SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Cefenil RTU, 50 mg/ml, Suspension for Injection for Swine and Cattle

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains:

Active substance:

Ceftiofur (as hydrochloride) 50 mg

Excipient(s):

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Suspension for injection.

A white to yellowish coloured oily suspension.

4. CLINICAL PARTICULARS

4.1 Target species

Swine and Cattle

Infections associated with bacteria sensitive to Ceftiofur:

Swine:

For the treatment of bacterial respiratory disease associated with Pasteurella multocida, Actinobacillus pleuropneumoniae and Streptococcus suissensitive to ceftiofur.

Cattle:

For the treatment of bacterial respiratory disease associated with Mannheimia haemolytica, Pasteurella multocidaand Histophilus somni sensitive to ceftiofur.

For the treatment of acute interdigital necrobacillosis (panaritium, foot rot), associated with Fusobacterium necrophorum and Bacteroides melaninogenicus(Porphyromonas asaccharolytica) sensitive to ceftiofur.

For treatment of the bacterial component of acute post-partum (puerperal) metritis within 10 days after calving associated with, Arcanobacterium pyogenesand Fusobacterium necrophorum, sensitive to ceftiofur. The indication is restricted to cases where treatment with another antimicrobial has failed.

4.3 Contraindications

Do not administer to an animal previously found to be hypersensitive to Ceftiofur and other -lactam antibiotics or to any of the excipient(s).

Do not use in cases of known resistance to other cephalosporins or beta-lactam antibiotics

Do not use intravenously.

Do not use in poultry (including eggs) due to risk of spread of antimicrobial resistance to humans

4.4 Special warnings for each target species

None known

4.5 Special precautions for use

Special precautions for use in animals

This product selects for resistant strains such as bacteria carrying extended spectrum betalactamases (ESBL) and may constitute a risk to human health if these strains disseminate to humans e.g. via food. For this reason, the product should be reserved for the treatment of clinical conditions which have responded poorly, or are expected to respond poorly (refers to very acute cases when treatment must be initiated without bacteriological diagnosis) to first line treatment. Official, national and regional antimicrobial policies should be taken into account when the product is used. Increased use, including use of the product deviating from the instructions given in the SPC, may increase the prevalence of such resistance. Whenever possible, the product should only be used based on susceptibility testing.

This product is intended for treatment of individual animals. Do not use for disease prevention or as a part of heard health programmes. Treatment of groups of animals should be strictly restricted to ongoing disease outbreaks according to the approved conditions of use.

Do not use as prophylaxis in case of retained placenta.

Special precautions to be taken by the person administering the medicinal products to animals

Penicillins and cephalosporins may cause hypersensitivity (allergy) following injection, inhalation, ingestion or skin contact. Hypersensitivity to penicillins may lead to cross reactions to cephalosporins and vice versa. Allergic reactions to these substances may occasionally be serious.

1. Do not handle this product if you know you are sensitised, or if you have been advised not to work with such preparations.

2. Handle this product with great care to avoid exposure, taking all recommended precautions.

3. If you develop symptoms following exposure such as a skin rash, you should seek medical advice and show the doctor this warning. Swelling of the face, lips or eyes or difficulty with breathing, are more serious symptoms and require urgent medical attention.

Wash hands after use.

4.6 Adverse reactions (frequency and seriousness)

In cattle, mild inflammatory reactions such as hardness at the injection site have been observed in some animals. Clinical resolution is reached in most animals by 21 days after injection.

In pigs, mild reactions at the injection site, such as discoloration of the fascia or fat, have been observed in some animals for up to 20 days after injection.

Hypersensitivity reactions unrelated to dose can occur. Allergic reactions (e.g. skin reactions, anaphylaxis) may occasionally occur

Studies in laboratory species have not produced any evidence of teratogenic, foetotoxic or maternotoxic effects or of abortion. Safety of the product has not been investigated in the target species during pregnancy. Use only according to the benefit/risk assessment by the responsible veterinarian.

