SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

STRENZEN 500/125 mg/g powder for use in drinking water for pigs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gram contains:

Active substance

Amoxicillin 500 mg

(corresponding to 573.88 mg of Amoxicillin trihydrate)

Clavulanic acid 125 mg

(corresponding to 148.88 mg of Potassium clavulanate)

Excipients:

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for use in drinking water

Yellowish to yellow fine powder

4. CLINICAL PARTICULARS

4.1 Target species

Pigs

4.2 Indications for use, specifying the target species

Treatment of clinical infections

• respiratory tract infections caused by Actinobacillus pleuropneumoniae, Pasteurella multocida, Streptococcus suis.

• gastrointestinal infections caused by Clostridium perfringens., E. coli . and Salmonella Typhimurium

where the causative pathogens are beta-lactamase producing strains of bacteria susceptible to amoxicillin in combination with clavulanic acid and where clinical experience and/or susceptibility testing indicates the combination as the drug of choice.

4.3 Contraindications

Do not use in case of hypersensitivity to penicillin or cephalosporin antibioticsor anyof the excipients.

The product should not be given to rabbits, guinea pigs, hamsters, gerbils or small herbivores.

4.4 Special warnings

The product should be given to pigs only.

4.5 Special precautions for use

The uptake of medication by animals can be altered as a consequence of illness. In case of insufficient uptake of feed/ water animals should be treated parenterally.

Use of the product should be based on susceptibility testing and should take into account official national and regional policies with respect to the use of broad spectrum antibiotics. Do not use in cases of bacteria sensitive to narrow spectrum penicillins or to amoxicillin as a single substance. Use of the product deviating from the instructions given in the SPC may increase the prevalence of bacteria resistant to amoxicillin and clavulanic acid, and may decrease the effectiveness of treatment with other β-lactam antibiotics, due to the potential for cross resistance.

Due to the resistance rate detected in some countries in porcine isolates of E. coli against amoxicillin in combination with clavulanic acid the product should be used for the treatment of infections caused by E. coli only after susceptibility testing has been carried out.

Administration of the product should not be used as a method to control non-clinical salmonella infections in pig herds. It is strictly recommended, that the product should not be used as a tool of salmonella control programmes.

In the case of a history of MRSA on a farm it is inappropriate to use a combination of amoxicillin and clavulanic acid as there is a likelihood to co-select for MRSA.

The use of the product should be combined with good management practices e.g. good hygiene, proper ventilation, no overstocking.

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.

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 with breathing are more serious symptoms and require urgent medical attention.

Avoid inhalation of dust. Wear either a disposable half-mask respirator conforming to European Standard EN149 or a non-disposable respirator to European Standard EN140 with a filter to EN143.

Wear gloves during preparation and administration of medicated water.

Wash any exposed skin after handling the product or medicated water.

Wash hands after use.

4.6 Adverse reactions (frequency and seriousness)

It is known that adverse reactions including mild gastrointestinal signs (diarrhoea and vomiting) and allergic reactions (skin reactions, anaphylaxis) may occur after administration of penicillins.

4.7 Use during pregnancy, lactation or lay

Laboratory studies in rats and mice have not produced any evidence of mutagenicity, teratogenic and foetotoxic effects.

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

Use only accordingly to the benefit/risk assessment by the responsible veterinarian.

4.8 Interaction with other medicinal products and other forms of interaction

In general penicillins may be inhibited by the antibiotics with bacteriostatic action such as macrolides, sulfonamides and tetracyclines. No specific data on interaction of the combination have been described in the veterinary literature available. Neomycin given orally inhibits the intestinal absorption of penicillin.

4.9 Amounts to be administered and administration route

Administration in drinking water.

Give 10mg of amoxicillin (in the form of trihydrate) and 2.5mg of clavulanic acid (in the form of potassium salt) per kg of body weight twice daily, i.e. 2g of product per 100 kg body weight twice daily. Treat for 5 days.

For the calculation of the amount to be administered every 12 hours the following formula can be used:

Number of pigs x average body weight (kg) x dose rate (0.02 g of product / kg body weight) twice daily. During the twice daily treatment periods, medicated drinking water should be the only water supply available. After all the medicated drinkingwater hasbeen consumed, resume the supply of unmedicated water.

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

The intake of medicated drinking water depends on the clinical conditions of the animals as well as on the weather/temperature. In order to obtain the correct dosage the concentration of the product should be adjusted accordingly.

For bulk medication twice daily : Half the calculated total daily dosage of the product is scattered onto the surface of tepid water (approximately 20°C) and stirred until evenly dispersed. Add the required amount of water to achieve a concentration of 0.6g – 3.0g of product per liter of drinking water and stir for 20 minutes to reach full solubility.

The administration of the medicated drinking water should be repeated every 12 hours.

Do not administer the product through a dosing pump (proportioner).

Do not use a water acidifier simultaneously

After reconstitution the medicated drinking water has to be consumed within 24 hours.

Do not use the product with water systems composed of metal.

4.10 Overdose

In case of severe hypersensitive reactions, the treatment should be discontinued and corticosteroids and adrenaline should be administered. Treatment should be symptomatic in other cases of adverse reactions.

