Active substance / Generic: Difloxacin hydrochloride
This medicine is approved for use in the European Union
|International Non-proprietary Name:||Difloxacin hydrochloride|
|Target species (with associated Pharmaceutical form):||Chickens (broilers and future breeders): Oral solution|
|Turkeys (young, up to 2kg bodyweight): Oral solution|
|Cattle (calves and young cattle): Solution for injection|
|Dogs: Solution for injection; Coated tablets|
|Therapeutic indications:||Chickens and Turkeys:|
|• for treatment of chronic respiratory infections caused by sensitive strains of Escherichia coli and Mycoplasma gallisepticum.|
|• for the treatment of infections caused by Pasteurella multocida.|
|• for the treatment of bovine respiratory disease (shipping fever, calf pneumonia) caused by single or mixed infections with Pasteurella haemolytica, Pasteurella multocida, and/or Mycoplasma spp.|
|• for the treatment of acute uncomplicated urinary tract infections caused by Escherichia coli or Staphylococcus spp.|
|• for the treatment of superficial pyoderma caused by Staphylococcus intermedius.|
|Withdrawal periods:||Chicken and turkeys: Meat: 24 hours|
|Cattle: Meat and offal 46 days|
|ATCvet code and Pharmacotherapeutic Group:||QJ01MA94
General anti-infectives for systemic use; antibacterials for systemic use; quinolone antibacterials.
|Marketing Authorisation Holder:||Fort Dodge Animal Health Holland|
Dicural contains difloxacin (as the hydrochloride), which is an antibiotic of the fluoroquinolone group. Fluoroquinolones exert their antibacterial effect against both replicating and dormant microorganisms. Difloxacin hydrochloride can be bactericidal in activity and acts primarily through inhibition of bacterial DNA gyrase.
Dicural Oral Solution: Quality Assessment
Dicural oral solution is a clear yellowish solution containing difloxacin hydrochloride (100 mg difloxacin base per ml) (10%) as the active ingredient for administration via the drinking water.
The product contains per ml:
Difloxacin hydrochloride, corresponding to Difloxacin ― 100.0 mg
Propylene glycol, benzyl alcohol, potassium hydroxide, edetic acid, purified water.
The oral solution is presented in 250 and 1000 ml plastic (HDPE) white bottles with tamper evident polypropylene screw caps. The bottles are packed in individual cartons, as well as in 6-bottle pack for the 1000 ml bottles.
Product Development Studies:
This product is a high pH product, which can be diluted at all concentrations with water of different temperature, hardness and pH without precipitation.
Dicural Oral Solution: Clinical studies
In both broilers and turkeys the enteric claim was dropped by the applicant, because in the Committee’s opinion it had not been supported by sufficient data.
Experimental studies involving Escherichia coli infection were conducted in the US and a European country and these supported the 10 mg/kg dose rate. Similar studies were conducted for Mycoplasma gallisepticum infection as well as for a single mixed infection by Escherichia coli/Mycoplasma gallisepticum. Although the data on Mycoplasma and mixed infections were less substantive, they were considered adequate to support the recommended dose of 10 mg/kg.
The field trials supporting the treatment in broilers in the initial application were not considered adequate, although they provided many indications that the product was effective in terms of reduced mortality, improved clinical signs and pathology and in some cases a reduction in the number of pathogens isolated. The applicant was asked by the Committee to conduct further, better designed field trials.
Seven additional field trials involving Escherichia coli and/or Mycoplasma gallisepticum were conducted in Europe. These included (a) one trial in which efficacy of difloxacin treatment was studied versus non-treatment for the control of post vaccinal Escherichia coli respiratory disease; (b) one trial comparing the efficacy of difloxacin in drinking water to a reference product (enrofloxacin) to control respiratory disease caused by Escherichia coli and/or Mycoplasma gallisepticum; (c) five other trials on the efficacy of difloxacin for the treatment of Escherichia coli and/or Mycoplasma gallisepticum infections.
The lesion scores that were present in 20 randomly sacrificed birds before and 5 days after therapy were evaluated in 3 studies. The mean lesion scores for heart and liver were 0.13 and 0.06 respectively before treatment and zero for both tissues following treatment. Airsac and trachea mean lesion scores were both reduced post treatment compared to pre-treatment.
For the same 3 studies the total number of birds was 37,502. As a whole 24 out of 60 randomly selected birds had lesions infected with Escherichia coli before treatment, while after treatment only 2 out of 56 birds had lesions infected with Escherichia coli. This reduction was highly significant (Chi2 p<0.001).
With regard to mortality the applicant reported determination of the efficacy of Dicural oral solution was difficult because in most of the trials, the total mortality was due to a mixture of causes such as ascites, emaciation due to malabsorption (poor growers) and cardiac arrest.
In four of the studies the growth of the birds was well maintained despite the presence of disease.
The Committee agreed that these data supported the efficacy of the product for Escherichia coli respiratory infections but asked for assurances with regard to the Mycoplasma gallisepticum data and invited the applicant to comment on the minimal clinical trial data provided in support of the claim for respiratory infections caused by Mycoplasma gallisepticum.
