The withdrawal period; a guideline

For all veterinary medicinal products intended for food producing animals, a withdrawal period has been determined. This is however an advice rather than a period set in stone. In this article we will explain what a withdrawal period is and which factors can be of influence. Additionally, we will provide two examples to demonstrate the importance of a good understanding of this subject in everyday practice.

What is a withdrawal period?

The withdrawal period is the time period required after cessation of treatment to assure that drug residues in animal products are below the Maximum Residue Limit (MRL).

The advised withdrawal period is based on the use of veterinary medicines according to the product registration and was determined in healthy animals. The advised product withdrawal period is the minimal withdrawal period that should be applied. Veterinarians prescribing the treatment can advise to prolong the withdrawal period when they deem this necessary.

Which factors can influence the withdrawal period?

There are several factors that can influence the withdrawal period.

Diseases

Several diseases can result in a slower elimination rate of medicinal products. Primarily liver and kidney disease are known risk factors; they might delay elimination and therefore prolong the withdrawal period.

Drug combinations

The pharmacokinetics of a veterinary medicinal product can be influenced by other medicines which are administered before, together with or after the veterinary medicinal product issued. Prolongation of the elimination period occurs in particular when you combine veterinary medicinal products that are excreted via the same elimination route.

Treatment repetition

When the treatment is repeated immediately or shortly after the first treatment period, this may result in accumulation of the active substance in the body.

Acidification of the drinking water

Acidification of the drinking water is sometimes used to increase the solubility and stability of veterinary medicinal products. It can however also increase the biological bioavailability of the drugs and therefore prolong the withdrawal period. Only when veterinary medicinal products already contain citric acid or another acid as part of their formulation, the marketing authorisation holder has taken this into account when determining the advised withdrawal period.

Contamination of the drinking water system

Medicinal residues can stick to contaminants in the drinking water system and when acids are then used post treatment, these residues can re-dissolve. This means that the animals are exposed to the active substances again after the treatment is supposed to have been ceased already.

Not completely emptying the bulk tanks

When bulk tanks are used it is important to empty the tanks completely before the water tap is opened again. This will prevent dilution of the product with clean drinking water and thus the exposure of animals for prolonged periods of time.

Cascade and off label use

When veterinary medicinal products applied via the cascade are used to treat other species than those mentioned in the registration, it is mandatory to maintain a withdrawal period of at least 7 days for milk and eggs and 28 days for meat. When veterinary medicinal products are applied for a different indication, but for a species mentioned in the registration, it is officially not needed to adjust the withdrawal period. A different off label indication can however influence the withdrawal period by altering/influencing the rate of elimination. In such cases it is advised to prolong the advised withdrawal period after all.

Veterinary medicinal products should be administered according to the product characteristics. When it is however needed to administer a veterinary medicinal product in a different dosage or via a different method in the context of Good Veterinary Practice, it can be needed to derogate from the registration. In these cases it can be needed to adjust the withdrawal period too. This is preferably done based upon trials in which the pharmacokinetics of the medicinal product in that dosage and for that route of administration are determined in the animal species treated.

Two examples

Below you can find two examples to demonstrate the importance of withdrawal periods in everyday life.

Acidification of the drinking water

Acids are often used to improve the solubility and stability of veterinary medicinal products, such as doxycycline containing products. Dopharma’s Doxylin® 50% WSP already contains citric acid and under normal circumstances it is not needed to add extra citric acid. However, when other doxycycline products are used, it is often necessary to use an acid as water conditioner. Some acids are also used on their own, such as Vitamin C.

The addition of acids to the pre-solution as well as the separate use of acids can influence the withdrawal period. When acids are used together with antibiotics, the biological bioavailability of the antibiotics administered can be increased. When acids are used after completion of the antibiotic treatment, they can re-dissolve residues of veterinary medicinal products that are present in the drinking water system. Animals will then be exposed again. Depending on the concentration of the residues in the drinking water and the period until slaughter this can result in residues.

