- 1 Active substance / Generic: Difloxacin hydrochloride
- 1.1 Dicural Solution for Injection: Quality Assessment
- 1.2 Dicural Solution for Injection: Tolerance in the target species
- 1.3 Dicural Solution for Injection: Risk-Benefit Assessment And Conclusion
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 Solution for Injection: Quality Assessment
Dicural 50 mg/ml solution for injection for cattle and dogs contains difloxacin hydrochloride as the active substance. It is a clear yellowish solution containing 50 mg/ml difloxacin for subcutaneous administration. The solution is packaged in amber coloured glass vials of 50 ml (cattle and dogs), 100 ml (cattle only) or 250 ml (cattle only), fitted with a bromobutyl rubber stopper and an aluminium overseal.
The product is to be packed in amber coloured glass vials of 50, 100 or 250 ml with bromobutyl rubber stoppers and aluminium overseals. The vials are packed in a carton outer box. The suitability of the stoppers, in terms of leaching, fragmentation and self-sealability characteristics, using suitably sensitive techniques was not addressed adequately in the original dossier. Therefore a commitment from the Applicant to repeat the experiments on leaching using Dicural 50 mg/ml Solution for Injection for cattle and dogs was requested. Fragmentation and self-sealability data were presented for a type of stopper which is closely related to the proposed stopper. The data demonstrated that this stopper could withstand 15 punctures using a 21-gauge needle. The Applicant has now committed to present similar data for the proposed stopper. Post-authorisation note: These data have since been provided and assessed as satisfactory.
Taking into account the recommended dosage regimen, it has been estimated that for dog, the 100 and 250 ml vial will allow the treatment of a considerable number of animals. In order therefore to reduce the number of punctures per stopper for dogs, the only vial to be used should be the 50 ml one. The applicant has been advised to develop a more appropriate vial size, e.g. 10 ml for dogs.
Dicural Solution for Injection: Tolerance in the target species
One study has been submitted to investigate the systemic tolerance in five groups of calves aged from 6 to 9 months.
|Group number||Dose (mg/kg/day)||Route||Duration of treatment||Day of necropsy|
|1||0 (saline)||i.m.||15 days||D16|
At the recommended dosage the use of Dicural 50 mg/ml solution for injection for cattle and dogs is not likely to cause any serious systemic side-effects in calves. Some unsteadiness may occur, especially after prolonged treatment. In most cases minor injection site reactions were observed, but occasionally more severe reactions have been seen. Examination of the knee joint showed some swelling and oedema, without any abnormalities of the cartilage. At overdose CNS symptoms, such as ataxia, unsteadiness, shaking, tremors, twitching occur.
Approximately 200 calves aged between 2 and 4 weeks old at the start of treatment have been treated. There was no indication of arthropathy. This is the most reassurance that can be given, although the joints were not specifically monitored.
Dicural 50 mg/ml solution for injection for cattle and dogs was injected intramuscularly or subcutaneously for 5 consecutive days. During the treatment the usual clinical parameters were assessed (body temperature, heart rate, respiratory rate, growth, food consumption blood and urine composition, etc.). Animals were killed 1 or 32 days after the last injection. At necropsy the injection sites were investigated.
There were no significant, adverse effects as measured by the clinical parameters. The main side-effects were transient injection site reactions. Severity and size were dependent on the actual site (i.e. deep intramuscular injection caused more severe reactions than injection in the neck). In the period from D6 to D33 recovery of muscular tissue took place; scar tissue remained present. Generally, the size of the injection site reactions was small (2x2x2 cm), but occasionally larger ones occurred (50-400 cm3). Also, at overdoses the injection site reactions were more severe. Finally, swelling and oedema formation in the knee joints were also observed in calves.
Reference is made to 4 toxicity studies of difloxacin after repeated administration to dogs. Although informative, they do not contain information on the tolerance of dogs towards the product. In addition, two references concerning the tolerance of dogs towards difloxacin tablets have been provided. From these studies it can be concluded that the maximum tolerated dosage of tablets in mature dogs lies between 25 and 50 mg/kg bw/day.
In general, Dicural at the proposed dose level is well tolerated. The main side-effect is the occurrence of joint lesions in immature dogs (reported in the previous section – repeated dose toxicity). The lesions may even occur at the proposed dosage. The use of Dicural during the rapid growth phase of dogs is therefore contra-indicated.
Occasionally vomiting may occur, but mainly at higher doses (3-5 times the proposed dose). At very high overdoses adverse reactions of the CNS have been noticed (ataxia, tremors, convulsions, etc.). At recommended dosage these CNS symptoms are not likely to occur.
