1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Dicural 100 mg/ml oral solution for chickens and turkeys

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains:

Difloxacin (as hydrochloride)

Benzyl alcohol

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Oral solution

4. CLINICAL PARTICULARS4.1 Target species

Chickens (broilers and future breeders)

Turkeys (young turkeys up to 2 kg body weight).

4.2 Indications for use, specifying the target species

In chickens and turkeys: Dicural oral solution is indicated for treatment of chronic respiratory infections caused by sensitive strains of Escherichia coli and Mycoplasma gallisepticum.

In turkeys : Dicural oral solution is also indicated for the treatment of infections caused by Pasteurella multocida.

4.3 Contraindications

Since no studies were performed in clinically lame birds, Dicural should not be used in birds with existing leg-weakness or in birds suffering from osteoporosis.

• ♦X

4.4 Special warnings for each target species

None.

4.5 Special precautions for use

Heavy reliance on a single class of antibiotics may result in the induction of resistance in a bacterial population. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions that have responded poorly, or are expected to respond poorly, to other classes of antibiotics.

Official and local antimicrobial policies should be taken into account when the product is used.

Whenever possible, fluoroquinolones should only be used based on susceptibility testing.

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

People with known hypersensitivity to quinolones should avoid any contact with the product. In order to avoid irritation of skin and/or eyes, use gloves and a face-protecting device w this product.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

4.7 Use during pregnancy, lactation or lay

Do not use in birds in lay and/or within 4 weeks before the onset of the laying period.

4.8 Interaction with other veterinary medicinal products and other forms of interaction

None known.

4.9 Amounts to be administered and administration route.

Dicural oral solution must be administrated daily via the drinking water in such a concentration that the dose is 10 mg/kg bodyweight. The administration must be continued for 5 days.

Taking into account the content of difloxacin in the oral solution (10%w/v), the following calculation should be made to determine the volume (ml) to be added for each 1000 litres of water:

number of animals in the house X mean weight of individual animal(kg) X 100 total water consumption of the house at the previous day (litres)

The medicated drinking water should be prepared freshly each day.

No other source of drinking water should be available during the medication period.

At concentrations in the water of 0.03% (= 300 ml in 1000 litres) or greater, palatability for turkeys may be affected.

4.10 Overdose (symptoms, emergency procedures, antidotes)

Target animal safety studies in chickens and turkeys demonstrated that, when administered in drinking water at 30 mg/kg (chickens) or 22 mg/kg (turkeys) for three times the recommended duration (15 consecutive days), difloxacin hydrochloride appeared to be safe for the birds.

Meat and offal (chickens and turkeys): 24 hours.

Not permitted for use in laying birds producing eggs for human consumption.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: general anti-infectives for systemic use; antibacterials for systemic use, quinolone antibacterials.

ATC vet code: QJ01MA94

The fluoroquinolones exert their antibacterial effect against both replicating an micro-organisms. Difloxacin hydrochloride is bactericidal in activity and ac DNA gyrase.

Strains of Escherichia coli , Pasteurella multocida , Mycoplasma gallisepticum isolated from broilers and turkeys have been shown to be sensitive to difloxacin.

5.2 Pharmacokinetic properties

Difloxacin is rapidly absorbed after oral administration to reach steady state plasma concentrations in a few hours after initiation of medication. Difloxacin is well distributed throughout the animal body, as was demonstrated by the tissue to plasma ratios. Difloxacin concentrations equal to or greater than the MICs for the relevant pathogens are achieved in all relevant tissues and maintained for as long as medication is continued.

Chickens :

In chickens difloxacin is nearly completely absorbed after oral administration (approx. 96%). It is well distributed in the body (Vd = 4.7 l/kg) and has a plasma elimination half-life of approximately 7 hours. Following continuous oral dosing with Dicural oral solution at 10 mg/kg/day for five consecutive days the mean difloxacin steady state plasma concentrations are approximately 200 ng/ml. Tissue to plasma ratios range from 0.6 (abdominal fat), 2.4 (lung), 4.5 (muscle) to 14.1 (liver).