Benzylpenicillins and the Delvotest

When the Delvotest is used to determine the presence of benzylpenicillin in milk, residues are sometimes found whilst the withdrawal period has been respected. False positive testing results can be the explanation for this. Please find below three factors that can cause false positive results when using the Delvotest.

The detection level

The MRL of benzylpenicillin in milk is 4 μg/kg (4 ppb). The detection level of the Delvotest is however much lower than this. The Delvotest detection level for benzylpenicillin appears to be roughly 1 ppb, which is only one fourth of the MRL.

Contamination
Research at Dopharma’s laboratory showed that the Delvotest showed positive results on some samples which did not contain any antimicrobials. These false positives were the result of contamination. Despite all precautions (use of new materials, clean working environment, etc.) contamination resulted in false positive results. This even occurred under laboratory conditions. It can therefore be concluded that the Delvotest is very sensitive to contamination.

Natural inhibitors

The product description of the Delvotest mentions that milk can contain some natural inhibitors such as lactoferrin or lysozymes. These molecules can also result in false positive test results.

The Delvotest does not seem to be sensitive to the presence of disinfectants in the milk. One disinfectant that can be used to disinfect the udder after milking has been studied in our laboratory: 4XLA.

The Delvotest is a non-specific, qualitative test and a correct and reproducible quantification of benzylpenicillin in milk to determine if this exceeds the MRL is therefore not possible. The Delvotest appeared to be extremely sensitive to contamination and all precautions should be taken to avoid contamination when using this test.

When the result of the Delvotest is positive it is advised to do a confirmatory re-test. The milk can be heated (a few minutes at 80˚C) to neutralise some contaminants. The milk that has to be tested can also be diluted with milk from the tank (in a ratio of 1:3) to decrease the sensitivity of the test to the level of the MRL.

The Delvotest appears to be the most commonly used test, but there are several other similar tests on the market. Dopharma has not performed any laboratory tests with those tests. However, looking at the specifications of several other tests, the same problems are to be expected. The sensitivity of most tests is at or below the MRL which means that you can expect positive test results whilst the level of the antibiotic(s) examined is still below the MRL.

References

  • Huyghebaert, A. (2006), Advies 42-2006 (Wetenschappelijk Comité van het Federaal Agentschap voor de Veiligheid van de Voedselketen, Brussel).
  • Dutch legislation: Wet dieren, Besluit diergeneesmiddelen en Regeling diergeneesmiddelen.
  • European legislation: Directive 2001/82 and Regulation EEG nr 37/2010.
  • Reference picture: Different kinds of meat, eggs and two bottles of milk — Image by © Imagemore Co., Ltd./Corbis

Gastric ulcers in horses; ECEIM consensus statement

In 2015 the “European College of Equine Internal Medicine (ECEIM)” published the new “consensus statement” regarding gastric ulcers in adult horses.

This “consensus statement” is written by B.W. Sykes, M. Hewetson, R.J. Hepburn, N. Luthersson and Y. Tamzali. It was published in the “Journal of Veterinary Internal Medicine” (29: 1288-1299) and available as “open access” article. Below you can find a summary.

Terminology

“Equine Gastric Ulcer Syndrome” (EGUS) is the general term used for all erosive and ulcerative diseases of the horse stomach. Based upon the affected regions in the stomach, two categories can be distinguished: “Equine Squamous Gastric Disease” (ESGD) and “Equine Glandular Gastric Disease” (EGGD).

ESGD is further divided into primary ESGD and secondary ESGD. Primary ESGD affects horses with normal gastric emptying, while secondary ESGD occurs in horses with delayed gastric emptying due to underlying pathology such as pyloric stenosis. EGGD is specified further based upon the anatomical location and the appearance of the lesion.

Prevalence

The prevalence of gastric ulcers varies with breed, use and level of training. There is also a difference in prevalence between ESGD and EGGD. ESGD has the highest prevalence in thoroughbred racehorses. The prevalence of EGGD is less well understood. Most lesions of EGGD are found in the antrum pyloricum.

