Veterinary pharmacovigilance. Part 6. Predictability of adverse reactions in animals from laboratory toxicology studies

Toxicological studies are conducted on constituents of veterinary medicinal products for a number of reasons. Aside from being a requirement of legislation, they are carried out for predictive purposes in the assessment of user safety or for the determination of consumer safety, for example, in the elaboration of maximum residue limits or tolerances. Alternatively, the results of toxicology studies may be available as they have been generated for registration of the drug for human medicinal purposes. This paper examines if the results of such studies have any predictive value for adverse reactions, which might occur during clinical use in animals. A number of adverse reactions, notably the Type A (toxicology or pharmacology dependent) should be predictable from these laboratory studies. However, as with human pharmaceutical products, they have less utility in predicting Type-B reactions (idiosyncratic in nature).     

Suspected adverse reactions to medicines during 1989

There was an increase in reports of suspected adverse reactions to veterinary medicines in 1989 with 329 reports (compared with 206 in 1988), from veterinary surgeons, farmers and the public, comments the Veterinary Medicines Directorate (VMD). Suspected adverse reactions to clostridial/pasteurella vaccines in sheep were a dominant feature and important experience was gained both in terms of liaison with the farming press, and in handling large scale incidents involving PML products. The general trend towards increased reporting of adverse drug effects continues. The UK is the only EC member state to have a PML system and the VMD is looking with some urgency at ways of ensuring the more representative reporting of all categories of drug. Substantial liaison with the veterinary pharmaceutical industry occurred during the year and 204 product reports were requested from companies.     

Adverse reactions to veterinary drugs reported in Sweden during 1991–1995

The present article gives a summary of suspected adverse reactions reported by Swedish veterinarians during the period 1991–1995. The summary shows that severe adverse drug-reactions sometimes occur in Swedish veterinary practice. In horses, several cases of acute reactions in animals treated with procaine benzylpenicillin were reported and seven horses died within a few minutes after intramuscular injections of the drug. In cattle and swine most reports referred to the use of antimicrobial agents. In dogs reactions to vaccines were the most frequently reported adverse effects. The reactions were, however, usually rather mild. In dogs there were also several reports of severe reactions related to treatments with non-steroid anti-inflammatory drugs (NSAID) and α₂-receptor agonists. Amongst the reports six deaths were observed for each of these groups of drugs. In cats, as in dogs, adverse effects to vaccines were the most frequently reported reactions.     

Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2003 - February 2004)

The Veterinary Pharmacovigilance and Medicines Information Centre is responsible for the monitoring of veterinary adverse drug reactions in South Africa. An overview of reports of suspected adverse drug reactions received by the centre during the period March 2003 to February 2004 is given. A total of 20 reports was received. This had declined from the previous year. The general apathy with regards to the reporting of adverse drug reaction has prompted the Medicines Control Council to make reporting a legal obligation on all members of the veterinary and medical profession as from August 2004. The majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most of the products implicated were Stock Remedies. Veterinarians predominantly administered these products. Only two reports were received from a veterinary pharmaceutical company.     

Drug hypersensitivity reactions targeting the skin in dogs and cats

Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.     

Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2002 - February 2003)

The Veterinary Pharmacovigilance and Medicines Information Centre is responsible for the monitoring of veterinary adverse drug reactions in South Africa. An overview of reports of suspected adverse drug reactions received by the centre during the period March 2002 to February 2003 is given. In total, 40 reports were received. This had declined from the previous year. Most reports involved suspected adverse reactions that occurred in dogs and cats. Most of the products implicated were Stock Remedies. The animal owner predominantly administered these products. Only 1 report was received from a veterinary pharmaceutical company. Increasing numbers of reports are being received from veterinarians.     

Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2010

In 2010, we observed again an increase in the number of declarations reported to the vigilance system for veterinary medicinal products up to a total of 160. The species and drug classes reported remained the same as in previous years: the majority of adverse drug reactions (ADRs) concerned either dogs or cats and the most frequently involved drugs were either antiparasitic products or antiinfectives. Adverse reactions following reconversions and 8 cases of suspected allergic reactions following the use of amoxicillin-clavulanic acid combinations in dogs were reported. Additional enquiries were processed by the Swiss Toxicological Information Centre and transmitted to Swiss medic. 11 of these reported accidental ingestions of flavoured tablets in overdose by dogs and some cats. The vaccino vigilance program received 179 declarations following immunization against blue tongue disease as well as 82 declarations following the application of other vaccines. The vigilance system increases the chance to identify rare reactions or interactions and thereby contributes to the security of veterinary medicinal products.     

