in veterinary clinics and on farm throughout the reassessment process, there will be products in circulation and on farm that are still labelled with the ‘old’ label.
When a product is reassessed, one of the aims of the reassessment is to determine whether the label changes need to be actioned immediately or can be phased in over time. If there is a critical risk to be managed that requires immediate label changes, NZFS will require product registrants to recall existing stock in the market and relabel stock under their control, as well as notify veterinarians, owners, and farmers of the change to make sure the risk is managed. A critical risk can be related to inefficacy, animal safety, food safety, trade, or other risks that require immediate attention and action.
For all other situations, NZFS will usually allow registrants to keep existing products in the market with the ‘old’ label while advising vets, owners, and farmers of the change to come and directing them to the ACVM Register to review the ‘new’ label. This transition period is allowed to ease potential problems with product availability and the costs associated with recalling and relabelling with the understanding that any new product to be manufactured, imported, or sold will be sent to market with the new label in place.
This leads to an important question: are veterinarians expected to authorise penicillins based on the use pattern (dose rates and withholding periods) on the ‘old’ label in the clinic, or the use pattern on the ‘new’ label on the ACVM Register?
First, a word on withholding periods. The legal requirement when using any veterinary medicine in a food-producing animal is to ensure the resulting residues will conform to the MRL, not conformance to the withholding period itself. The withholding period on the product label is evidence-based advice that has been confirmed to ensure MRL conformance when the veterinarian authorises used according to the approved dose rate and treatment duration.
Where they have been changed, the increased penicillin dose rates have been driven by the most up to date information available that demonstrates the lower historic on-label dose rates can no longer be relied on to effectively treat some infections. While using the ‘old’ dose rate means that applying the ‘old’ withholding periods can be expected to ensure MRL compliance, it also means there is a potential that treatment may not effectively treat the infection. The vet must therefore decide based on the individual animal’s diagnosis, potential AMR risk, and other clinical factors whether to use the ‘new’ dose rates based on current evidence or continue with the ‘old’ dose rate.
Where veterinarians have in the past used these products off label at a higher dose rate than the ‘old’ label indicated it is expected they will have automatically applied a longer withhold period in order to ensure MRL compliance.
The following advice therefore applies:
- If a veterinarian authorises use according to the ‘old’ use pattern where the dose rate and/or treatment duration has now changed, the ‘old’ withholding period can apply though the veterinarian must be aware of and manage the potential risk of inefficacy at that dose. (e.g. In a situation where a farm has an existing RVM Authorisation this can be updated at the next planned Farm / RVM Consultation).
- If a veterinarian authorises use according to the ‘new’ use pattern, the ‘new’ withholding period should apply as it has been assessed to ensure MRL conformance when the updated use pattern is used.
- If a veterinarian is authorising according to the updated use pattern for a product that still bears the ‘old’ label, the veterinarian’s authorisation is the source of the instructions (dose rate, duration, and withholding period) to be followed, this could effectively be considered during this transition phase as still being ‘on label’.
- Where a vet has already issued their authorisation and wishes to update it to the ‘new’ use pattern and withholding periods, they can revoke the existing authorisation and replace it with a new one even if the packaging still bears the ‘old’ label.
- If a veterinarian authorises use according to a use pattern that does not match the ‘old’ or ‘new’ label, they will be authorising off-label use of that product and should be assigning a withholding period they have assessed will be sufficient to ensure MRL compliance.
- Once new product is available with the ‘new’ labelling, it is expected that veterinarians will ensure any new authorisations have use patterns and withholding patterns that comply with the new label requirements to better manage efficacy and AMR risk.