Epidemiology

Several studies show that there is a correlation between the presence of ulcers and the breed. The influence of age and gender is inconsistent which suggests that other factors, such as intensity and duration of training, are more important. Other factors, of which it has been described that they are a possible risk factor, are described below.

  • Grazing is shown to decrease the risk of gastric ulcers, but supporting evidence is contradictory.
  • Unlimited/frequent access to roughage is considered to reduce the risk on EGUS, but supporting evidence is not available. Besides, findings suggest that the impact of roughage without reduction of other risk factors might be less than expected. The occurrence of ESGD is more likely when straw is the only form of roughage provided. This suggests that also the type of roughage influences the prevalence of ESGD.
  • An increased interval (> 6 hours) between roughage meals increases the risk on ESGD, when compared to more frequent (< 6 hours) roughage supply.
  • An increased starch intake is consistently associated with an increased risk on ESGD in animals trained at different levels.
  • Intermittent water access increases the risk on EGUS.
  • Fasting is an often described risk factor for ESGD; intermittent fasting causes ESGD and increases its severity.

More large-scale research is needed to understand the epidemiology behind EGUS, especially behind EGGD.

Clinical symptoms

Stomach ulcers in adult horses are associated with a broad range of clinical symptoms: a decrease in appetite, slower eating, poor body condition score or weight loss, chronic diarrhoea, a bad coat condition, teeth grinding, behavioural changes, acute or recurring colic and bad performance. There is however no strong epidemiological evidence for the correlation between the presence of these clinical symptoms and the occurrence of gastric ulcers.

A broad range of clinical symptoms can occur in individual EGUS cases. On population level the different gradations of a decreased appetite and a poor body condition score are most common. Behavioural changes, including stereotypes, are inconsequent, but not unusual. EGUS can also contribute to bad performance, but considering the number of factors that can contribute to this, other factors should also be taken into account. Differences in clinical symptoms occurring with ESGD or EGGD are currently not known. Despite the large variety of possible symptoms, all these symptoms are badly correlated to the presence of EGUS. Diagnosing EGUS based on the presence of “typical clinical symptoms” should thus be avoided.

Diagnosis

Gastroscopy remains the only reliable ante-mortem method to determine accurately if a horse has gastric ulcers. The entire stomach, including pylorus and proximal duodenum, should be included because lesions in one of these regions are easily missed.

There is no correlation between the presence of ESGD and EGGD. The presence of one cannot serve as an indication for the presence or absence of the other.

There are currently no reliable haematological or biochemical markers that can be helpful in diagnosing gastric ulcers.

Ulcer grading

The 0 – 4 “Equine Gastric Ulcer Council” system is recommended as a standard scoring system for ESGD.

Due to a lack of data to support the validity of the hierarchical grading system for EGGD, the use of this type of grading system is not recommended. For EGGD it is recommended to describe the lesion based on the presence or absence, anatomical location, distribution and appearance.

The biggest challenge is to determine the clinical relevance of the individual lesions found. There is little evidence that the presence and grading of the lesions correlates with the presence of clinical symptoms. The clinician should try to interpret the results of the endoscopy in relation to the complete clinical picture, history, etc.

Pathophysiology

ESGD is caused by an increased exposure of the squamous mucosa to acids. The relation between exposure of the squamous mucosa to gastric content and fasting and training has been described clearly. During gaits faster than a walk, the acid gastric content will be pushed up to the squamous mucosa by the increased intra-abdominal pressure.

The pathophysiology of EGGD, on the contrary, is poorly understood. The glandular mucosa differs fundamentally from the squamous mucosa by the fact that it is exposed to gastric acid in physiological conditions. For this reason it is thought that EGGD is caused by failure of the normal defence mechanisms that usually protects the mucosa against the acid gastric content. There is still no evidence that bacteria are the direct cause of EGGD.

NSAIDs have the potential to induce EGGD in individual animals, but on population level they do not contribute significantly to the prevalence of EGGD. The ulcerogenic capacity of some NSAIDs has been shown when dosages were administered that are 50% higher than the recommended dosages. When the recommended dosages are administered, phenylbutazone and suxibuzone however do not induce gastric ulcers.

