Adverse Experiences Report 1999 Section 2 and Section 3

SECTION 2 Tables and discussions on adverse experiences by species

The following tables set out the details of all adverse experience reports received by the NRA during 1999 that have been classified. The text following each table discusses those reports where it has been decided that the adverse experience was product-related or possibly product-related. This summary is intended only to provide general information about the types of reactions that animal owners, veterinarians and others have voluntarily reported to the NRA or the manufacturer after use of the product. The information in the text is not by itself a basis for determining the safety and efficacy of a given product or for comparing one product with another, nor can it be used to predict the frequency of occurrence of a reaction.

2.1 Adverse experiences reported for birds during 1999

Table 6 - Birds

Product Category

No. of Reports Received

No.

Treated

No.

Affected

No.

Died

Product Related

Possibly Product Related

Not Product Related

Caused by not using product according to label directions

External parasiticide

The NRA was notified of three suspected adverse experiences involving use of chemicals on birds during 1999. Only one report is included in this table and it was classified as caused by not using the product according to label directions. The other two reports could not be classified under the AERP as they involved products that are not registered veterinary chemical products.

2.2 Adverse experiences reported for cats during 1999

Table 7 - Cats

Product Category	No. of Reports Received	No. Treated	No. Affected	No. Died	Product Related	Possibly Product Related	Not Product Related	Caused by not using product according to label directions
External parasiticides	2	2	2	2	0	0	0	2
Anthelmintics	2	2	2	0	1	1	0	0
Anti-inflammatory agents	1	1	1	0	0	0	1	0
Antimicrobials	1	1	1	0	0	0	1	0
Ear cleaners	1	1	1	0	0	1	0	0

2.2.1 External parasiticides

Three reports of suspected adverse experiences in cats to external parasiticides were received during 1999. Of these, two were classified as caused by not using the products according to label directions and one has not yet been classified as it is still under investigation.

2.2.2 Anthelmintics

Two reports involving use of anthelmintics in cats and suspected adverse experiences were reported during 1999. One was classified as product-related the other as possibly product-related.

Following treatment of a cat with a product containing praziquantel, febantel and pyrantel embonate for routine worming a veterinarian observed the following reaction. Approximately three and a half hours after the treatment was given, the cat's third eyelids started to prolapse and it became unsteady on all four legs. The registrant of this product indicated that there has been a low level of similar types of experiences to this product reported previously. A new formulation has been developed, which has markedly reduced reports of such adverse experiences. This incident was classified as product-related.

Another cat was treated with a product containing the active constituents niclosamide monhydrate and pyrantel embonate for routine worming. The cat was observed to be panting approximately one hour after the treatment was given. Within another hour, the cat began calling and hypersalivating. The cat was treated by the attending veterinarian with intravenous fluids and was discharged the following day bright and alert. The attending veterinarian and the investigating veterinarian both believe that the experience was possibly product-related.

2.2.3 Ear cleansers

A product containing boric acid, menthol and chlorothymol was instilled into a cat's ears to clean the external aural canals. Within fifteen minutes of treatment, the left third eyelid started to prolapse. No reaction occurred in the right ear. This is the fourth time this veterinarian has observed this type of adverse experience in cats. The clinical signs observed in this cat only occur when foreign material damages the middle ear (1, 2) and for this to occur the tympanic membrane must have been damaged. This incident has therefore been classified as possibly product-related.

2.3 Adverse experiences reported for cattle during 1999

Table 8 - Cattle

Product Category	No. of Reports Received	No. Treated	No. Affected	No. Died	Product Related	Possibly Product Related	Not Product Related	Caused by not using product according to label directions
External parasiticides	4	398	68	14	1	1	0	2
Antimicrobials (Injectable)	3	2+	2+	0	2	0	0	1
Antimicrobials (Intra-mammary)	3	126	55	0	3	0	0	0
Hormones	3	820	83	6	2	1	0	0
Anti-bloat therapies	1	40	1	1	1	0	0	0
Anti-inflammatory agents	1	1	1	0	NA*	NA*	NA*	NA*
Sedatives	1	1	1	1	0	0	1	0

* See text below.

A total of 19 reports were received for suspected adverse experience reports to veterinary chemical products involving cattle. Only 15 were classified as three were not followed up by the reporting people after they made initial contact with the NRA and one was referred to the Good Manufacturing Practice group of the NRA for investigation and action.

2.3.1 External Parasiticides

External parasiticides were the subject of four adverse experience reports submitted to the NRA during 1999. A total of 398 cattle were treated, 68 were affected and 14 died. Two of the reports involved the products not being used according to label directions, one was classified as possibly product-related and one product-related.