Turkeys :

In turkeys difloxacin has a moderate oral bioavailability (approx. 58%). It is very well distributed in the body (Vd = 9.9 l/kg) and has a plasma elimination half-life of approximately 7 hours. Following continuous oral dosing of Dicural oral solution at 10 mg/kg/day for five consecutive days the mean difloxacin steady state plasma concentrations are approximately 60 ng/ml. Tissue to plasma ratios range from 2.5 (abdominal fat), 3.7 (muscle), 4.8 (lung) to 36.5 (liver).

In both species difloxacin may be conjugated (glucuronidated or sulphated), desmethylated into sarafloxacin or oxidised into N-oxide-difloxacin. The main metabolites are hydrolysable conjugates of difloxacin, the other metabolites are proportionally minor ones.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Edetic acid

Potassium hydroxide

Propylene glycol Benzyl alcohol Purified water

6.2 Incompatibilities

No additional chlorine, for example from the use of water chlorinators, or hydrogen peroxide should be added to the drinking water used with this product.

• 6.3 Shelf-life

  
  

Shelf life of the veterinary medicinal product as packaged for sale: 3 years.

Medicated water must be freshly prepared daily.

Shelf life after first opening the container: 1 month.

6.4 Special precautions for storage

Do not store above 25 °C. Protect from light. Do not freeze.

6.5 Nature and composition of immediate packaging

White HDPE bottles with a screw cap containing 250ml or 1litre of Dicural oral solution.

The screw cap on the 1 litre bottle can be used as measuring device. If filled to the brim the measuring device provides 50ml. For the 250ml bottle a separate measuring device is placed on the screw cap.

Measuring lines indicate the volume supplied.

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products, if any

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich

Kent CT13 9NJ United Kingdom

8. MARKETING AUTHORISATION NUMBERS9. DF RENEWAL OF THE AUTHORISATION

Not applicable.

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Dicural 15 mg coated tablets for dogs Dicural 50 mg coated tablets for dogs Dicural 100 mg coated tablets for dogs

Dicural 150 mg coated tablets for dogs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Each tablet contains:

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Coated tablets

4. CLINICAL PARTICULARS4.1 Tar­get species

Dogs

• 4.2 Indications for use, specifying the target species

For the treatment of:

• • Acute uncomplicated urinary tract infections caused by Escherichia coli or Staphylococcus spp
• • Superficial pyoderma caused by Staphylococcus intermedius.

4.3 Contraindi­cations

As for other quinolones, due to possible adverse effects on the articular cartilage of weight bearing joints difloxacin should not be used during the rapid growth phase, that is, do not use in small and medium-sized breeds of dogs up to and including 8 months of age, in large breeds up to 1 year of age and in giant breeds up to 18 months of age.

• ♦ \ i

Do not use in epileptic dogs.

None known.

• 4.5 Special precautions for use

  Heavy reliance on a single class of antibiotics may result in the induction of resistance in a bacterial population. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions that have responded poorly, or are expected to respond poorly, to other classes of antibiotic.

Special precautions to be taken by the person administering the veterinary medicinal produc animals.

People with known hypersensitivity to quinolones should avoid any contact with the product.

• 4.6 Adverse reactions (frequency and seriousness)

Adverse reactions were rare in dogs treated with difloxacin. The observed reac

emesis, diarrhoea, and anal irritation. These adverse reactions were self-limiting within one or two days and did not require additional treatment.

• 4.7 Use during pregnancy, lactation or lay

The reproductive safety of the veterinary medicinal product has only been evaluated in laboratory animals, the use of difloxacin in pregnant or lactating bitches or male stud dogs is therefore not recommended.

• 4.8 Interaction with other veterinary medicinal products and other forms of interaction

The use of fluoroquinolones in combination with non-steroidal anti-inflammatory drugs (NSAIDs) may cause seizures.

Antacids may interfere with gastro-intestinal absorption.

Nitrofurantoin may impair quinolone efficacy if used concurrently in the treatment of urinary tract infections.

• 4.9 Amounts to be administered and administration route

The recommended dose of difloxacin is 5 mg/kg bodyweight per day. Dicural coated tablets should be given once a day for at least 5 days. Superficial pyoderma may require treatment for up to a maximum of 21 days. The tablets should be administered for at least 2 days beyond the cessation of clinical signs.