It is most likely that a combination of different factors contributes to the development of EGGD in horses.

maagzweren-bij-paarden

Treatment and prevention

The therapy of both ESGD and EGGD focuses on adequate suppression of acid production. The proton pomp inhibitor omeprazole is the first choice treatment. Omeprazole is superior to ranitidine.

The duration of acid suppression needed to heal ESGD and EGGD has not yet been described. Clinical studies suggest that a period of 12 hours during which the acid production is suppressed may be sufficient for the treatment of ESGD. GastroGard gives a consistent healing rate of 70-77% when administered at the registered dose of 4 mg/kg per os, once daily, during 28 days. A lower dosage and/or shorter period of administration can however be taken into consideration based on the evidence available.

The success rate of EGGD treatment is only 25%. The reason for this poor response is unknown. A longer duration of treatment may be indicated in the case of EGGD. Bacteria might also play a part. In the absence of evidence to support this theory and in the context of responsible antibiotic use, it is however not recommended to use antimicrobials in the routine treatment of EGGD.

Considering the role of mucosal defence mechanisms failing in the pathogenesis of EGGD, protecting the mucosa as part of the therapy seems legit. Sucralfate is best studied for this indication. The combination of omeprazole (4 mg/kg PO once daily) and sucralfate (12 mg/kg PO twice daily) improves the success rate of EGGD when compared to omeprazole only.

The pharmacological approach of the prevention of ESGD is comparable to the treatment. Omeprazole is used as prevention in a dosage of 1 mg/kg per os, once daily. The efficacy of omeprazole as prophylaxis for EGGD is unclear, but so far there is no difference in the prevention strategy of both.

Nutraceuticals are attractive because of the ease of use and their availability. Pectine-lecithine complexes have been shown to increase the total mucus concentration in gastric juice. Antacids seem to provide some symptomatic relief, but their effect is short-lived.

There is no strong evidence to support a specific nutritional advice. There is only little evidence for the role of the diet in the occurrence of EGGD and therefore the recommendations are primarily based on the well-known risk factors of ESGD. Continuous access to a good quality grass pasture is considered ideal. Unlimited or frequent (4-6 times daily) access to hay (at least 1.5 kg (DM)/100 kg bodyweight/day) can be an appropriate alternative. Straw should not be the only type of roughage, but it can be included safely in the diet with a maximum of 0.25 kg (DM)/100 kg bodyweight. Concentrates should be used as cautiously as possible. Sweet feed should be avoided. The diet should not contain more than 2 gram starch per kg bodyweight per day, or no more than 1 gram starch per kg bodyweight per meal. The interval between feeding concentrates should be at least 6 hours. Maize oil could help to decrease the risk of EGGD development. Water should always be available. When pastes with electrolytes are given orally, they should be diluted in water first, or mixed with the feed.

EMA advice on the withdrawal period of lidocaine in food producing animals

The EMA recently published a report on the withdrawal period of lidocaine for milk. In general, when veterinary medicinal products are used through the cascade, the minimal withdrawal period for milk is 7 days. Based on the EMA advice, the withdrawal period for lidocaine should be extended to 15 days.

advies-van-de-ema-over-de-te-hanteren-wachttermijn-bij-het-gebruik-van-lidocaine-bij-landbouwhuisdieren

The cascade

In the Netherlands lidocaine is only registered for use in dogs and cats. Lidocaine can only be used in food producing animals when the cascade is applicable. Lidocaine is mentioned on the list of active ingredients belonging to regulation (EU) no 37/2010. This is a prerequisite for the application of the cascade in food-producing animals. Other conditions are the need for treatment, particularly to avoid suffering in the animals, and the lack of a registered veterinary medicinal product for the species and indication concerned.