4.11 Withdrawal period

Meat and offal: 1 day

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Combination of penicillins, incl. beta- lactamase inhibitors

ATC vet. code: QJ01CR02

5.1 Pharmacodynamic properties

The product is a combination of a β-lactam antibiotic with a β¬lactamase inhibitor which restores the potency of amoxicillin against strains producing β¬lactamases.

Amoxicillin is a bactericidal antibiotic, which acts by inhibiting the synthesis ofbacterial cell walls during bacterial multiplication. It inhibits cross-linkage between the linear peptidoglycan polymer chains in the cell wall of Gram-positive bacteria. Broad spectrum penicillin antibiotic amoxicillin is active also against a limited range of Gram negative bacteria where the outer layer of bacteria cell-wall is made up of lypopolysaccharide and protein.

There are three principal mechanisms of resistance to ß-lactam antibiotics: production of ß-lactamases, alteration of the PBP, diminished outer membrane permeation. One of the most important is inactivation of penicillin antibiotic with β-lactame enzymes produced by certain bacteria. These enzymes cleave the penicillin β-lactam ring and render the penicillin drug inactive.

Clavulanic acid acts as inhibitor of bacterial β-lactamases. It prevents destruction of the β-lactam ring and penicillins by β-lactamase enzymes. The reaction is irreversible and both the enzyme and the clavulanate are destroyed while the antibiotic activity is preserved.

The role of the clavulanic acid in the combination is not only to act as a ß-lactamases inhibitor. Clinical efficacy is dependent upon a number of factors including not only intrinsic antibacterial properties but also a positive interaction with host defenses. After exposure to an antibacterial compound, the resulting alteration of cell-wall integrity and changes in bacterial expression of surface proteins, surface charges and hydrophobicity can influence the rate of phagocytosis and the extent of intracellular killing of bacteria. An effect on the rates of phagocytosis and the intracellular killing functions of polymorphonuclear leucocytes was demonstrated in experimental studies.

Susceptibility and resistance patterns can vary with geographical area and bacterial strain, and may change over time.

Minimum inhibitory concentrations of the combination amoxicillin /clavulanic acid were determined against different bacterial strains:

Species (no. isolates/year)	MIC range (µg/ml)	MIC50 (µg/ml)	MIC90 (µg/ml)
P. multocida (888/’07-’11)	0.5 – 4.0	≤0.5	≤0.5
pleuropneumoniae (433/’09-’11)	0.5 –2.0	≤0.5	≤0.5
S. suis (110/’09)	0.06-0.25	≤0.06	≤0.06
E.coli (343/’09-’11)	0.5 – 128	8.0	32.0
C.perfringens (46/’11)	＜0.01-8.0	＜0.01	1.0
S.Typhimurium (509/’07)	2.0 -16.0	2.0	8.0

5.2 Pharmacokinetic particulars

The plasma pharmacokinetic properties of amoxicillin and clavulanic acid are relatively similar. Both compounds are stable in acid environment of the gastrointestinal tract.

After oral administration, amoxicillin and clavulanic acid are readily absorbed.

The absorption following oral administration does not appear to be inhibited by presence of food in the alimentary tract.

Both compounds penetrate well into diverse tissue fluids (pleural, synovial, peritoneal fluids) and inflammatory exudates but not through the blood-brain barrier.

Both compounds are largely eliminated by renal excretion.

Elimination half-lives of amoxicillin and clavulanic acid are not significantly different (i.e. 0.73 and 0.67h respectively).

Repeated treatment does not appear to result in any accumulation of amoxicillin and clavulanic acid.

Therapeutic concentrations of amoxicillin and clavulanic acid are achieved approximately one hour after dosing and may persist for several hours after administration.

The mean p.o. bioavailability was found to be 22.8% for amoxicillin and 44.7% for clavulanic acid.

The mean maximum plasma concentrations (Cmax) of amoxicillin and clavulanic acid were 3.14 and 2.42 mg⁄ L, and these were reached after 1.19 and 0.88 h respectively.

These pharmacokinetic parameters were obtained after administration of a combination of 20 mg/kg amoxicillin and 5 mg/kg clavulanic acid given as a single oral dose.

5.3 Environmental properties

Not applicable

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium citrate

Citric acid

Mannitol

6.2 Incompatibilities

This veterinary medicinal product must not be mixed with other veterinary products.

6.3 Shelf life

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

Shelf-life after first opening the immediate packaging: 7 days

Shelf-life after dilution or reconstitution according to directions: 24 hours

6.4. Special precautions for storage

Store below 25 °C.

Keep the container tightly closed in order to protect from moisture.

Store in a dry place.

6.5 Nature and composition of immediate packaging

Pack size 500g.

Product in a low density polyethylene (LDPE) bag packed in another polyethylene bag with desiccant sachet included in a Polypropylene container closed with tamper-evident push down lid.

Alternatively, the product is packaged in a laminated aluminum bag with a zipper closure.

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

Elanco Europe Ltd

Lilly House

Priestley Road

Basingstoke

Hampshire

RG24 9NL

8. MARKETING AUTHORISATION NUMBER

Vm00879/4076

9. DATE OF FIRST AUTHORISATION

03 December 2013

10. DATE OF REVISION OF THE TEXT

September 2016

Approved: 30 September 2016