One report involved the use of a vaccine for ticks that contains an antigen that attacks the intestinal system of the ticks. The owner of the cattle had used this product a number of times throughout the year without incident, but the latest two treatments had resulted in possible adverse reactions in the cattle. Approximately nine to eleven hours after treatment, 30% of the cattle developed large swellings at the injection sites with varying degrees of lameness and depression. Some cattle also developed slight fevers and had muscle tremors or were ataxic. Swellings at the injection sites of oil-based injections can occur at times and this is mentioned in the product information. The associated lameness is unusual but may be related to localised pain. Therefore the swellings that developed at the injection sites and the associated lameness were most likely related to use of the product. The other systemic signs such as depression, muscle tremors and ataxia are again unusual and it is difficult to determine whether they were related to the use of the product or not. Retention samples of this batch have been tested and conform to specifications. Therefore it is not possible to conclude that the clinical signs of depression, muscle tremors and ataxia were associated with use of this product, however it still remains possible.

Ongoing monitoring of these types of incidents is necessary so that appropriate steps can be taken to maintain the high quality of veterinary products in the Australian market.

Another report, which was classified as product-related, involved the use of a product containing cypermethrin and chlorfenvinphos. Two hundred cattle were treated according to label directions with this product. Within four hours, a number of the cattle started frothing at the mouth became ataxic and eight of the smaller calves died. These clinical signs are consistent with of organophosphate toxicity (3). The active constituent chlorfenvinphos is currently under review and this incident has been included in this review process.

2.3.2 Antimicrobials

2.3.2.1 Injectable antimicrobials

A total of four reports were received regarding use of injectable antimicrobial agents in cattle during 1999. One report was not followed up by the reporting person despite an adverse experience reporting form being sent to him. Of the three reports that were investigated, two were classified as product-related and one was unusual in that it related to storage of the product after release from the manufacturer.

One report involved the use of procaine penicillin in a bull. Immediately after the injection was given, the bull collapsed, its heart rate increased, its respiratory rate decreased and the gums became very pale. The animal took approximately four hours before it could stand and complete recovery took 24-48 hours. These clinical signs are classical of a type-I hypersensitivity reaction (4) and the incident was therefore classified as product-related. Hypersensitivity reactions of this type, occurring following treatment with procaine penicillin, have been well documented and recorded in the scientific literature (4). They only occur in a very small percentage of animals treated. Although they are unavoidable, continued reporting and monitoring of these reactions is necessary to identify any increase in frequency of reactions to specific products, which may indicate a problem with a specific batch.

Another report involved the use a product containing oxytetracycline in a dairy cow to treat suspected septic arthritis. The cow was given one injection of this product daily for four days. It was also given injections of an anti-inflammatory agent daily for two days for pain control. The cow's milk was withheld from the vat according to the label directions on the oxytetracycline product. The first day the milk was put back into the vat the screening test used by the milk factory recorded a positive residue violation for this farm. Other tests were performed on this cow, and it was confirmed that oxytetracycline was still present in this cow's milk outside the recommended withholding period, although it was not confirmed whether the level was above the allowable maximum residue level. During the course of the investigation it was discovered that the screening test used by the milk factories can return false positives. As it was confirmed that oxytetracycline was present in the milk, this incident was classified as product-related.

2.3.2.2 Intramammary antimicrobials

Three reports were received involving intramammary preparations of antimicrobial agents used for mastitis control or treatment. In all three reports the cattle were treated at drying-off with a preparation containing cloxacillin. 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. It was reported in these three incidents that the blue dye was still visible in the milk of a number of cattle after the recommended withholding period. As a result of these reports, the level of blue dye used in this product has been reduced.

2.3.3 Hormones

Three reports involving use of hormones in cattle were received during 1999. Two of the reports were classified as product-related and one possibly product-related.

In the first two reports, a total of 320 cattle were treated with a product containing oestradiol to improve growth rates. A small number of the cattle treated developed preputial prolapse and required veterinary attention or treatment. All the affected cattle have recovered fully. A label change has been recommended to inform users that these reactions have occurred. The incidents were classified as product-related.

In the third report, 500 cattle were treated with the hormone dinoprost trometamol to synchronise the oestrus cycles. Approximately two weeks after the injections were given, 60 animals developed lumps at the injection sites, which were diagnosed as abscesses by the attending veterinarian. All affected cattle were treated with antibiotics, although six cattle died. It is well recognised that injections must be given under hygienic conditions with appropriately sterilised equipment. This type of problem can occur with any injection, as bacteria can be transported under the skin along with the insertion of the needle.