Therapy should be re-evaluated if no improvement is seen within 5 days, or 10 days in the case of superficial pyoderma.

4.10 Overdose (symptoms, emergency procedures, antidotes)

• ♦ vJ

Dogs treated orally with difloxacin (as hydrochloride) at 10 times the recommended dose for 10 days occasionally showed mild adverse reactions such as orange/yellowing discoloration of the faeces, emesis and hypersalivation.

Histopathological changes were noted in the articular cartilage of weight bearing joints of young (3.5 months old) beagle dogs after the oral administration of difloxacin at doses of greater than 5 mg/kg/day (as the hydrochloride) for 90 days.

No specific antidotes for difloxacin (or other quinolones) are known, therefore, in case of overdose symptomatic treatment should be given.

• 4.11 Withdrawal period

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: general anti-infectives for systemic use; antibacterials for s quinolone antibacterials.

ATC vet code: QJ01MA94

Difloxacin is an aryl-fluoroquinolone with a broad spectrum of antimicrobial activity. Difloxacin can be bactericidal against many Gram-negative micro-organisms and a selection of Gram-positive microorganisms.

5.1 Pharmacodynamic properties

The fluoroquinolones exert their antibacterial effects against both replicating and dormant microorganisms. Difloxacin acts primarily through inhibition of bacterial DNA gyrase.

The following organisms were tested and found to be susceptible to difloxacin in vitro :

Escherichia coli

Klebsiella spp.

Pasteurella spp.

Pseudomonas spp.

Staphylococcus intermedius

The following organisms were found to be of intermediate susceptibility:

,O

5.2 Pharmacokinetic properties

Following an oral dose (a plain tablet) in dogs of 5 mg/kg bodyweight, difloxacin reached its average peak plasma concentration of 1.8 ^g/ml in approximately 3 hours. Approximately 95 % of the oral dose was absorbed. The elimination half-life averaged 9.3 hours.

Long term daily oral treatment over 180 days at 5 mg/kg bodyweight did not influence difloxacin kinetics, neither by accumulation nor by increased drug metabolism.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium starch glycollate Microcrystalline cellulose Magnesium stearate Colloidal silicon dioxide Sodium lauryl sulphate

Lactose

Sodium croscarmellose

Micronised brewer’s yeast

Aromatic liver flavour

6.2 Incompati­bilities

Not applicable.

• 6.3 Shelf-life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years

6.4 Special precautions for storage

Do not store above 25°C. Store in a dry place.

6.5 Nature and contents of container

PVC/aluminium blisters with 10 tablets per blister. Cardboard boxes of 1, 2 or 10 blisters.

Not all pack sizes may be marketed.

• 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products, if any

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDERHORISATION NUMBERS

Pfizer Limited Ramsgate Road Sandwich

Kent CT13 9NJ United Kingdom

EU/2/97/003/004–015

RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Dicural 50 mg/ml solution for injection for cattle and dogs.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Difloxacin (as hydrochloride)

Excipients:

Benzyl alcohol

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS4.1 Tar­get species

Cattle (calves and young cattle)

Dogs.

• 4.2 Indications for use, specifying the target species

In cattle: Dicural 50 mg/ml solution for injection is indicated 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.

In dogs : Dicural 50 mg/ml solution for injection is indicated for the treatment of:

• • Acute uncomplicated urinary tract infections caused by Escherichia coli or Staphylococcus spp
• • Superficial pyoderma caused by Staphylococcus intermedius.

4.3 Contraindi­cations

Cattle:

None. f(j

Dogs:

As for other quinolones, due to possible adverse effects on the articular cartilage of weight bearing joints difloxacin should not be used during the rapid growth phase. Therefore, do not use in small and medium-sized breeds of dogs up to and including 8 months of age, in large breeds up to 1year of age and in giant breeds up to 18 months of age.

Do not use in epileptic dogs.

• 4.4 Special warnings for each target species

None known.