Veterinary pharmacovigilance. Part 3. Adverse effects of veterinary medicinal products in animals and on the environment

Like humans, animals may experience adverse effects when treated with medicinal products. These effects may be related to the pharmacological or toxicological properties of the substances used or they may arise because of hypersensitivity. Veterinary medicinal products may also possess the ability to harm the environment. This paper reviews the potential of veterinary medicinal products to cause adverse effects in animals and on the environment.     

Principles of transfusion medicine in small animals.

The purpose of this review was to provide the reader with an updated overview of small animal transfusion medicine, and an approach to integrating it into private practice, based on a review of the veterinary and human literature spanning the last 3 decades. Electronic, online databases that were searched included CAB International and Medline; multiple keywords or subject headings were searched that were appropriate to each of the sections reviewed: canine and feline blood groups, blood-typing and crossmatching, donors, blood collection, storage, blood components, blood transfusion, blood component therapy, blood substitutes, and adverse reactions. The safe use of blood component therapy requires knowledge of blood groups and antibody prevalence, and knowledge of the means to minimize the risk of adverse reactions by including the use of proper donors and screening assays that facilitate detection of serological incompatibility. The 2 assays available to the practitioner are crossmatching, which is readily done in-house, and blood typing. Blood typing is available in the form of a commercial testing kit, through use of purchased reagents, or via a request to an external laboratory. The risk of potentially fatal adverse reactions is higher in cats than in dogs. The decision to transfuse and the type of product to administer depend on several factors, such as the type of anemia and the size of the animal. In conclusion, transfusion medicine has become more feasible in small animal practice, with improved access to blood products through either on-site donors, the purchase of blood bank products, external donor programs, or the availability of blood component substitutes.     

Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2004 - February 2006)

The Veterinary Pharmacovigilance and Medicines Information Centre is responsible for the monitoring of veterinary adverse drug reactions in South Africa. An overview of reports of suspected adverse drug reactions received by the centre during the period March 2004 to February 2006 is presented. A total of 21 reports was received in the 2-year period, continuing the decline in the number of reports to a lower figure than in any previous year. This is surprising considering the legal obligation of the veterinary professionals to report all adverse drug reactions. Once again the majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most of the products implicated were stock remedies. Veterinarians predominantly administered these products.     

Global veterinary leadership.

The public needs no reminder that deadly infectious diseases such as FMD could emerge in any country at any moment, or that national food security could be compromised by Salmonella or Listeria infections. Protections against these risks include the knowledge that appropriate and equivalent veterinary education will enable detection and characterization of emerging disease agents, as well as an appropriate response, wherever they occur. Global veterinary leadership is needed to reduce the global threat of infectious diseases of major food animal and public health importance. We believe that the co-curriculum is an excellent way to prepare and train veterinarians and future leaders who understand and can deal with global issues. The key to the success of the program is the veterinarian's understanding that there is a cultural basis to the practice of veterinary medicine in any country. The result will be a cadre of veterinarians, faculty, and other professionals who are better able (language and culture) to understand the effects of change brought about by free trade and the importance of interdisciplinary and institutional relationships to deal effectively with national and regional issues of food safety and security. New global veterinary leadership programs will build on interests, experience, ideas, and ambitions. A college that wishes to take advantage of this diversity must offer opportunities that interest veterinarians throughout their careers and that preferably connect academic study with intensive experiential training in another country. At its best, the global veterinary leadership program would include a partnership between veterinarians and several international learning centers, a responsiveness to the identified international outreach needs of the profession, and attention to critical thinking and reflection. The global veterinary leadership program we have described is intended to be a set of ideas meant to promote collaboration, coalitions, and discussion among veterinarians and veterinary educators who may be intrigued by the concept. The impact of the program can be summarized as follows: Outreach Programs: The global veterinary leadership program will establish new partnerships between veterinarians and veterinary college faculty as they supervise the international internships and see a relationship between their goals and the value of food safety to this country. Strategic Opportunity: The program will build on the critical role that US veterinarians and veterinary colleges already play in strengthening the safety of free trade in this hemisphere. Diversity in an Age of Specialization: The program will combine a global orientation, language ability, and access to comprehensive, research- and economic-related work/study opportunities to expose veterinarians to the expanding world market for veterinary expertise. New Linkages Through Corporate Partners: Through the success and high visibility of current research and education programs, most veterinary colleges are well positioned to engage industry, government, and university leaders in ways to use the proposed program to increase the flow of new ideas and talent into the world food enterprise. International Funding: A new partnership among veterinarians, industry, government, and university leaders can coordinate strong multilateral requests for funding from national and international sources. An Interdisciplinary Strategy that Benefits Veterinary Medicine: The program will combine the diverse veterinary research and education system with our strong national and international network of collaborators to provide globally competent veterinarians who will be needed for the corporate and public opportunities of the future.     

