Advocin 180 solution is a clear sterile aqueous formulation of danofloxacin mesylate that contains 180 mg danofloxacin per ml. Also contains the excipients phenol (2.5 mg/ml) and monothioglycerol (5 mg/ml).

Treatment of bovine respiratory disease caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, and for the treatment of acute bovine mastitis caused by Escherichia coli sensitive to danofloxacin.

Treatment of enteric infections caused by Escherichia coli sensitive to danofloxacin.

Intravenous or subcutaneous routes.

6 mg/kg bodyweight (1 ml/30 kg bodyweight) as a single injection.

If clinical signs of respiratory or enteric disease persist 48 hours after the first injection, an additional dose at 6 mg/kg bodyweight may be administered. It is recommended to treat animals in the early stages of disease and to evaluate the response to treatment within 48 hours.

For the treatment of acute bovine mastitis, the veterinary medicinal product should be administered at 6 mg/kg bodyweight (1 ml/30 kg bodyweight) as a single injection by the subcutaneous or intravenous route. The clinical signs should be monitored carefully and supportive therapy should be given as appropriate. If clinical signs of acute bovine mastitis persist 36-48 hours after the first injection, the antibiotic treatment should be reviewed. It is recommended to treat animals in the early stages of disease and to evaluate the response to treatment within 36-48 hours.

For treatment of cattle weighing more than 450 kg, divide the subcutaneous dose so that no more than 15 ml are injected at one site. When dosing a large number of animals from a single vial, the use of an automatic syringe is recommended to avoid excessive broaching of the rubber stopper.

To ensure a correct dosage, bodyweight should be determined as accurately as possible.

Do not use in cases of hypersensitivity to the active substance, to other (fluoro)quinolones or to any of the excipients.

Do not use in cases where the pathogen involved is resistant to other fluoroquinolones (due to the potential for cross resistance).

Use of fluoroquinolones should be based on susceptibility testing and take into account official and local antimicrobial use policies. It is prudent to reserve fluoroquinolones for the treatment of clinical conditions which have responded poorly to other classes of antimicrobials. Efficacy against gram positive strains has not been established.

For fluoroquinolones as a class, over-dosage at multiples of the recommended dose has been shown to induce erosion of articular cartilage. Care should be taken to dose accurately and the veterinary medicinal product should be used with caution in animals with joint disease or cartilage growth disorders.

Use of the veterinary medicinal product deviating from the instructions given above may increase the prevalence of bacteria resistant to fluoroquinolones and may decrease the effectiveness of treatment with other quinolones due to the potential for cross resistance.

Cattle:

TABLE

1 In sensitive animals, immediate or delayed.

Reporting adverse events is important. It allows continuous safety monitoring of a veterinary medicinal product. Reports should be sent, preferably via a veterinarian, to either the marketing authorisation holder or the national competent authority via the national reporting system. See also ‘Contact details’ of the package leaflet.

At doses of three times the therapeutic dose (18 mg/kg bw), erythema of the nasal and ocular mucosae was induced and food intake was reduced. At even higher doses and prolonged exposure, there was damage to the cartilage in the joints and some animals displayed paresis, ataxia or nystagmus.

Studies in laboratory animals have shown adverse effects on reproduction. At high doses in rats (100 to 200 mg/kg/day), increase in foetal delayed ossification and in dilation of the cerebral ventricles were observed. Dams given high doses produced fewer live pups per litter and pup weight and survival were adversely affected. The safety of the product has not been established during pregnancy in cows.

The safety of the veterinary medicinal product has not been established during pregnancy in cows nor assessed in breeding bulls.

Meat and offal: 8 days.

Milk: 4 days.

People with known hypersensitivity to (fluoro)quinolones should avoid contact with the veterinary medicinal product.

Care should be taken to avoid accidental self-injection as it can induce a slight irritation. In case of accidental self-injection, seek medical advice immediately and show the package leaflet or label to the physician.

In case of contact with skin or eyes rinse with plenty of water.

Wash hands after use. Do not eat, drink or smoke during application.

Store in the original packaging in order to protect from light.

Do not freeze.

Shelf life after first opening the immediate packaging: 28 days.

Medicines should not be disposed of via wastewater or household waste. Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

Keep out of the sight and reach of children.

For animal treatment only.

Multidose glass vials containing 50 ml or 100 ml. Not all pack sizes may be marketed.

Advocin 180 is rapidly and extensively absorbed from the site of injection. Bioavailability is around 90%. Danofloxacin is only poorly metabolised and subsequently eliminated via both the renal and hepatic routes. A difference in elimination kinetics is observed between pre-ruminant animals (half-life of 12 hours) and ruminant animals (half-life of 4 hours). Following a single subcutaneous administration at 6 mg/kg body weight, peak plasma and tissue concentrations are achieved within one to two hours after treatment. High drug concentrations in lung, enteric and lymphatic tissues are observed with concentrations in lung and enteric tissues approximately four times greater than in plasma. The dose selected for Advocin 180 was based on the optimisation of the concentration dependent bactericidal activity of danofloxacin against respiratory and enteric pathogens.

The mean milk concentrations of danofloxacin were 4.61 and 0.2 µg/ml at the 8 and 24 hour milking, respectively, following a single subcutaneous injection.

Heavy reliance on a single class of antibiotic may result in the induction of resistance in a bacterial population. Cross-resistance to fluoroquinolones can occur.

The antimicrobial activity of danofloxacin is based upon the inhibition of microbial DNA gyrase and topoisomerase IV. The inhibitory effect is on the second step of the enzymatic process, uncoupling the breakage and reunion functions. Danofloxacin produces a stable complex between the enzyme and DNA. This results in the cessation of DNA replication and transcription. The bactericidal effect is also observed on bacteria in the stationary growth phase. Although there is the possibility for cross resistance developing within any class of antimicrobial, because of the specific mode of action of fluoroquinolones cross resistance with other major antibiotics which act on the cell wall or on protein synthesis is unlikely to occur. Danofloxacin is efficacious in the treatment of field cases of acute mastitis with a Gram negative bacterial aetiology.

UK(GB): Vm 42058/5107

UK(NI): Vm 42058/3008