• 4.5 Special precautions for use

  Heavy reliance on a single class of antibiotics may result in the induction of resistance in a bacterial population. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions that have responded poorly, or are expected to respond poorly, to other classes of antibiotic.

Whenever possible, fluoroquinolones should only be used based on susceptibility testing.

Official and local antimicrobial policies should be taken into account when the product is used.

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

Special precautions to be taken by the person administering the veterinary medicinal product to animals

People with a known hypersensitivity to quinolones should avoid any contact with the product.

• 4.6 Adverse reactions (frequency and seriousness)

Cattle:

In target animal safety studies, subcutaneous administration was generally well tolerated. Transient swelling at the injection site following administration may occur.

Dogs:

In target animal safety studies, subcutaneous administration was generally well tolerated. Pruritis and/or local swellings and occasionally a slight pain reaction on injection have been observed. In general the pruritis disappears within a few minutes and the local swelling within a few days.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation.

• 4.8 Interaction with other veterinary medicinal products and other forms of interaction

The use of fluoroquinolones in combination with non-steroidal anti-inflammatory drugs (NSAIDs) may cause seizures.

Antagonism may be observed with nitrofurantoin.

• 4.9 Amounts to be administered and administration route

• ♦ vJ

Subcutaneous use

Cattle:

The recommended dose is 2.5mg difloxacin/kg bodyweight/day for 3 days (i.e. 5ml/100 kg bodyweight/day). If there is insufficient improvement after 3 days, the treatment can be continued for another 2 days.

For complicated respiratory disease the dose can be doubled to 5 mg/kg bodyweight/ day.

The volume administered per injection site in cattle should not exceed 7 ml. A new injection site should be used each day

Dogs:

The recommended dose is a single injection of 5.0 mg difloxacin/kg bodyweight Treatment must be continued with Dicural coated tablets (see that SPC)

The volume administered per injection site in dogs should not exceed 5 ml.

4.10 Overdose (symptoms, emergency procedures, antidotes)

Cattle:

At very high doses adverse effects on the nervous system (ataxia, unsteadiness, twitching, tremors, convulsions, etc) may occur in cattle. Overdosage may also give rise to oedema and swelling in the knee joints.

Dogs:

The oral administration of difloxacin at up to 5 times the recommended dose rate for 30 days did not result in any adverse reactions.

In another study, dogs treated orally with difloxacin at 10 times the recommended dose for 10 days showed occasionally mild adverse reactions such as orange/yellowing discoloration of the faeces, emesis and hypersalivation.

No specific antidotes for difloxacin (or other quinolones) are known, therefore in case of overdosage symptomatic treatment should be given.

• 4.11 Withdrawal period

Cattle :

Meat and offal: 46 days

Dogs:

Not applicable

5. PHARMACOLOGICAL PROPERTIES5.1 Phar­macodynamic properties

Pharmacotherapeutic group: general anti-infectives for systemic use; antibacterials for systemic use, quinolone antibacterials.

ATC vet code: QJ01MA94

The 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.

The following organisms were tested and found to be susceptible to difloxacin in vitro :

MPaysctoepulraella spp.

sma spp.

Escherichia coli

Staphylococcus intermedius

The following organism was found to be of intermediate susceptibility:

Staphylococcus spp.

Induction of resistance against quinolones can develop by mutations in the gyrase gene of bacteria and by changes in cell permeability towards quinolones

5.2 Pharmacokinetic properties

Cattle:                                X.

After subcutaneous administration of difloxacin peak plasma levels of 1.7 pg/ml are achieved at 6 hours post dosing. After subcutaneous administration the bioavailability is 88% and the volume of distribution is 2.5 l/kg.

The parent compound difloxacin is the major component in the faeces and tissues. In the urine, liver, fat and kidneys the metabolites desmethyl-difloxacin and difloxacin N-oxide can be found in small amounts in addition to the major (parent) compound.

The clearance of difloxacin after subcutaneous administration to cattle is 229 ml/h/kg. A half-life time of 7.7 hours has been observed. The majority of difloxacin (i.e. 68 – 82%) is excreted via the faeces. A fraction of difloxacin (i.e. 7 – 18%) is eliminated via the urine.