Relationships between young stallions’ temperament and their behavioral reactions during standardized veterinary examinations

Horse handling and veterinary examination can induce hazardous stress reactions. Such reactions occur especially in young and less-trained horses, particularly stallions, and make their handling a risk for breeders, grooms, and medical staff. Moreover, these stressful situations will affect the animal’s health and welfare. Because stress reactivity is thought to be partly determined by genetic factors, scientists, veterinarians, and breeders are likely to be interested in adding temperament assessments to stallion selection schemes, as it is already done in some countries. This study assesses young stallions’ temperament and its comparison with their stress reactions during a standardized veterinary examination for studbook admission. The assessment consists of a general examination, a lameness examination including flexion tests, an endoscopy of the upper airway, and a standardized radiological examination. During the years 2008 and 2009, 93 stallions were evaluated. Stallions were observed from the moment they were unloaded from the trailer at the clinic until the end of veterinary examinations. In addition to the behavioral observations made by the experimenter, each staff member in charge of the examination filled in a short questionnaire about the horse’s temperament and the “easiness of manipulation” for the performed examinations. Breeders were asked to complete a longer questionnaire about their horse’s temperament. The assessments of “aggressiveness,” “sociability,” and “learning level” temperament traits were the most consistent, as shown by the significant Spearman correlations between judges’ assessments. Undesirable behaviors during veterinary examinations leading to handling difficulties were associated with a low “easiness of manipulation” score assessed by the clinical staff. These low “easiness of manipulation” scores were positively correlated to temperament traits such as “anxiousness” and “aggressiveness” and negatively correlated to others such as “sociability” or “learning level.” Temperament assessment and behavioral observations can therefore be used to anticipate behaviors that make a horse difficult to handle during veterinary examinations. Thus, it may be important to include temperament assessment as a feature in the selection of breeding stallions—as already practiced for some breeds in some countries. Such evaluations may promote the welfare of horses and ease of handling as well as safety for the handler.     

Systemic adverse reactions in young Simmental calves following administration of a combination vaccine.

Combination vaccines containing viral and bacterial antigens are commonly used in veterinary practice and have been associated with adverse reactions. A group of young Simmental calves developed fever and depression following administration of a mixed vaccine, and 1 died with pulmonary edema, suggesting that endotoxins or other bacterial components may interact synergistically with some adjuvants to cause an enhanced pathologic inflammatory response in some individuals.     

Reported adverse reactions due to veterinary drugs in 2006

We received 190 reports of suspected adverse events (SARs) following the use of veterinary drugs for the year 2006: 118 declarations for veterinary drugs and 72 declarations following the application of immunolgical medicinal products. Most of the 118 declarations relate to the use of antiparasitic drugs (48%) and every second declaration to drug use in dogs. Other drug classes concerned were, in decreasing order, antiinfectives (20%) and drugs used off-label (12%; other target species or other indication). For the vaccines, most of the reactions occurred in dogs (62%) followed by horses (11%) and cattle (10%). The most frequently reported reactions concerned the use of a vaccine against piroplasmosis. Another 349 requests for information were processed by the Swiss Toxicological Information center. We also present a case of a serious adverse reaction in form of a Stevens-Johnson syndrome in a cat as well as a case of ketamine abuse. We note the growing interest of practicing veterinarians with pleasure and are currently working on further adaptations to the system.     

Selected herbal hazards.

One of the most important considerations in treating herbal ingestions is product quality assurance. Although most herbal companies are reputable, there are numerous reports of adulterated products (addition of substances not noted on the label). This has been particularly true of Chinese herbal products, which frequently contain pharmaceutical agents. Plant identification errors occur, and entire batches of product have been mixed using the wrong herb. In some cases, labels are written in a foreign language or only contain directions for mixing, making interpretation difficult. In cases where a known ingestion produces unexpected clinical signs, the potential for adulteration or other errors should be considered. When a product is not standardized, a consumer cannot be sure what dose of active constituents has been used or how bioavailable the product may be. Standardization also provides assurance that the actual herb is in the product [26]. Clients who use herbal products should be advised to treat them as a medication and to keep them away from pets. Specifically, ask clients if they take or use any natural or herbal products. Many people do not consider these substances drugs or assume, "If natural, it is harmless." Clients should be encouraged to learn about the herbal and neutraceutical products they are taking or giving their pets. Owners need to discuss the proper use of herbal products in pets with their veterinarian. Clients can be encouraged to discuss alternative therapies by discussing a pet's diagnosis and suggested treatments thoroughly. Discuss the client's expectations and opinions of alternative and conventional medicine. Issues of safety and efficacy must be fully explained to clients. Clients should be encouraged to report potential adverse reactions or to discuss different routes of therapy if a pet's medical condition is not improving. Clients who want to use alternative medical treatments should obtain a thorough medical workup so as to make a correct diagnosis and be referred to a veterinarian trained in alternative medicine. In choosing an alternative medicine practitioner, the same criteria would be used as for any other specialist: education, training, and professionalism [14].     