For equines, no MRL (Maximum Residue Level) is needed as long as the product is used for local or regional anaesthesia. For the other food producing species no MRL has been determined. When using a product through the cascade, the minimal withdrawal period should be at least as long as the withdrawal period mentioned in the SPC for the species concerned. When there is no withdrawal period mentioned for the species concerned, the withdrawal period must be at least 7 days for eggs and milk and 28 days for meat.

New insights

The MEB (Medicines Evaluation Board) in the Netherlands has requested the EMA in December 2012 to provide a scientific opinion on the usage of lidocaine in food producing animals. This request was made as a result of recent research studies in which it was shown that 2,6-xylidin is one of the most important metabolites of lidocaine in cattle and pigs. This metabolite is considered carcinogenic and genotoxic.

Besides the possible effects of exposure to the metabolite 2,6-xylidin, the MEB was also concerned about exposure to the active ingredient lidocaine. Humans are also capable of producing this carcinogenic and genotoxic metabolite of lidocaine.

What did the EMA think?

The CVMP (Committee for Medicinal Products for Veterinary Use) of the EMA concluded that 2,6-xylidin has indeed got a potential genotoxic effect, but that the conclusions drawn in different studies differ largely. A carcinogenic effect was however clearly shown according to the CVMP. Changes in the DNA could be a possible mode of action for this carcinogenic effect.

The CVMP recognised the potential risk of exposing people to lidocaine and therefore the possible formation of potentially carcinogenic and genotoxic metabolites. But it was also pointed out that, on the other hand, lidocaine is also registered for human use as a short-term oral or topical treatment. However, they did comment that the benefit-risk assessment done for the approval of lidocaine as human medicinal product also factors in the positive effects of treatment which do not count when consuming residues through animal products.

Horses

The MEB mentioned that when it was decided that no MRL was needed for equines, it was taken into consideration that the metabolite 2,6-xylidin is not produced in horses. The CVMP contradicts this and states that this metabolite is produced in horses, but to a lesser extent than in other animal species.

The CVMP did conclude that with the available information, there is no need to change the MRL for equines as mentioned in Regulation EU No 37/2010.

Cattle

Previously, it was not known if cattle were able to produce the metabolite 2,6-xylidin. Based on this it was decided not to allow a MRL for use in cattle.

Recent research has shown that 2,6-xylidin is the most important metabolite that is formed in hepatocytes and microsomes extracted from livers of cattle and pigs when exposed to lidocaine. This was an in vitro study. The metabolite was however also found in the urine of cattle and pigs after the intravenous administration of lidocaine.

Hoogendoorn et al have recently published a study in which the pharmacokinetics of lidocaine and its metabolite 2,6-xylidin were described in 8 dairy cows. In these animals lidocaine with adrenaline was injected subcutaneously and intramuscularly as is done for a caesarean. Five times 30 ml was used. This study group showed that both lidocaine and 2,6-xylidin can be found in plasma, milk, muscles and kidneys.

The CVMP has calculated values below which, in theory, there should be no risk for public health. This had to be done because there is no MRL available. Based on the studies done by Hoogendoorn et al a termination half-life of 17.7 hours was used. When a two-compartment model with a rapid elimination phase is used, the advised withdrawal period for meat would have to be at least 11 days. When the same method is used, the minimal withdrawal period for milk should be 15 days.

Based on these studies and the calculations made by the CVMP, the EMA concluded that a withdrawal period of 28 days for meat is sufficient. It was however advised to extend the withdrawal period for milk to 15 days.

Pigs

When it was determined that no MRL was required for equines, there was also no information available about the metabolism in pigs. Recent reports do not include information about the metabolism of lidocaine in pigs either. The metabolism in pigs is however similar to that of cattle. It can thus be concluded that the withdrawal period of 28 days for meat is also sufficient to ensure public health. For pigs, it was also taken into account that lidocaine is primarily used during castration, which is usually done within the first week of life, resulting in a long period between the administration of lidocaine and slaughter.