Remarks on bio-equivalence of the various tablets, capsules and solution for injection:
Based on the conclusion of the assessment of the dossier “Dicural coated tablets”, the plain tablets, the capsules and the tablets (Dicural coated tablets) may be regarded as bio-equivalent. Similarly, it was shown that for the evaluation of safety and efficacy Dicural coated tablets and Dicural 50 mg/ml solution for injection for cattle and dogs may be regarded as bio-equivalent. Therefore, the results of the toxicity studies using plain tablets (tolerance) and capsules (repeated dose toxicity) are also applicable to Dicural 50 mg/ml solution for injection for cattle and dogs. Similarly, the results of the repeated dose toxicity studies and the tolerance studies may be also regarded as applicable to Dicural 50 mg/ml solution for injection for cattle and dogs. Local effects of oral and parenteral formulations will not be the same.
The applicant has provided a recent study on the local tolerance of dogs towards Dicural 50 mg/ml solution for injection for cattle and dogs. Daily doses of difloxacin were administered subcutaneously to Beagles (10 months old, 10 kg bw). Dosage: 0 (saline), 5 or 15 mg/kg bw/day during 5 consecutive days. For each dosage 2 male and 2 female dogs were used. One or 8 days after treatment 1 male and 1 female animal of each dose group were killed and necropsied. Both macroscopic and microscopic post-mortem examinations were performed. During treatment all animals were observed for clinical signs of intolerance (behaviour, appetite, injection site reactions, etc.); body weights and food consumption were recorded regularly.
No changes in the clinical parameters were observed. Growth and food uptake of treated animals were similar to those of animals in the control group. However, in 100% of the difloxacin-treated animals there were injection site reactions. Generally, these reactions were transient, and disappeared within 2 days after administration of 5 mg/kg bw. The size of the largest injection site reaction was 10 x 50 cm. The extent (haemorrhage, inflammation, oedema, necrosis) and the size of the injection site reactions appeared to be dose-dependent. Microscopic examination of injection sites revealed that recovery of the tissue took about 12 days.
In conclusion, although the numbers of animals were small, local side-effects will occur when the product is used as recommended in the SPC; the main effect being the occurrence of injection site reactions. Macroscopic swelling, sometimes in combination with pruritic reactions, will occur. Microscopic haemorrhage, inflammation, oedema and necrosis may also be observed. However, the injection site reactions are transient. The results of this study are confirmed by the results of the monitoring of adverse reactions in the clinical efficacy trials.
Dicural Solution for Injection: Reproductive effects, including teratogenicity
The dossier of Dicural 50 mg/ml solution for injection for cattle and dogs contains no data on this subject. The Dicural coated tablets dossier contains several reports on maternal and foetal toxicity of difloxacin.
Reproductive toxicity studies were carried out in rats using oral administration. In a fertility and general reproductive performance study and a peri/post-natal study, no significant effects were found on reproductive performance, physical development, reflex responses or behaviour of the pups. There were adverse effects on maternal body weight gain and food consumption and foetal weight and pup body weight gain at 45 and/or 150 mg/kg bw. In a 3-generation study of reproductive performance in rats, fertility was reduced at 100 mg/kg bw but not at 50 mg/kg bw.
Difloxacin was not teratogenic in rats or rabbits. In rats, administration of oral doses of 65 mg/kg bw to the dams caused reduced foetal weight and foetal delayed ossification. The NOEL for foetoxicity was 15 mg/kg bw/day. Oral administration of 75 mg/kg bw per day to pregnant rabbits caused severe maternal toxicity and consequent foetotoxicity. No side-effects were seen at an oral dose of 35 mg/kg bw/day.
Although considerable data concerning reproductive toxicity, including teratogenicity, was provided, it was not possible to come to a final assessment of this issue and therefore a warning that the safety in pregnant, breeding or lactating animals has not been established will be included in the SPC, labelling and package inserts.
Difloxacin is considered to be a non-genotoxic substance.
Difloxacin was not carcinogenic in 2-year studies in rats and mice.
No specific data concerning the immunotoxicity of difloxacin were provided. The results of the repeated-dose studies in dogs and rodents revealed no haematological or histopathological changes indicative of an immunotoxic effect.
In a Magnusson and Kligman maximisation test in guinea pigs, difloxacin did not induce delayed contact hypersensitivity.
