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 Coated Tablets are available in four strengths and contain difloxacin hydrochloride. (The tablet strengths are expressed in terms of the difloxacin content.) The tablets are round, biconvex coated tablets with no break-line. The difloxacin-containing tablet cores are coated (by compression) to protect the active ingredient from light. The coating mixture includes both brewer’s yeast and an aromatic liver flavour to improve the palatability to the target species. The tablets are presented in PVC/aluminium heat sealed blister packs which are packed in outer cartons.
Dicural Tablets: Composition of the veterinary medicinal product
All the four strengths of these tablets are manufactured from common blends of both the core powder blend and also the coating powder blend. Their compositions are detailed below:
|Difloxacin (as difloxacin hydrochloride)||MS||15||50||100||150|
|Total tablet weight:||180 mg||600 mg||1200 mg||1800 mg|
|Tablet diameter:||7.5 mm||12.6 mm||16 mm||18 mm|
MS = Manufacturer’s specification.
No overages were included.
The tablets are packed in polyvinylchloride blister packs (ten tablets per blister strip), sealed with thermo-adhesive lacquered aluminium foil, which are then packaged into a cardboard box. The outer boxes hold ten, twenty or one hundred tablets (as one, two or ten blister strips).
Dicural Tablets: Summary of target species tolerance studies
None of the products used in any of the target species tolerance studies were the same as the formulation to be marketed. In two studies difloxacin hydrochloride tablets were used which were not the same as the proposed product “Dicural”. In the other studies the active ingredient was administered in gelatin capsules. The Guidelines (Evaluation of the safety of veterinary medicinal products for the target animals) state that the product to be evaluated must be identical to the product to be marketed i.e. same chemical, same particle size and same formulation. As the “plain” tablets and capsules used in the tolerance studies were demonstrated to be bioequivalent to the final product to be marketed, that is coated tablets, the concentrations of active ingredient in plasma, organs and tissues will be similar.
As useful information regarding the safety of the active ingredient in the target species was also provided, it was concluded that sufficient reassurance on tolerance was provided. Furthermore, as the products are already marketed in some EU Member States pharmacovigilance data could be examined. No suspected adverse reactions were reported from approximately 150,000 treated animals.
However, there were several areas of concern regarding difloxacin hydrochloride in dogs. Those of greatest concern included the occurrence of joint abnormalities in young dogs, vomiting and convulsions, ataxia and tremors. Renal and hepatic toxicity (including the occurrence of biliary crystalline deposits) appear to only occur at very high doses. Retinal lesions were noted at higher doses (4-5 X the recommended dosage, up to 90 days) from electro-retinographic examinations.
It was noted that the CNS related signs (i.e. convulsions, ataxia and tremors) only seemed to occur at doses greatly in excess of the recommended dose. Facial swelling was reported in some dogs but the data appeared to demonstrate that this was not directly related to the administration of the product, and the low incidence of this justified the absence of a warning on the product literature.
Joint problems were seen in dogs given the recommended dose. All of the target species tolerance studies were performed in Beagle dogs, which are not representative of large or giant breeds in which the rapid growth phase may be considerably longer. The SPC therefore, contained a contra-indication for the use of this product during the rapid growth phase: in small and medium breeds up to and including 8 months of age, in large breeds up to one year of age and in giant breeds up to 18 months.
Vomiting and some loss of appetite at the recommended dose level were noted. In the SPC, therefore, it also stated that clinical signs recorded in the field trials included inappetence, emesis, diarrhoea and anal irritation, although the signs were self-limiting within one or two days and did not require additional treatment.
As no data were provided on the safety of this product in pregnant or lactating bitches or in male stud dogs, a contra-indication was included under section 5.6 of the SPC for the use of this product in pregnant or lactating bitches and in male stud dogs.
Dicural Tablets: Risk-Benefit Assessment And Conclusion
Based on the original and supplementary data presented, the Committee for Veterinary Medicinal Products concluded that the quality, safety and efficacy of the product were in accordance with the requirements of Council Directive 81/852/EEC and supported the claims for simple uncomplicated urinary tract infections caused by Escherichia coli and Staphylococcus spp., and superficial pyoderma caused by Staphylococcus intermedius.