Adverse Experiences Report 1999 Section 1 Summary tables

Summary table and discussion of all reports received since the beginning of the program

This section represents a descriptive overview of all the voluntary reports involving adverse experiences that have been received since 1995 in order to provide an accurate assessment of adverse experiences in Australia since the program's commencement. The discussion includes a list of all the outcomes of the program, including label changes, product formulation changes and other recommendations that have been made as a result of the information collected by the AERP.

1.1 Number of reports received each year

Since 1995, the AERP has received a total of 555 voluntary reports that have been submitted by private practice veterinarians, the public (animal owners/farmers or other chemical users) or other sources (eg NSW Agriculture). The following table lists the number of reports received for the last five full calendar years.

Table 2 - Voluntary adverse experience reports by year

Year	Number of reports
1995	174
1996	95
1997	104
1998	75
1999	107
Total	555
Mean per annum	111 +/- 33

During the first year of introduction, the program received its greatest exposure and promotion which is reflected by the highest number of reports received during that year. Since then the number of reports has fluctuated without a definite trend. Throughout 2000 the program will again be actively promoted in an effort to encourage reporting of all adverse experiences with veterinary chemical products.

It is important that the veterinary profession, the public and manufacturers of veterinary chemical products continue to support the AERP by reporting all suspected adverse experiences so that appropriate steps can be taken to maintain the high quality of veterinary products in the Australian market.

1.2 The source of voluntary adverse experience reports

The voluntary adverse experience reports come from a wide range of the general community. Many of the reports come from veterinarians in private practice, but we also receive reports from manufacturers, companion animal owners, farmers and other organisations including State Departments of Agriculture. Table 2 lists the percentage of reports received each year by source.

Table 3 - Number of reports received each year by source

Source	Number of reports					Percentage
	1995	1996	1997	1998	1999	1995	1996	1997	1998	1999
Registrants	50	18	35	22	64	29	19	34	29	60
Veterinarians	108	68	59	40	28	62	72	57	53	26
Animal owners	14	7	9	10	11	8	7	9	13	10
Other	2	2	1	4	4	1	2	1	4	4
Total	174	95	104	75	107

Table 3 indicates that the largest proportion of adverse experience reports previously came from veterinarians, but this has fallen over the last few years. Throughout 2000, a number of articles will be published in the Australian Veterinary Journal to raise the profile of the program amongst veterinarians.

1.3 Number of reports received by product category

Table 4 lists the number of reports received for each product category by species affected for 1999. Table 5 combines the same information for the calendar years 1995 to 1999. The majority of reports involve antimicrobial agents, external and internal parasiticides used in companion animals and cattle. This reflects the animal management and health care associated with the most commonly kept species in Australia.

1.4 Outcomes of the AERP over the past five years

Prior to registration the NRA subjects veterinary chemical products to a very thorough assessment of their safety, quality and efficacy. However, that assessment cannot determine the full potential for unexpected effects of the chemical because of:

the relatively small numbers of plants and animals, or areas of crops used in trials compared with the field population;
the wide range of environmental conditions encountered under practical farming conditions;
the fact that it is impossible to include in clinical or field trials all breeds of animals, age groups, varieties of plants, strains of pests and diseases that may be exposed to the product; and
off-label use (including veterinarians exercising their right to prescribe).

Thus, a product with potentially wide use may not be trialed on all groups, or under the conditions, that fully reflect its ultimate market.

Surveillance after registration is therefore an important aspect of the regulatory control of agricultural and veterinary chemical products. It plays an important role in detecting unusual, rare or idiosyncratic conditions, that were not evident in clinical or field trials conducted before registration.

The following is a list of actions that have been taken as a result of adverse experiences being recorded and evaluated under the AERP. As Registrants are required by the NRA to record and investigate all adverse experiences reported to them, a number of potential problems were identified promptly and acted on accordingly. The AERP has also identified a number of matters that required follow up and resulted in action being taken to prevent future adverse experiences and ensure the safety of veterinary chemical products in the Australian market.

Manufacturing or formulation issues

An extensive review was carried out into the manufacturing procedure of an anti-bloat therapy for cattle. It was found that a minor change had occurred during the manufacturing process that may have resulted in a weakness to the product. The mould used in the manufacture of the product has now been changed to ensure that the product will not separate when used according to label directions.

A number of problems arose after dogs were treated with an external/internal combined parasiticide during 1995. Some dogs developed a mild reaction to the preparation, which included vomiting and gastric upsets without systemic disease. It was decided that the problems were dose related and therefore could be managed with dose manipulation and concurrent feeding. A small number of dogs also developed liver disease and some of these dogs died. The Registrant of this product notified all veterinarians in Australia by mail of these complications and ceased manufacture and distribution of the product.