2.3.4 Anti bloat therapies

Anti bloat treatments containing monensin were the subject of one report in 1999, which was classified as product-related.

A herd of 40 cattle were treated and 44 days later one steer was found in the paddock dazed and lethargic. The steer died overnight and a post mortem was performed. The product was recovered and found to have separated in the rumen. An extensive review was made into the manufacturing procedure of this product. It was found that a minor change had occurred during the manufacturing process that may have resulted in a weakness to the mechanism for attaching the wing cap to the body of the capsule. The mould used during this manufacturing process has now been changed to ensure the capsule can not separate. Incidents similar to this have been published previously (5).

2.4 Adverse experiences reported for dogs during 1999

Table 9 - Dogs

Product Category	No. of Reports Received	No. Treated	No. Affected	No. Died	Product Related	Possibly Product Related	Not Product Related	Caused by not using product according to label directions
External parasiticides	6	8	8	1	1	3*	0	2
Anthelmintics	4	18	18	17	0	2	0	2
Vaccines	2	2	2	0	2	0	0	0
Anti-inflammatory	1	1	1	1	0	1	0	0
Anti-sedatives	1	1	1	1	0	1	0	0
Hormones	1	3	3	0	1	0	0	0
Ocular treatments	1	1	1	0	0	1*	0	0

* See text below.

There were a total of 24 suspected adverse experiences to veterinary chemical products recorded in dogs throughout 1999. A further seven reports were received concerning suspected lack of efficacy (see section 4). However, nine reports are not included in this table as they were unable to be followed up adequately for various reasons. For example three reports could not be investigated as the reporting people did not complete an adverse experience reporting form. A further three reports involved products that are not registered veterinary chemical products and under the legislation, the NRA does not have any regulatory control over products that are not classed as veterinary or agricultural chemical products.

2.4.1 External parasiticides

Six reports involving a suspected adverse experiences in dogs after use of a variety of external parasiticides were received during 1999. Eight dogs were treated, eight dogs were affected and one died. Only one report was classified as product-related, three possibly product-related and two relating to not using the product according to label directions.

The initial development of wheals on the dog's skin appears to be related time-wise to the administration of this product. However, this does not necessarily mean that this product caused this reaction. Previous exposure to the product did not result in such reactions and it is difficult to know if prior administration of the non-steroidal anti-inflammatory products played any role in sensitising the skin on this occasion. The NRA concludes that it is possible that the administration of this product led to the development of wheals, but cannot conclude that there was a definite cause and effect relationship.

It is impossible to determine whether the development of further clinical signs observed (eg depression, anorexia, painful abdomen and biochemical and electrolyte disturbances) was related to the use of this product, but it would appear that this was highly unlikely. The lack of other reports of similar experiences supports this.

In another report, the reporting person indicated that she had been treating her dog with a product containing diethyl carbamazine and cyromazine for three years. Approximately two years after starting the treatment, the dog developed an irritation of its paws. The dog was recently diagnosed as having possible liver, kidney and immune dysfunction, resulting in toxins being pushed through the skin. A veterinary pathologist diagnosed the paw irritation as pododermatitis with severe folliculitis and furunculosis, which suggests a bacterial infection. There are other possible causes of this type of disease process, including allergic inhalant dermatitis (atopy), food allergy, bacterial dermatitis (infection), mite infestation and Type 1 hypersensitivities.

No follow up diagnostic blood work, radiology or biopsy tests were performed to identify the cause of the liver, kidney or immune system problems. The NRA has not been presented with enough evidence that supports a diagnosis of liver, kidney or immune dysfunction in the dog. It is therefore not possible to say that the use of this product was responsible for any of these changes.

Another report involved use of a product containing carbaryl to control fleas. The dog developed ataxia and salivation 12 hours after treatment with this product. It was treated at a veterinary clinic (stomach lavage and external wash) and recovered uneventfully. This incident was classified as product-related as the clinical signs observed in this dog were consistent with carbaryl toxicity. This type of experience appears to be an idiosyncratic reaction and is very rare.

Another dog developed an exudative sore (swollen red, painful and causing hair to stick together) within a few hours of being treated with a product containing imidacloprid. The area was thoroughly cleaned and washed and followed by corticosteroid administration (symptomatic treatment) and the lesion healed in 10-14 days. During the investigation it was discovered that the product was applied to the dog when it was clinically affected by severe flea allergy dermatitis. As a result of this incident it was recognised that these types of products should be used with caution in animals with damaged skin. This incident was classified as possibly product-related.

