SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Cepravin Dry Cow 250mg Intramammary suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Constituent: per syringe

Cefalonium 0.250 g

(as cefalonium dihydrate)

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Intramammary suspension

4. CLINICAL PARTICULARS

4.1 Target species

Cattle

4.2 Indications for use, specifying the target species

Recommended for routine dry cow therapy to treat existing sub-clinical infections and to prevent new infections which occur during the dry period.

4.3 Contraindications

Not for use in the lactating cow.

Not intended for use within 54 days of calving.

4.4 Special Warnings:

No special warnings are considered necessary.

4.5 Special precautions for use

i. Special precautions for use in animals

Do not bend the nozzle.

Do not contaminate the nozzle

If calving occurs before 54 days after treatment, the absence of antibiotic should be confirmed by testing before the milk is used for human consumption. Milk for human consumption may be taken after 54 days plus 96 hours after treatment.

In cows suffering from hypocalcaemia it may be necessary to discard milk for a longer period.

If the product is used in heifers during their first pregnancy the same precautions should be observed as in cows, i.e. infusions should be given not less than 54 days before calving and milk discarded for the statutory four days after calving.

Summer Mastitis - It is unlikely that antibiotic treatment alone will control Summer Mastitis and therefore other measures should be implemented as part of routine management. These measures include:

- Practising some form of fly control on the farm.

- Avoiding pasturing cattle on wet or wooded fields which are known to be associated with Summer Mastitis.

- Post-infusion teat dipping of cows and heifers receiving prophylactic intramammary infusions for the disease.

- Prompt attention to teat injuries or sores as these rapidly attract flies.

- Farms with an intractable problem should consider changing the calving pattern to avoid having animals at risk during the summer months.

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

Wash hands after use.

Penicillin and cefalosporins may cause sensitisation (allergy) following injection, inhalation, ingestion or skin contact. Sensitivity to penicillin may lead to cross-sensitivity to cefalosporin and vice versa. Allergic reactions to these substances may occasionally be serious.

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

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

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 breathing are more serious symptoms and require urgent medical attention.

4.6 Adverse reactions

None known

4.7 Use during pregnancy, and lactation or lay

Intended for use during the last trimester of pregnancy once the lactating cow has been dried off. There is no adverse treatment effect on the foetus.

Not to be used in cows that are lactating.

4.8 Interaction with other medicinal products and other forms of interaction

There are no known interactions.

4.9 Amounts to be administered and administration route

For intramammary infusion.

The contents of one syringe should be infused into the teat canal of each quarter immediately after the last milking of the lactation. Before infusion, the teat should be thoroughly cleaned and disinfected. Avoid contamination of the nozzle after removing the cap. After infusion it is advisable to dip the teats in an antiseptic preparation specifically designed for this purpose.

After milking is complete thoroughly clean and disinfect the end of the teat with the cleaning towel provided.

Option 1: For short nozzle intramammary administration hold the barrel of the syringe and the base of the cap in one hand and twist off the small upper part of the cap above the indent mark (the base portion of the cap remains on the syringe). Take care not to contaminate the short exposed part of the nozzle.

Option 2: For full nozzle intramammary administration remove the cap fully by holding the barrel of the syringe firmly in one hand and with the thumb and push up and along the length of the cap until the cap clicks off. Take care not to contaminate the nozzle.

Insert the nozzle into the teat canal and apply steady pressure on the syringe plunger until the full dose has been delivered. Holding the end of the teat with one hand, gently massage upwards with the other to aid dispersion of the antibiotic into the quarter.

Finally immerse the teats in a teat dip.

4.10 Overdose

Repeated doses in cattle on three consecutive days did not demonstrate or produce any adverse effects.

4.11 Withdrawal period

Milk for human consumption may only be taken 96 hours after calving.

If calving occurs before 54 days after treatment, milk for human consumption may be taken after 54 days plus 96 hours after treatment, ensuring that the milk from at least 7 complete milking is discarded.

The absence of antibiotic should be confirmed by testing before its milk is used for human consumption. This is advisable because of variation in the milking cows ability to excrete antibiotic from dry cow products. In cows suffering from hypocalcaemia, it may be necessary to discard milk for a longer period.

Animals for human consumption should not be slaughtered until 21 days after last treatment.

5. PHARMACOLOGICAL PROPERTIES

Cepravin Dry Cow is a long-acting intramammary cerate containing cefalonium dihydrate, a semi-synthetic cefalosporin antibiotic. It is formulated to give persistent antibiotic levels in the dry udder.

5.1 Pharmacodynamics

The cefalosporins are a family of drugs which are similar in chemical structure to the penicillins. The major difference being that penicillins are based on a -lactam ring fused with a dihydrothiazine ring and cephalosporins on a -lactam ring fused with a thiazolidone ring. The two families of antibiotics are collectively known as -lactams.

Both cefalosporins and penicillins kill susceptible bacteria and the mode of action of the individual antibiotics of both families is the same.

The cell wall of bacteria is essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall which gives it rigidity. Peptidoglycan consists of glycan chains which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are linked by peptide chains. Cefalonium and other -lactams act by inhibiting the enzyme transpeptidase, usually following interaction with penicillin binding protein (PBP), which is responsible for the final stage of peptidoglycan synthesis. This inhibition of cell wall synthesis produces unstable forms of the bacterium during reproduction and these unstable forms lyse.