Dogs:

After subcutaneous administration of difloxacin peak plasma levels of 1.4 –1.9 pg/ml are achieved in 3.1 hours post dosing. After subcutaneous administration the bioavailability is 96%. The volume of distribution is 2.6 l/kg. A half-life time of 5.8 hours has been observed. The majority of difloxacin is excreted via the faeces. A fraction of difloxacin is eliminated by the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Ethanol

Benzyl alcohol Propylene glycol Arginine

Water for injections

In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products

• 6.3 Shelf-life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years

Shelf life after first use of the product: 28 days

6.4 Special precautions for storage

Do not store above 25 °C.

Do not freeze.

Keep the container in the outer carton.

• 6.5 Nature and composition of immediate packaging

Dogs:

Cardboard box with one glass vial of 50ml with a rubber stopper and aluminium cap.

Cattle:

Cardboard box with one glass vial of 50ml, 100ml or 250 ml with a rubber stopper and aluminium cap.

Not all pack sizes may be marketed.

• 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products, if any

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

• 8. MARKETING AUTHORISATION NUMBERS

• 9. DATE OF RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Dicural 15 mg coated tablets for dogs Dicural 50 mg coated tablets for dogs Dicural 100 mg coated tablets for dogs

Dicural 150 mg coated tablets for dogs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Coated tablets

4. CLINICAL PARTICULARS4.1 Target species

Dogs

4.2 Indications for use, specifying the target species

For the treatment of:

• • Acute uncomplicated urinary tract infections caused by Escherichia coli or Staphylococcus spp
• • Superficial pyoderma caused by Staphylococcus intermedius.

4.3 Contraindications

As for other quinolones, due to possible adverse effects on the articular cartilage of weight bearing joints difloxacin should not be used during the rapid growth phase, that is, do not use in small and medium-sized breeds of dogs up to and including 8 months of age, in large breeds up to 1 year of age and in giant breeds up to 18 months of age.

• ♦ \ i

Do not use in epileptic dogs.

None known.

4.5 Special precautions for use

Heavy reliance on a single class of antibiotics may result in the induction of resistance in a bacterial population. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions that have responded poorly, or are expected to respond poorly, to other classes of antibiotic.

People with known hypersensitivity to quinolones should avoid any contact with the product.

4.6 Adverse reactions (frequency and seriousness)

Adverse reactions were rare in dogs treated with difloxacin. The observed reac

emesis, diarrhoea, and anal irritation. These adverse reactions were self-limiting within one or two days and did not require additional treatment.

4.7 Use during pregnancy, lactation or lay

The reproductive safety of the veterinary medicinal product has only been evaluated in laboratory animals, the use of difloxacin in pregnant or lactating bitches or male stud dogs is therefore not recommended.

4.8 Interaction with other veterinary medicinal products and other forms of interaction

The use of fluoroquinolones in combination with non-steroidal anti-inflammatory drugs (NSAIDs) may cause seizures.

Antacids may interfere with gastro-intestinal absorption.

Nitrofurantoin may impair quinolone efficacy if used concurrently in the treatment of urinary tract infections.

4.9 Amounts to be administered and administration route

The recommended dose of difloxacin is 5 mg/kg bodyweight per day. Dicural coated tablets should be given once a day for at least 5 days. Superficial pyoderma may require treatment for up to a maximum of 21 days. The tablets should be administered for at least 2 days beyond the cessation of clinical signs.

Therapy should be re-evaluated if no improvement is seen within 5 days, or 10 days in the case of superficial pyoderma.

4.10 Overdose (symptoms, emergency procedures, antidotes)

• ♦ vJ

Dogs treated orally with difloxacin (as hydrochloride) at 10 times the recommended dose for 10 days occasionally showed mild adverse reactions such as orange/yellowing discoloration of the faeces, emesis and hypersalivation.

Histopathological changes were noted in the articular cartilage of weight bearing joints of young (3.5 months old) beagle dogs after the oral administration of difloxacin at doses of greater than 5 mg/kg/day (as the hydrochloride) for 90 days.

No specific antidotes for difloxacin (or other quinolones) are known, therefore, in case of overdose symptomatic treatment should be given.