References

  1. Thuesen, L.R., and Friis, C. (2012) In vitro metabolism of lidocaine in pig, cattle and rat. Poster presentation EAVPT Congress 2012, The Netherlands.
  2. F. Verheijen, Medicines Evaluation Board Agency (2012) Request for a scientific opinion.
  3. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (2015) CVMP assessment report regarding the request for an opinion under Article 30(3) or Regulation (EC) No 726/2004.
  4. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (2015) Opinion of the Committee for Medicinal Products for Veterinary Use regarding a request pursuant to Article 30(3) of Regulation (EC) No 726/2004.
  5. European Medicines Agency (EMA), Committee for Medicinal Products for Veterinary Use (CVMP) (1999) Lidocaine Summary Report.

Clostridium assaults the intestines of poultry

In many flocks of laying hens the bacteria Clostridium perfringens causes a large amount of damage to the intestines. Other problems, like coccidiosis or worm infestations, facilitate the problems caused by clostridium.

“In one out of every four post mortems performed on chickens intestinal problems were the underlying reason for referral to the GD”, knows Noami de Bruijn, poultry vet and pathologist at the GD Animal Health Service. “And in one out of every three post mortems done, we actually did find enteritis”, she explained at the Poultry Relation Days held in Barneveld.

Bacterium

Acute intestinal problems are often caused by Clostridium perfringens. This bacterium is a natural inhabitant of the intestines and is always present. It is not exactly known yet why the bacterium sometimes suddenly turns pathogenic. “In practice, preventing stress is one of the most important preventative management measures that can be taken to minimize intestinal damage”, says poultry vet Pim Eshuis. “And that already starts in the rearing period”.

Deworming

Go and visit the rearer to discuss deworming and minimising the transition to the laying farm, advised Eshuis. “Give the hens a lot of attention, especially at the start of each new round”.

Research done at the GD Animal Health Services shows that in chickens with intestinal problems caused by Clostridium perfringens, coccidiosis often plays a part as well.`

Source: De Nieuwe Oogst.

Responsible use of veterinary medicines

Lately there has been a broad societal interest in the use of veterinary medicines and specifically the use of antimicrobials. The use of antibiotics and the need to reduce their usage are in the news regularly. Also the induction of resistance and the occurrence of zoonosis are discussed often.

Mitigate risks

Every time micro-organisms are exposed to antibiotics there is a certain risk for the development of resistance. Prolonged exposure, especially in low doses, can result in the selection of resistant bacteria. Theses resistant bacteria can be transferred to humans and thus pose a threat to public health.

Applying the advised withdrawal period is important. Residues of veterinary medicines in meat, milk or eggs can pose a potential threat to public health. To minimize the risks the usage of veterinary medicines could pose to public health, it is essential to increase awareness of the risks among veterinarians and farmers and to encourage preventative measures to avoid diseases and infections. Personal protection is an easy way to reduce direct contact with antimicrobials and the possible risks. Dopharma therefore has dust masks and latex gloves in their assortment.

Responsibility - street sign illustration in front of blue sky with clouds.

Recommendations

The Dutch society for Veterinary medicine and the FIDIN (board for manufacturers and distributors of veterinary medicines) have developed the following recommendations on the responsible use of veterinary medicines:

  1. A good treatment starts with the correct diagnosis: determine which causative agent is responsible for the disease and focus your treatment on this micro-organism specifically.
  2. Use registered veterinary medicines: check the registration number, read the label and, if applicable, the leaflet. Consult your veterinarian regarding the right treatment.
  3. Use the recommended dosage.
  4. Do not change the method of administration (e.g. injection, intramammary treatment, treatment via drinking water or feed or topical application).
  5. Complete the treatment, even though the animals seem to already have recovered. This is important to prevent re-occurrence of the disease and development of resistance.
  6. Do not combine veterinary medicines unless this is advised by your veterinarian.
  7. Think about your own safety.
  8. Avoid exceedance of the maximum residue levels (MRLs) in animal (by-) products.
  9. Document the important details of the veterinary medicines used.
  10. Evaluate the treatment on a regular basis with your veterinarian. Always report adverse events.
  11. Read the storage conditions as mentioned on the package and always apply them.