Dicural Solution for Injection: Observations in humans
Difloxacin is not authorised for administration to humans. Oral administration of difloxacin to male human volunteers at (single) doses ranging from 100 – 600 mg resulted in a low incidence of adverse reactions including headache, dizziness, disturbed sleep, nausea, vomiting and upset stomach. Some volunteers reported visual disturbances. Prothrombin time was significantly increased in comparison with controls, but not by more than 2 seconds above the normal range.
In vitro MIC data were provided for a range of micro-organisms which were representative of those found in the human gut. Based on these data, a microbiological ADI of 40.6 ug/kg bw per day was established. Because the microbiologically-derived ADI was higher than the toxicologically-derived ADI, the latter was used for the derivation of MRLs for difloxacin in cattle.
Dicural Solution for Injection: Risk-Benefit Assessment And Conclusion
The suitability of the specification for the active ingredient, the method of manufacture of the product and the validity of the test methods applied to the product have been satisfactorily presented in the Quality Part of the application. The quality data submitted confirm the acceptability of the proposed formulation.
In dogs, the product is to be administered once at 5 mg/kg body weight. Adverse effects such as pruritis and/or local swelling and pain reaction have been reported in the SPC. Symptoms of overdose have been observed at 10 times the recommended dose by oral administration showing mild adverse clinical signs such as orange/yellowing discoloration of the faeces, emesis and hypersalivation. Since signs of arthrogenic potential (induction of cartilage lesions) of difloxacin were observed in studies with immature dogs even at the recommended dose, the use of difloxacin in skeletally immature dogs is contraindicated.
The use of Dicural 50 mg/ml solution for injection is not likely to cause any serious systemic side-effects in cattle (calves and young cattle). However, incidental unsteadiness may occur especially at prolonged treatment. In most cases minor injection site reactions were observed, but occasionally more severe reactions have been found. At overdoses CNS symptoms, such as ataxia, unsteadiness shaking, tremors, twitching will occur. Also, at overdoses the injection site reactions are more severe. Finally, swelling and oedema formation in the knee joints have also been observed in calves, but without cartilage abnormalities.
Effects on pregnancy and lactation have not been investigated for Dicural 50 mg/ml solution for injection for cattle and dogs as it is stated in the SPC.
The use of difloxacin may result in an increase in prevalence of resistant strains. The SPC includes the statement that “heavy reliance on a single class antibiotic may result in the induction of resistance in a bacterial population”. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions which have responded poorly, or are expected to respond poorly, to other classes of antibiotic. Dicural 50 mg/ml solution for injection for cattle and dogs should only be used based on susceptibility testing due to known problems with increasing fluoroquinolone resistance. Given these limitations, the risk of an increase in prevalence of resistant strains is considered to be very limited within the target species for which the product is intended.
Due to the fact that the use of fluoroquinolones like difloxacin in combination with non steroidal anti-inflammatory drugs may cause seizures in dogs, a statement was included in the section 5.6 of the SPC: Interactions with other medicaments and other forms of interactions.
In dogs, it was concluded that Dicural 50 mg/ml solution for injection for cattle and dogs could be considered as bioequivalent from efficacy point of view to the Dicural coated tablets. Systemic tolerance also can be considered as similar with both products.
In view of the relatively good susceptibility of Pasteurella multocida and Mycoplasma spp. to difloxacin, and the pharmacokinetic data, it is expected that Dicural 50 mg/ml solution for injection for cattle and dogs in a dosage of 2.5-5 mg/kg bw/day for 3-5 days may be efficacious in the treatment of respiratory tract infections, caused by these two pathogens, in calves.
Based on preclinical results, the efficacy against Pasteur ella haemolytica is questionable. With MICs of 1-2 ug/ml Dicural at a dose of 2.5 mg/kg bw/day is not likely to be efficacious. Even the efficacy of a dose of 5 mg/kg bw/day is doubtful. However, based on the results from model studies and field trials, it was concluded that Dicural may also be efficacious against this pathogen.
The submitted clinical trials were considered to support the following claims:
- Treatment of superficial pyoderma caused by Staphylococcus intermedius,
- Treatment of acute, uncomplicated urinary tract infections, caused by Staphylococcus spp. and Escherichia coli.
Cattle (calves and young cattle) :
- Treatment of bovine respiratory disease (shipping fever, calf pneumonia) caused by single or mixed infections with Pasteurella haemolytica, Pasteurella multocida and/or Mycoplasma spp.
Based on the original and complementary data presented, the Committee for Veterinary Medicinal Products concluded that the quality, safety and efficacy of the product were considered to be in accordance with the requirements of Council Directive 81/852/EEC and supported the above claims.