2.4.2 Anthelmintics

One report concerned the use of a product containing levamisole and niclosamide in combination to treat intestinal worms. The dog was taken to a veterinary clinic to be clipped and washed. It was given the tablet on leaving. The dog started coughing and gagging within minutes of the treatment, bringing up small amounts of yellow/green material. The dog died within forty minutes. Two post mortems were performed, which revealed that there was some minor damage to the pharyngeal area, some swelling of the brain and cardiomegaly was present. The temporal relationship between treatment and observed clinical effects may indicate that they are related. However, there are a number of other factors important in this incident. For example, the post mortem also revealed that the dog had an underlying heart problem, and death through cardiac arrhythmia cannot be excluded. The incident was therefore classified as possibly product-related.

Another report involved the use of a product containing praziquantel, pyrantel embonate and oxantel embonate. Approximately 45 minutes after treatment the dog seemed to become paralysed and was taken to a veterinarian. On presentation, the dog had recovered and no treatment was given. The attending veterinarian suggested that the observed clinical signs might have been associated with the use of the product. The incident was classified as possibly product-related.

2.4.3 Vaccines

Only two reports involving suspected adverse experiences in dogs after use of vaccines were recorded during 1999.

In one report the dog started sneezing and developed facial swelling shortly after being vaccinated. This was considered to be a Type I Hypersensitivity reaction and therefore classified as product-related.

The second report was similar to an incident reported previously in the scientific literature (5). A firm swelling was noticed by the owner at the site of injection soon after vaccination. The timing post-vaccination and the fact that this was not a painful reaction would suggest that this was a reaction to the adjuvant in the vaccine and therefore classified as product-related.

2.4.4 Anti-inflammatory agents

The dog was initially given an injection of this product and a vaccination. It was then treated daily for three days with the oral formulation of this product. The owner phoned to say dog lacked coordination and failed to eat two days after being given the last dose. The dog was examined the following day and found to have a neurological deficiency in the hind legs. The owner declined further clinical pathology tests. It was reported that the dog had died mid morning the following day - and had vomited blood during the preceding night. It appears unlikely that the death of this dog was a result of using this product, although it is impossible to rule out the possibility entirely. As no post mortem was performed it is unknown if the dog was suffering from an underlying, undiagnosed disease which may have contributed to the problems encountered.

2.4.5 Anti-sedative agents

A dog was sedated with another product by intravenous administration. Approximately eight minutes later the dog was given this product intravenously to reverse the effects of the sedative. Within five minutes, the dog experienced excitation and seizures. Medication was given to control the seizures and was initially effective, although within 30 minutes the seizures began again, and had a grand mal seizure and became semi-conscious. Cyanosis, elevated heart rate and a high fever developed. The dog suffered a cardiac arrest and died six hours later. This incident was classified as possibly product-related.

2.4.6 Hormones

Three dogs were given an injection of a product containing proligestone to delay the onset of oestrus. Approximately five months after the injections were given the owner noticed that there was some hair loss and depigmentation at the injection sites of all three dogs. In two of the dogs there was some muscle wasting and tissue deficit below the injection sites. Although this reaction was apparently associated with the use of this product the injection site used was inappropriate as there is advice on product label that similar types of problems might be avoided by using recommended injection sites.

2.4.7 Ocular therapies

Two products were used to treat a superficial ulcer of the cornea in one dog. One product contained copper indomethacin and the other a combination of bacitracin, neomycin sulfate and polymixin B sulfate. The ulcer developed into a deep melting ulcer over the following week. It was decided that it was unlikely that either product was involved although it could not be completely ruled out.

2.5 Adverse experiences reported for horses during 1999

Table 10 - Horses

Product Category

No. of Reports Received

No.

Treated

No.

Affected

No.

Died

Product Related

Possibly Product Related

Not Product Related

Caused by not using product according to label directions

Antimicrobials

Anthelmintics

Only three reports involving suspected adverse experiences in horses were submitted during 1999, which is a significant drop compared to last year (twelve reports). Two reports involved antimicrobial agents and one involved an anthelmintic.

2.5.1 Antimicrobials

Two adverse experience reports concerning use of injectable procaine penicillin in horses were received. In the first report immediately after the injection was administered the horse went into extreme excitation and galloped uncontrollably around the paddock but escaped injury. The incident was classified as product-related and it is recognised that these types of excitation reactions can occur in a small percentage of horses treated with products containing procaine penicillin (6).

Another horse was anaesthetised for treatment of an infected wound. Within minutes of an injection of the product it developed cardiac irregularities and respiratory arrest. The anaesthetic was ceased and various treatments were given to attempt resuscitation however the horse died. This incident was classified as possibly product-related.

2.6 Adverse experiences reported for pigs during 1999

Table 11 - Pigs

Product Category

No. of Reports Received

No.

Treated

No.