The applicant at an oral presentation stressed the difficulty of isolating Mycoplasma organisms, the fact that serological diagnosis of Mycoplasma gallisepticum infection was performed by ELISA techniques and made the point that Mycoplasma gallisepticum may have been present in some of the other studies. The Committee were satisfied with these explanations and agreed that the efficacy of the product for the treatment of Escherichia coli/Mycoplasma gallisepticum respiratory infections in broiler chickens had been demonstrated.
The Committee discussed at length whether or not the indications should be for a claim for ‘metaphylaxis’ in chickens and turkeys as proposed earlier in the evaluation phase. However, having taken account of the fact that the product is to be used in flocks in which signs of the disease have just become apparent, with a view to curing the minority of already clinically affected birds and preventing the spread of infection to healthy or subclinical birds, the majority of members agreed that a claim for ‘treatment’ would be more appropriate. It was generally agreed that ‘treatment’ would be a clearer and more accurate reflection of product characteristics since the term ‘metaphylaxis’ is rarely or ever used in many EU countries, and that the matter would be addressed satisfactorily by the application of Good Veterinary Practice.
Experimental studies were provided only for Pasteurella multocida infections (fowl cholera) with justification being provided for extrapolation of data from broilers for Escherichia coli and Mycoplasma gallisepticum on the basis of the turkey being a minor poultry species and the provision of pharmacokinetic/MIC data for turkeys. There were 3 experimental infection studies presented which demonstrated efficacy against P. multocida at dose levels corresponding to, and below the recommended dose of 10 mg/kg. In its response, the applicant replied that it would be almost impossible to conduct field trials to investigate efficacy against fowl cholera in Europe since it is a reportable disease. In addition, the applicant defended the model study confirming that it demonstrates satisfactory efficacy and that European P. multocida isolates had shown good sensitivity to difloxacin.
Two trials were carried out in an EU member state involving naturally occurring respiratory diseases to demonstrate efficacy against Mycoplasma gallisepticum and Escherichia coli. The first trial was unsuccessful for a variety of reasons including late treatment and a mixed viral infection being diagnosed in the flock. The Committee could not draw any conclusion from this trial. The second field trial, which involved 3000 17 day old turkeys with respiratory disease treated at 10 mg/kg for 5 days, demonstrated efficacy against mixed Escherichia coli/Mycoplasma gallisepticum infections. Escherichia coli was isolated from the affected birds and Mycoplasma infection was diagnosed serologically.
The applicant was advised by the Committee that on the basis of these data, only a claim for Pasteurella infections appeared supportable but that further data would be required to justify the Escherichia coli and Mycoplasma claim. Two further trials were then conducted in 16 day old poults. The first trial involved 3000 poults suffering a severe respiratory infection caused by Escherichia coli. The second trial involved 4000 poults suffering a moderate to severe respiratory infection caused by Escherichia coli.
In the first trial therapy was initiated too late but, in the other, the treatment reduced clinical signs and mortality. The Committee therefore considered that these results were not entirely satisfactory and that further reassurances would be required with regard to the turkey claims. The applicant was consequently invited to provide oral explanations on the clinical data supporting the claim of treatment of respiratory infections caused by Mycoplasma gallisepticum and Escherichia coli in turkeys. The Committee also invited the applicant to discuss the fact that the fowl cholera claim was not supported by European data and to further justify the recommended dose.
At the oral presentation the applicant provided a justification for the extrapolation of Escherichia coli and Mycoplasma data in broilers to turkeys since the respiratory symptoms are comparable in chicks and turkeys, the growth rate and physiology of young turkeys are comparable to chicks, and MIC data are comparable. The applicant indicated that the poor results in some of the field trials could be explained by initiating treatment too late or because birds had other disease problems such as haemorrhagic enteritis or herpes virus infections.
The Committee accepted the explanation of the applicant and considered that in view of the two successful trials involving a total of 7000 birds, the claim for Escherichia coli/Mycoplasma gallisepticum respiratory infections could be granted. A minority of members considered these data to be inconclusive, in that they did not appear to support the claims against Mycoplasma gallisepticum and Escherichia coli, and furthermore they could not accept the extrapolation of data from broilers to turkeys particularly as the bioavailability of difloxacin in turkeys is just over half that in chickens.
In relation to fowl cholera, the applicant agreed that 5mg/kg was efficacious but maintained that as the initial symptoms would resemble Escherichia coli/Mycoplasma gallisepticum infections it would be necessary to begin therapy at the highest dose of 10 mg/kg. One dose on the label would avoid confusion at user level. The Pasteurella claim was defended by the experimental studies and also in relation to MIC data from both US and EU. The Committee considered that in view of these arguments a dose of 10 mg/kg was appropriate in the treatment of both fowl cholera and Escherichia coli/Mycoplasma gallisepticum infections.
Dicural Oral Solution: Risk-Benefit Assessment And Conclusion
Based on the original and complementary data presented, the Committee for Veterinary Medicinal Products concluded, by a majority decision, that the quality, the safety and the efficacy of the product were considered to be in accordance with the requirements of Council Directive 81/852/EEC and supported the claims proposed by the applicant.
Consequently, the Committee decided on June 11, 1997 that the product could be recommended for the granting of a Community marketing authorisation.