4.11 Withdrawal period

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: general anti-infectives for systemic use; antibacterials for s quinolone antibacterials.

ATC vet code: QJ01MA94

Difloxacin is an aryl-fluoroquinolone with a broad spectrum of antimicrobial activity. Difloxacin can be bactericidal against many Gram-negative micro-organisms and a selection of Gram-positive microorganisms.

5.1 Pharmacodynamic properties

The fluoroquinolones exert their antibacterial effects against both replicating and dormant microorganisms. Difloxacin acts primarily through inhibition of bacterial DNA gyrase.

The following organisms were tested and found to be susceptible to difloxacin in vitro :

Escherichia coli

Klebsiella spp.

Pasteurella spp.

Pseudomonas spp.

Staphylococcus intermedius

The following organisms were found to be of intermediate susceptibility:

5.2 Pharmacokinetic properties

Following an oral dose (a plain tablet) in dogs of 5 mg/kg bodyweight, difloxacin reached its average peak plasma concentration of 1.8 ^g/ml in approximately 3 hours. Approximately 95 % of the oral dose was absorbed. The elimination half-life averaged 9.3 hours.

Long term daily oral treatment over 180 days at 5 mg/kg bodyweight did not influence difloxacin kinetics, neither by accumulation nor by increased drug metabolism.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium starch glycollate Microcrystalline cellulose Magnesium stearate Colloidal silicon dioxide Sodium lauryl sulphate

Lactose

Sodium croscarmellose

Micronised brewer’s yeast

Aromatic liver flavour

6.2 Incompatibilities

Not applicable.

• 6.3 Shelf-life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years

6.4 Special precautions for storage

Do not store above 25°C. Store in a dry place.

6.5 Nature and contents of container

PVC/aluminium blisters with 10 tablets per blister. Cardboard boxes of 1, 2 or 10 blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products, if any

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDERHORISATION NUMBERS

Pfizer Limited Ramsgate Road Sandwich

Kent CT13 9NJ United Kingdom

EU/2/97/003/004–015

10. DATE OF REVISION OF THE TEXT

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Dicural 50 mg/ml solution for injection for cattle and dogs.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Difloxacin (as hydrochloride)

Benzyl alcohol

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS4.1 Target species

Cattle (calves and young cattle)

Dogs.

4.2 Indications for use, specifying the target species

In cattle: Dicural 50 mg/ml solution for injection is indicated 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.

In dogs : Dicural 50 mg/ml solution for injection is indicated for the treatment of:

• • Acute uncomplicated urinary tract infections caused by Escherichia coli or Staphylococcus spp
• • Superficial pyoderma caused by Staphylococcus intermedius.

4.3 Contraindications

Cattle:

None. f(j

Dogs:

As for other quinolones, due to possible adverse effects on the articular cartilage of weight bearing joints difloxacin should not be used during the rapid growth phase. Therefore, do not use in small and medium-sized breeds of dogs up to and including 8 months of age, in large breeds up to 1year of age and in giant breeds up to 18 months of age.

Do not use in epileptic dogs.

4.4 Special warnings for each target species

None known.

4.5 Special precautions for use

Heavy reliance on a single class of antibiotics may result in the induction of resistance in a bacterial population. It is prudent to reserve the fluoroquinolones for the treatment of clinical conditions that have responded poorly, or are expected to respond poorly, to other classes of antibiotic.

Whenever possible, fluoroquinolones should only be used based on susceptibility testing.

Official and local antimicrobial policies should be taken into account when the product is used.

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

People with a known hypersensitivity to quinolones should avoid any contact with the product.

4.6 Adverse reactions (frequency and seriousness)

Cattle:

In target animal safety studies, subcutaneous administration was generally well tolerated. Transient swelling at the injection site following administration may occur.

Dogs:

In target animal safety studies, subcutaneous administration was generally well tolerated. Pruritis and/or local swellings and occasionally a slight pain reaction on injection have been observed. In general the pruritis disappears within a few minutes and the local swelling within a few days.

4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation.