Rabies and brucellosis immunization status and adverse reactions to rabies vaccines in veterinary students.

Rabies pre-immunization has been recommended for high risk professions, including veterinarians. Cell-cultured rabies vaccines have considerably reduced the risk of post-vaccination neurological reactions found in earlier vaccines. However, some adverse reactions have been reported with Human Diploid Cell Vaccines. 329 French veterinary students were surveyed about their rabies and brucellosis vaccination status, the occurrence of adverse reactions to rabies vaccine, and their antibody titer monitoring practices. Questions also were asked to determine if mandatory rabies pre-exposure immunization upon entry to veterinary school motivated students to maintain their rabies pre-exposure vaccination. The overall vaccination rate was 98.5% for rabies and 17% for brucellosis. 19% of the rabies vaccinated students reported some form of adverse reaction, whatever the vaccine brand used, but not experienced systemic allergic reaction. Adverse reactions were twice more frequent in female than male students and were more frequent after primary series than revaccination series (Relative Risk = 1.76). Despite the mild reactions encountered, rabies pre-exposure vaccination has been well-accepted by French veterinary students. In contrast, vaccination against brucellosis was not as well-accepted for prophylaxis.     

Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2001 - February 2002)

An overview of reports of suspected adverse drug reactions received by the Veterinary Pharmacovigilance and Medicines Information Centre during the period March 2001 to February 2002 is given. A total of 77 reports were received. The majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most products implicated in the reports were Stock Remedies. The products were predominantly administered either by veterinarians or trained paraveterinary professionals. Although the majority of reports were received from veterinary pharmaceutical companies, the proportion of reports received directly from veterinarians increased compared with previous years.     

Veterinary pharmacovigilance. Part 5. Causality and expectedness

In the European Union and elsewhere there is a requirement to ascribe causality to adverse drug reactions which occur in treated animals. In the EU, the ABON system of causality assessment is used but the assignment of causality assigned is not always self evident, and it may be complicated for a variety of reasons. In this paper, the approaches to causality assessment, based on a number of key criteria which examine the administration of the drug in relation to the sequence of ensuing events and the presence of biological plausibility are examined, along with the utility of using algorithms to facilitate this process. Unexpected adverse drug reactions usually require expedited reporting, depending on national or regional regulatory requirements. Again, deciding on what might constitute an expected (or unexpected) adverse reaction, particularly when a product may be intended for use in a number of species, and when within any one species a number of breeds may be treated, is not necessarily a straightforward issue. However, an approach to facilitate the decision- making process, based on a similar approach used in the pharmacovigilance of human medicinal products is discussed.     

Increasing patient safety in veterinary transfusion medicine: an overview of pretransfusion testing

Objectives – To review the principles and available technology for pretransfusion testing in veterinary medicine and discuss the indications and importance of test performance before RBC transfusion.
Data Sources – Current human and veterinary medical literature: original research articles and scientific reviews.
Summary – Indications for RBC transfusion in veterinary medicine include severe anemia or tissue hypoxia resulting from blood loss, decreased erythrocyte production, and hemolyzing conditions such as immune-mediated anemia and neonatal isoerythrolysis. Proper blood sample collection, handling, and identification are imperative for high-quality pretransfusion testing. Point-of-care blood typing methods including both typing cards and rapid gel agglutination are readily available for some species. Following blood typing, crossmatching is performed on one or more donor units of appropriate blood type. As an alternative to technically demanding tube crossmatching methods, a point-of-care gel agglutination method has recently become available for use in dogs and cats. Crossmatching reduces the risk of hemolytic transfusion reactions but does not completely eliminate the risk of other types of transfusion reactions in veterinary patients, and for this reason, all transfusion reactions should be appropriately documented and investigated.
Conclusion – The administration of blood products is a resource-intensive function of veterinary medicine and optimizing patient safety in transfusion medicine is multifaceted. Adverse reactions can be life threatening. Appropriate donor screening and collection combined with pretransfusion testing decreases the occurrence of incompatible transfusion reactions.