4.8 Interaction with other medicinal products and other forms of interaction

The bactericidal properties of Beta-lactams are neutralised by simultaneous use of bacteriostatic antibiotics (macrolides, sulphonamides and tetracyclines).

4.9 Amount(s) to be administered and administration route

Swine:

3 mg Ceftiofur /kg bw/day for 3 days via intramuscular route, i.e. 1 ml/16 kg bw at each injection.

Cattle:

Respiratory disease: 1 mg Ceftiofur /kg bw/day for 3 to 5 days by subcutaneous injection, i.e. 1 ml/50 kg bw at each injection.

Acute interdigital necrobacillosis: 1 mg/kg bw/day for 3 days by subcutaneous injection, i.e. 1 ml/50 kg bw at each injection.

Acute post-partum metritis within 10 days after calving: 1 mg/kg bw/day for 5 consecutive days by subcutaneous injection, i.e. 1 ml/50 kg bw at each injection.

Subsequent injections must be given at different sites.

In case of acute post-partum metritis, additional supportive therapy might be required in some cases.

Before use, shake the bottle vigorouslyuntil the product appears adequately resuspended. The colour of the glass vial may not be uniform making it difficult to determine when the product is in suspension. Following shaking the absence of sediment can be confirmed most readily by inverting the vial and viewing the contents through the base of the vial.

To ensure a correct dosage body weight should be determined as accurately as possible to avoid underdosing.

The recommended maximum volume to be administered at a single injection site is 10 ml.

50 ml and 100 ml vials can only be broached a maximum of 50 times. 250 ml vials can only be broached a maximum of 85 times

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary

The low toxicity of Ceftiofur has been demonstrated in Swine using Ceftiofur sodium at doses in excess of 8 times the recommended daily dose of Ceftiofur intramuscularly administered for 15 consecutive days.

In cattle, no signs of systemic toxicity have been observed following substantial parenteral overdosages.

4.11 Withdrawal periods

Cattle:

Meat and offal: 5 days.

Milk: zero days.

Swine:

Meat and offal: 5 days.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antibacterials for systemic use, third generation cephalosporins

ATC vet code: QJ01D D90

5.1 Pharmacodynamic properties

Ceftiofur is a third generation cephalosporin, which is active against many Gram-positive and Gram-negative bacteria, including -lactamase producing strains. Ceftiofur inhibits the bacterial cell wall synthesis, thereby exerting bactericidal properties.

Beta-lactams act by interfering with synthesis of the bacterial cell wall. Cell wall synthesis is dependent on enzymes that are called penicillin-binding proteins (PBP's). Bacteria develop resistance to cephalosporins by four basic mechanisms: 1) altering or acquiring penicillin binding proteins insensitive to an otherwise effective -lactam; 2) altering the permeability of the cell to -lactams; 3) producing  -lactamases that cleave the -lactam ring of the molecule, or 4) active efflux.

Some -lactamases, documented in Gram-negative enteric organisms, may confer elevated MICs to varying degrees to third and fourth generation cephalosporins, as well as penicillins, ampicillins, -lactam inhibitor combinations, and first and second generation cephalosporins.

Ceftiofur is active against the following micro-organisms which are involved in respiratory diseases in Swine: Pasteurella multocida, Actinobacillus pleuropneumoniae and Streptococcus suis.

It is also active against bacteria involved in respiratory disease in cattle: Pasteurella multocida, Mannheimiahaemolytica, Histophilus somni; bacteria involved in acute bovine foot rot (interdigital necrobacillosis) in cattle: Fusobacterium necrophorum, Bacteroides melaninogenicus(Porphyromonas asaccharolytica); and bacteria associated with acute post-partum (puerperal) metritis in cattle: Arcanobacterium pyogenes and Fusobacterium necrophorum.