4.8 Interaction with other veterinary medicinal products and other forms of interaction

The use of fluoroquinolones in combination with non-steroidal anti-inflammatory drugs (NSAIDs) may cause seizures.

Antagonism may be observed with nitrofurantoin.

• 4.9 Amounts to be administered and administration route

• ♦ vJ

Subcutaneous use

Cattle:

The recommended dose is 2.5mg difloxacin/kg bodyweight/day for 3 days (i.e. 5ml/100 kg bodyweight/day). If there is insufficient improvement after 3 days, the treatment can be continued for another 2 days.

For complicated respiratory disease the dose can be doubled to 5 mg/kg bodyweight/ day.

The volume administered per injection site in cattle should not exceed 7 ml. A new injection site should be used each day

Dogs:

The recommended dose is a single injection of 5.0 mg difloxacin/kg bodyweight Treatment must be continued with Dicural coated tablets (see that SPC)

The volume administered per injection site in dogs should not exceed 5 ml.

4.10 Overdose (symptoms, emergency procedures, antidotes)

Cattle:

At very high doses adverse effects on the nervous system (ataxia, unsteadiness, twitching, tremors, convulsions, etc) may occur in cattle. Overdosage may also give rise to oedema and swelling in the knee joints.

Dogs:

The oral administration of difloxacin at up to 5 times the recommended dose rate for 30 days did not result in any adverse reactions.

In another study, dogs treated orally with difloxacin at 10 times the recommended dose for 10 days showed occasionally mild adverse reactions such as orange/yellowing discoloration of the faeces, emesis and hypersalivation.

No specific antidotes for difloxacin (or other quinolones) are known, therefore in case of overdosage symptomatic treatment should be given.

4.11 Withdrawal period

Cattle :

Meat and offal: 46 days

Dogs:

Not applicable

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: general anti-infectives for systemic use; antibacterials for systemic use, quinolone antibacterials.

ATC vet code: QJ01MA94

The 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.

The following organisms were tested and found to be susceptible to difloxacin in vitro :

MPaysctoepulraella spp.

sma spp.

Escherichia coli

Staphylococcus intermedius

The following organism was found to be of intermediate susceptibility:

Staphylococcus spp.

Induction of resistance against quinolones can develop by mutations in the gyrase gene of bacteria and by changes in cell permeability towards quinolones

5.2 Pharmacokinetic properties

Cattle:                                      X.

After subcutaneous administration of difloxacin peak plasma levels of 1.7 pg/ml are achieved at 6 hours post dosing. After subcutaneous administration the bioavailability is 88% and the volume of distribution is 2.5 l/kg.

The parent compound difloxacin is the major component in the faeces and tissues. In the urine, liver, fat and kidneys the metabolites desmethyl-difloxacin and difloxacin N-oxide can be found in small amounts in addition to the major (parent) compound.

The clearance of difloxacin after subcutaneous administration to cattle is 229 ml/h/kg. A half-life time of 7.7 hours has been observed. The majority of difloxacin (i.e. 68 – 82%) is excreted via the faeces. A fraction of difloxacin (i.e. 7 – 18%) is eliminated via the urine.

Dogs:

After subcutaneous administration of difloxacin peak plasma levels of 1.4 –1.9 pg/ml are achieved in 3.1 hours post dosing. After subcutaneous administration the bioavailability is 96%. The volume of distribution is 2.6 l/kg. A half-life time of 5.8 hours has been observed. The majority of difloxacin is excreted via the faeces. A fraction of difloxacin is eliminated by the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Ethanol

Benzyl alcohol Propylene glycol Arginine

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products

6.3 Shelf-life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years

Shelf life after first use of the product: 28 days

6.4 Special precautions for storage

Do not store above 25 °C.

Do not freeze.

Keep the container in the outer carton.

6.5 Nature and composition of immediate packaging

Dogs:

Cardboard box with one glass vial of 50ml with a rubber stopper and aluminium cap.

Cattle:

Cardboard box with one glass vial of 50ml, 100ml or 250 ml with a rubber stopper and aluminium cap.

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products, if any

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

8. MARKETING AUTHORISATION NUMBERS

10. DATE OF REVISION OF THE TEXT