The AERP received a number of complaints from farmers that after they treated their cattle at drying-off with an intramammary antimicrobial agent and despite adhering to the recommended withholding period, blue dye was still present in the milk. Such intramammary preparations in Australia are required to contain a blue dye which is used to identify the milk of treated cattle and prevent it inadvertently being used in milk for human consumption. As a direct result of these reports the level of blue dye present in this product was reduced to prevent this occurring.

The cause of death in a number of cattle after use of an external parasiticide was considered to have been as a result of chemical degradation of the active constituent into toxic breakdown products. The cause of the breakdown of the chemical was considered to have been facilitated by improperly sealed containers and water contamination. As a result of these incidents the product was withdrawn from the market because of stability problems with that particular formulation.

A change was made to the manufacturing process of certain vaccines for cattle after it was discovered that the finished product may contain trace levels of polyvinylpyrrolidone (PVP). A possible link was identified between cattle initially vaccinated with this product and later being treated with a long-acting antibiotic which contains PVP. A number of cattle suffered severe hypersensitivity reactions after being treated with the antibiotic due to the previous sensitisation with the vaccine.

A veterinarian reported that he had experienced a number of problems after using one particular brand of antimicrobial product. After investigation of the matter it was discovered that a number of veterinarians and farmers had experienced similar problems with the product. The problems included discolouration, agglutination and lumps forming at the site of injection. It was discovered that at temperatures above the recommended storage temperature changes to the product could occur, which could cause such problems. The recommended storage temperature on the label will be decreased to limit the likelihood of those changes occurring to the product.

The NRA's Existing Chemical Review Program (ECRP) is currently reviewing a number of chemicals that are present in products involved in adverse experience reports. The information and investigation findings of reports involving such chemicals are forwarded onto the ECRP for inclusion in the review process.

Label changes

The AERP has identified a number of problems associated with labelling of veterinary chemical products. The language used on the labels is not always meaningful to users and in some cases the warning statements are not clear enough to inform users what to expect. Where specific labelling problems have been identified the NRA has discussed the issue with the Registrant and requested appropriate label amendments.

A number of cats treated with a broad spectrum anthelmintic preparation developed unusual clinical signs of ataxia, protrusion of the third eyelid, depression, vomiting and weakness. The manufacturer of this product has included warning statements on the label and has released a new formulation which has significantly reduced the incidence of these problems.

A number of other reports included the use of sheep drenching products that were being administered incorrectly. Damage was caused to the pharyngeal area of a number of sheep due to the poor administration technique. A warning statement has since been included on the label of these products to increase user awareness of these potential problems.

The AERP received a number of adverse reaction reports involving a flea treatment for cats and dogs being used off-label on rabbits. In these reports, after the rabbits were treated, they developed neurological signs and in most instances died within two days. An article was published in the Australian Veterinary Journal to warn the profession of these potential complications. The label has since been updated to ensure the product is only used in the target species.

In one report a dog died after ingesting a small quantity of a product used to treat a horse for intestinal parasites. As a result of the investigation into this matter the product labels have been updated to include a warning that the active constituent is potentially dangerous to dogs and all efforts should be made to ensure that dogs do not gain access to the product.

Following an adverse experience report sent to the NRA by a farm worker, a comprehensive review of the toxicological aspects, scheduling requirements and safety directions for ten animal feed additives was performed by the Therapeutic Goods Administration (TGA) and the National Occupational Health and Safety Commission (NOHSC). As a result of this review a number of recommendations were made concerning the First Aid Instructions and Safety Directions (FAISD's) of these products. These recommendations were considered by the NRA and Industry at a Veterinary Chemicals Consultative Committee (VCCC) meeting who agreed to an implementation date of 30 June 2000 for incorporation of the label amendments to the feed additive chemicals assessed. The proposed label amendments are intended to minimise the chances of adverse experiences occurring.

After careful consideration (with input from both the Therapeutics Goods Administration and the National Occupational Health and Safety Commission) of a number of possible human reactions to an external parasiticide used in cats and dogs, the label directions for use on this product have been updated. The label now warns against using the product if the user or animal has a known hypersensitivity to alcohol or insecticides.

Other issues

It has been recognised that there is a need to ensure that there is adequate sensitivity on the part of manufacturers when dealing with owners whose animals had suffered an adverse effect, or who themselves had been affected.

1.5 Conclusion

The AERP is a post-registration quality assurance program for identifying corrective action necessary to ensure continued safety, quality and efficacy of registered veterinary chemical products. The corrective action may, as demonstrated to date, take the form of changes to product formulation, manufacturing processes, use practices, labelling or product review under the NRA's Chemical Review Program. Overall the AERP has provided a valuable and useful contribution to maintaining the integrity of the National Registration Scheme. It also has provided valuable contributions to the public and Registrants of veterinary chemical products.