Affected

No.

Died

Product Related

Possibly Product Related

Not Product Related

Caused by not using product according to label directions

Vaccines

1159

Two reports involving use of vaccines in pigs were submitted to the NRA during 1999. One report was classified as caused by not using the product according to label directions and the other as product-related.

In the second of these reports a group of fifty pigs were vaccinated and three days later, two of the pigs were found dead. Both pigs were presented for post mortems. The pathology report stated that one of the pigs had lung lesions typical with that of a delayed hypersensitivity reaction type 2. This incident was therefore classified as product-related.

2.7 Adverse experiences reported for rabbits during 1999

Table 12 - Rabbits

Product Category

No. of Reports Received

No.

Treated

No.

Affected

No.

Died

Product Related

Possibly Product Related

Not Product Related

Caused by not using product according to label directions

External parasiticides

Five reports involving use of an external parasiticide to control fleas in rabbits were received during 1999. Two similar reports were recorded during 1998 and were published earlier in the scientific literature (5). In all reports the rabbits died with varying signs of restlessness, anorexia, seizures and blindness over a number of days. The registrant of this product released a statement in the March 1999 edition of the Australian Veterinary Journal to inform the veterinary profession of these incidents. The label has since been updated to ensure the product is only used in the target species.

2.8 Adverse experiences reported for sheep during 1999

Table 13 - Sheep

Product Category

No. of Reports Received

No.

Treated

No.

Affected

No.

Died

Product Related

Possibly Product Related

Not Product Related

Caused by not using product according to label directions

Anthelmintics

437

A total of five adverse experience reports were received during 1999 relating to use of products in sheep. Only two are included in this report as one referred to a product that was not a registered veterinary chemical product, one had been reported on in a previous publication and one has not yet been finalised as it was received in late December 1999.

2.8.1 Anthelmintics

The first of the two reports relating to anthelmintics involved the use of a product containing levamisole and albendazole. The report was forwarded onto the AERP coordinator from the Department of Natural Resources and Environment, Victoria. A farmer reported that a ram had died approximately 30 minutes after being treated with this product. Three further rams died that morning and six more were sick, some became recumbent. A post mortem was carried out on one ram and it revealed no abnormalities. One further ram died overnight. The owner indicated that water was not available to the rams during the night prior to drenching - this is not recommended when using levamisole. Levamisole toxicity was postulated as the cause of the death of the rams, although this was not confirmed at post mortem. As there was a temporal relationship between the treatment of the animals with this product and the subsequent clinical signs observed the incident was classified as possibly product-related.

SECTION 3

Table of reports of adverse experiences in humans 1999

The following table and discussion sets out the details of those reports where it has been decided that the adverse experience is product-related or possibly product-related. This summary is intended only to provide general information about the types of reactions that animal owners, veterinarians and others have voluntarily reported to the NRA or the manufacturer after use of the product. The information in the text is not by itself a basis for determining the safety and efficacy of a given product or for comparing one product with another, nor can it be used to predict the frequency of occurrence of a reaction.

3.1 Adverse experiences reported for humans during 1999

Table 14 - Humans

Product Category	No. of Reports Received	No. Treated	No. Affected	No. Died	Product Related	Possibly Product Related	Not Product Related	Caused by not using product according to label directions
Parasiticides (cats and dogs)	14	NA	14	0	0	7	6	1
Parasiticides (cattle)	3	NA	3	0	0	1	0	2
Anti-arthritic	1	1	1	0	0	0	0	1
Anaesthetic	1	NA	1	0	0	0	0	1
Vaccines	1	NA	1	0	0	0	0	1

A total of 22 suspected adverse experiences in humans were reported to the NRA during 1999 relating to veterinary chemical products. The details of one report were published in the 1997/98 Annual Report of Adverse Experiences. Six other reports related to inappropriate use of veterinary chemical products or accidental exposure and have not been included in the discussion.

3.1.1 Parasiticides

Of the 14 reports of suspected adverse human experiences to parasiticides for cats and dogs, seven were classified as possibly related to exposure to the product. A number of people developed symptoms of redness or rashes of arms, legs, face etc after coming into close contact with their pets soon after they treated them with these products. For further details on the symptoms experienced by these people see Section 4. The label of one product is currently being updated to include a statement to advise against use if the owner or animal has a known hypersensitivity to alcohol or insecticides.

One report involving the use of a parasiticide used in cattle was classified as possibly related to the use of the product. Two people reported that they developed headaches, nausea, tingling sensations in the feet, numb and tingling lips soon after using the product. Other possible causes of these symptoms include reactions to plant allergens, sensitivity to other chemicals in the dairy and viral infections.