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BASEL, Switzerland — An extensive investigation of adverse drug reactions linked to the use of Econor (valnemulin) indicates that reactions were limited to a susceptible subpopulation of pigs and that the antibiotic is safe to use in the vast majority of swine, says Novartis Animal Health, Inc., the company that makes and markets the product.
“The in-feed antibiotic has proved to be highly effective for control of swine dysentery and enzootic pneumonia,” says Dr. Ulrich Klein, a veterinarian and professional services manager with Novartis. No adverse drug reactions, or ADRs, were reported in the Asian, Latin American or European countries where Econor was in use.
“It therefore came as a complete surprise when reports of Econor-related ADRs emerged in Scandinavia — an area where we were seeing excellent sales and interest,” he says.
The occurrence of ADRs prompted the European Union to suspend marketing authorization for Econor last October. “We responded by launching an exhaustive investigation that has helped explain the mysterious findings and should assure safe use of Econor in the future,” Klein says.
Background on ADRs
Of the 36 cases reported, 34 of them — or more than 94% — occurred in Denmark and Sweden. One was reported in Finland and another in Ireland. Still, overall incidence of ADRs in the affected countries ranged from 0.03% to 1.76% of all pigs treated. Mortality rate in affected herds ranged from 0.7% to 1.2%.
Clinical signs occurred from 2 to 6 days after treatment with Econor, and most affected animals were from 6 to 7 weeks of age. Common clinical signs included pyrexia and anorexia, stiffness and lethargy. Other less common signs reported included erythema and oedema. Pigs recovered after 3 to 4 days even when medication was continued. There was a high rate of concurrent infections.
One of the first studies launched by Novartis sought to identify risk factors that might account for the occurrence of ADRs. Nearly 200 farms were evaluated in seven countries: Belgium, Denmark, Germany, Ireland, Spain, Sweden and the UK.
The study involved farms that had ADRs and compared them with two control groups — one comprised Econor-treated herds without ADRs and another consisted of herds not treated with Econor.
“This study showed that breed structure is distinct from country to country and that certain breeds have an increased risk for ADRs if treated with Econor,” Klein says. “Specifically, the Danish and Swedish Landrace breeds and their cross-breeds showed an increased predisposition to the occurrence of ADRs.”
Tolerance studies
In a toxicity/tolerance study, Econor was found to have no effect on a wide range of physiological, biochemical, haematological and clinical parameters, even when administered at three times the dose involved in ADRs.
Pharmacokinetic studies showed that the product’s active ingredient, valnemulin, is rapidly metabolised within 24 hours, but that clearance is significantly slower in 5-week old pigs than in 7- or 9-week olds. Higher bioavailability in younger pigs, however, was not accompanied by signs of enhanced toxicity.
The interaction of valnemulin with deficiencies and excesses of zinc, vitamin E and selenium; the effects of degradants in feed, the pigs’ sex and the source and type of feed were also studied, but the trials yielded no significant findings.
When ADRs were reproduced on a number of farms in Denmark, they were not found to be strongly dose-related. Econor-treated pigs affected by ADRs recovered despite continued medication, and mortality was less than 1%.
Metabolic deficiency
One of the more telling studies sought to identify the characteristics of valnemulin metabolism in ADR pigs. Independent investigator Dr. Christian Friis of the Royal Veterinary and Agricultural University, Copenhagen, considered the possibility that ADRs associated with Econor might be related to a known metabolic deficiency of the enzyme CYP2A P450 that exists in a subpopulation of Danish pigs. This deficiency can slow the metabolic processes of the liver in swine and, in turn, make pigs more susceptible to ADRs.
Pigs in the study included those treated with Econor that did and did not have ADRs, as well as unmedicated controls.
Indeed, the investigators found that ADR pigs had a slightly reduced ability to metabolise valnemulin, but that they were almost completely deficient in CYP2A P450. In fact, the absence of CYP2A P450 can be considered a marker for ADRs.
Concurrent infections
Another suspected culprit that might help explain the ADR mystery in Econor-treated pigs was the standard of hygiene and the presence of concurrent infections, which were extremely widespread on ADR farms. Counts of faecal Gram-negative bacteria were found to be significantly higher in Econor-medicated pigs with ADRs than in medicated non-susceptible pigs, but were similar to those in unmedicated non-susceptible pigs.
Consequently, the response of pigs from a Danish ADR-susceptible herd to artificial challenge with endotoxins was studied and compared to that of pigs from France.
These findings indicate that a susceptibility to ADR in Econor-treated pigs might be associated with an exaggerated response to Gram-negative bacterial toxins such as the endotoxin of Escherichia coli.
Overall, the studies indicate that ADRs are strikingly restricted in geographical occurrence. They appear to be linked to pigs of the Danish and Swedish breeds and their crossbreeds and a deficiency in CYP2A P450 may be involved. The presence of poor hygiene and concurrent gram-negative infections may also increase the risk for ADRs in these breeds.
“We feel confident that the majority of pork producers in countries where Econor is used can reap the benefits of the antibiotic for control of swine dysentery and enzootic pneumonia without concern about the occurrence of ADRs,” Klein says.
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