Therefore, these antibiotics are bactericidal in their mode of action.

-Lactam antibiotics cannot kill or even inhibit all bacteria as there are various methods by which bacteria become resistant. These mechanisms include non-susceptible PBPs, failure of the antibiotic to penetrate to the site of action and production of -lactamase enzymes. These enzymes hydrolyse the -lactam ring producing an inactive derivative. Cefalosporins in general are not susceptible to the actions of -lactamase enzymes, especially when compared with penicllin, ampicillin or amoxicillin.

The penicillins and cefalosporins have a high therapeutic index in both animals and man. The reason for this probably relates to their highly specific mode of action in attacking the bacterial cell wall. As mammalian cells do not have an outer cell wall like that found in bacteria the -lactams are without effect on mammalian cell division. The most common adverse effect of the cefalosporins is a hypersensitivity reaction which in most cases manifests as maculopapular skin rashes after several days of therapy. They may be accompanied by eosinophilia and fever. Anaphylactic reactions are rare with the cephalosporins. There are no data available specifically on the effects of cephalonium in man.

Cefalonium is a broad spectrum cefalosporin antibiotic which has bactericidal activity against the majority of organisms associated with bovine mastitis. The antibacterial activity is not impaired in the presence of milk.

Cefalonium is active against non--lactamase and -lactamase producing organisms:

Actinomyces pyogenes Citrobacter spp.

Corynebacterium ulcerans Enterobacter spp.

Escherichia coli Klebsiella spp. Proteus spp. Staphylococcus aureus

Penicillin resistant strains of Staphylococcus aureus

Streptococcus agalactiae Streptococcus dysgalactiae

Streptococcus uberis

Effective levels of cefalonium are maintained in most quarters for up 10 weeks after infusion of Cepravin Dry Cow. Cattle treated with Cepravin Dry Cow have a lower incidence of Streptococcus uberis infection during the dry period and the immediate post-calving period, with accompanying lower somatic cell counts.

5.2 Pharmacokinetics

The serum pharmacokinetics of cefalonium have not been investigated in definitive studies so the serum half-life is not known. Some work in dogs has shown that the drug is absorbed following oral administration.

Pharmacokinetics of cefalonium in the target species has only been investigated following intramammary administration. Studies were originally conducted using Cepravin Dry Cow containing non-radiolabelled cefalonium. The presence of cefalonium and/or its biologically active metabolites was detected in urine or serum using a microbiological assay.

These original studies have been supplemented by a new study using C-14 radiolabelled cefalonium incorporated into the Cepravin Dry Cow formulation. In this study the serum, urine, faeces, tissue and milk were examined for the presence of radiochemical content. The results showed that cefalonium was extensively but slowly absorbed from the udder and excreted primarily in the urine. Between 7 and 13% of the radioactivity was eliminated in urine on each of the first three days post dosing whilst daily excretion in faeces was < 1% over the same period.

Mean blood concentration of radioactivity remained fairly constant during approximately 10 days after dosing which is consistent with slow but prolonged absorption of cefalonium from the udder. Plasma levels of radioactivity were generally higher than those found in blood indicating limited uptake of cefalonium and its metabolites into blood cells.

The results of the earlier work support the conclusion of the radiolabelled work. In these 2 studies Cepravin Dry Cow was given as a single infusion to 4 and 2 cows respectively. In one of the studies 2 additional cows were given repeated infusions of the formulation for 3 days. Antibiotic activity was detected in urine at concentrations which indicated rapid and significant absorption from the udder. Absorption and elimination of cefalonium and its metabolites was however more rapid in the older studies.

There are no data on the pharmacokinetics of cefalonium in humans. However, cefalonium is structurally related to cefaloridine, differing only by the presence of a carbamoyl moiety at the para-position of the pyridine ring. Cefaloridine is used in man and administered by the parenteral route. The half-life is about 1-1.5 hours and only about 20% is bound to plasma proteins. It is reported to be poorly absorbed after oral administration. Given the similarity in structures, cefalonium probably has similar properties.

Many cefalosporins are eliminated unchanged in urine by humans and laboratory animals. It is therefore very likely that most of the radioactivity in urine at early time points will be present as unchanged cefalonium. Results from the new study in cows show however that this is not the situation with milk. For the early milkings post calving the concentration of cefalonium in milk accounts for only a small proportion of the total radioactive residue. This indicates that any metabolism/degradation takes place within the udder. However, in addition to analysis for cefalonium concentrations milk samples were also analysed for microbiological residues using a validated method. It was determined that the metabolites/degradation products had no antibiotic activity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aluminium Distearate

Liquid Paraffin

6.2 Incompatibilities

There are no known incompatibilities.

6.3 Shelf-Life

3 Years

6.4 Special precautions for storage

Do not store above 30 C.

6.5 Nature and composition of immediate packaging

Single dose 3g white polyethylene syringes with a red polyethylene dual push-fit cap.

Boxes of 20 syringes and cleaning towels; ‘Herd Pack’ of 200 syringes (10 boxes of 20 syringes and cleaning towels)

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

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

Intervet UK Ltd

Walton Manor

Walton

Milton Keynes

MK7 7AJ

Vm 01708/4577

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 01/01/2003

10. DATE OF REVISION OF THE TEXT

Date: December 2011