The following Minimum Inhibitory Concentrations (MIC) have been determined for Ceftiofur in European isolates of target bacteria, isolated from diseased animals:

Swine
Organism (number of isolates)	MIC range (µg/mL)	MIC90 (µg/mL)
A. pleuropneumoniae (28)	≤0.03*	≤ 0.03
Pasteurella multocida (37)	≤ 0.03 - 0.13	≤ 0.03
Streptococcus suis (495)	≤ 0.03 - 0.25	≤ 0.03
Cattle
Organism (number of isolates)	MIC range (µg/mL)	MIC90 (µg/mL)
Mannheimia spp. (87)	≤ 0.03*	≤ 0.03
P.multocida (42)	≤ 0.03 - 0.12	≤ 0.03
H.somnus (24)	≤ 0.03*	≤ 0.03
Arcanobacterium pyogenes (123)	≤ 0.03 - 0.5	0.25
Fusobacterium necrophorum (67)(isolates from cases of foot rot)	≤ 0.06 - 0.13	ND
Fusobacterium necrophorum (2)(isolates from cases of acute metritis)	≤ 0.03 - 0.06	ND

*No range; all isolates yielded the same value. ND: not determined.

The following breakpoints are recommended by CLSI for bovine and porcine respiratory pathogens currently on the label

Zone Diameter (mm)	MIC (μg/mL)	Interpretation
≥ 21	≤ 2.0	(S) Susceptible
18 - 20	4.0	(I) Intermediate
≤ 17	≥ 8.0	(R) Resistant

No breakpoints have been determined to date for the pathogens associated with foot rot or acute post-partum metritis in cows.

After administration, ceftiofur is quickly metabolised to desfuroylceftiofur, the principal active metabolite.

Desfuroylceftiofur has an equivalent anti-microbial activity to ceftiofur against the bacteria involved in respiratory disease in animals. The active metabolite is reversibly bound to plasma proteins. Due to transportation with these proteins, the metabolite concentrates at a site of infection, is active and remains active in the presence of necrotic tissue and debris.

In pigs given a single intramuscular dose of 3 mg/kg body weight (bw), maximum plasma concentrations of 11.8 ± 1.67 µg/mL were reached after 1 hour; the terminal elimination half-life (t½) of desfuroylceftiofur was 16.7 ± 2.3 hours. No accumulation of desfuroylceftiofur has been observed after a dose of 3 mg ceftiofur/kg bw/day administered daily over 3 days.

The elimination occurred mainly via the urine (more than 70 %). Average recoveries in faeces accounted for approximately 12-15 % of the drug.

Ceftiofur is completely bioavailable following intramuscular administration.

After a single 1 mg/kg dose given subcutaneously to cattle, maximum plasma levels of 2.85 ± 1.11 µg/mL are reached within 2 hours after administration. In healthy cows, a Cmax of 2.25 ± 0.79 µg/mL was reached in the endometrium 5 ± 2 hours after a single administration. Maximum concentrations reached in caruncles and lochiae of healthy cows were 1.11 ± 0.24 µg/mL and 0.98 ± 0.25 µg/mL, respectively.

The terminal elimination half-life (t½) of desfuroylceftiofur in cattle is 11.5 ± 2.57 hours. No accumulation was observed after a daily treatment over 5 days. The elimination occurred mainly via the urine (more than 55 %); 31 % of the dose was recovered in the faeces.

Ceftiofur is completely bioavailable following subcutaneous administration.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitan oleate

Aluminium Monostearate

Medium Chain Triglycerides

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

Shelf-life of the veterinary medicinal product as packaged for sale: Glass: 2 years, Plastic: 2 years

Shelf-life after first opening of the immediate packaging: 28 days

Do not store above 25° C.

Keep the vial in the outer carton in order to protect from light

50 ml, 100mL and 250mL type I clear glass vials or high density polyethylene (HDPE) vials.

Each vial is closed with a nitryl bung and sealed with an aluminium cap. 100mL and 250mL type I clear glass vials are presented in a protective plastic sleeve in order to minimise breakage

Not all pack sizes may be marketed

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

Norbrook Laboratories Limited

Station Works

Camlough Road

Newry

Co. Down

BT35 6JP

Northern Ireland

8. MARKETING AUTHORISATION NUMBER

Vm 02000/4330

9. DATE OF THE FIRST AUTHORISATION

06 July 2012

10. DATE OF REVISION OF THE TEXT

May 2016

17 May 2016