Aivlosin - summary of medicine characteristics

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Tylvalosin (as tylvalosin tartrate) 42.5 mg/g

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Premix for medicated feeding stuff.

A beige granular powder.

4. CLINICAL PARTICULARS4.1 Target species

Pigs

• 4.2 Indications for use, specifying the target species

• • Treatment and metaphylaxis of swine enzootic pneumonia caused by susceptible strains of Mycoplasma hyopneumoniae in pigs. At the recommended dose, lung lesions and weight loss are reduced but infection with Mycoplasma hyopneumoniae is not eliminated.
• • Treatment of porcine proliferative enteropathy (ileitis) caused by Lawsonia intracellularis in herds where there is a diagnosis based on clinical history, post-mortem findings and clinical pathology results.
• • Treatment and metaphylaxis of swine dysentery, caused by Brachyspira hyodysenteriae in herds where the disease has been diagnosed.

4.3 Contraindications

None.

• 4.4 Special warnings for each target species

Acute cases and severely diseased pigs with reduced food or water intake should be treated with a suitable injectable product.

Generally, strains of B. hyodysenteriae have higher minimal inhibitory concentration (MIC) values in cases of resistance against other macrolides, such as tylosin. The clinical relevance of this reduced susceptibility is not fully explored. Cross-resistance between tylvalosin and other macrolides cannot be excluded.

• 4.5 Special precautions for use

Special precautions for use in animals

Good management and hygiene practices should be followed to reduce the risk of re-infection.

It is sound clinical practice to base treatment on susceptibility testing of the bacteria isolated from the animal. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of target bacteria.

Use of the veterinary medicinal product deviating from the instructions in the SPC may increase the risk of development and selection of resistant bacteria and decrease the effectiveness of treatment with other macrolides due to the potential for cross-resistance.

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

Tylvalosin has been shown to cause hypersensitivity (allergic) reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin should avoid contact with this product.

When mixing the veterinary medicinal product and handling the medicated premix, direct contact with eyes, skin and mucous membranes should be avoided. Personal protective equipment consisting of impervious gloves and a half-mask respirator conforming to European Standard EN 149 or a nondisposable respirator conforming to European Standard EN 140 with a filter conforming to European Standard EN 143 should be worn when mixing the product. Wash contaminated skin.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation in pigs. Use only in accordance with benefit-risk assessment by the responsible veterinarian.

Laboratory studies in animals have not produced any evidence of a teratogenic effect. Maternal toxicity in rodents has been observed at doses of 400 mg tylvalosin per kg bodyweight and above. In mice, a slight reduction in the foetal bodyweight was seen at doses causing maternal toxicity.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

• 4.9 Amounts to be administered and administration route

In-feed use.

For incorporation into dry feed only.

For treatment and metaphylaxis of swine enzootic pneumonia

The dose is 2.125 mg tylvalosin per kg bodyweight per day in-feed for 7 consecutive days.

Secondary infection by organisms such as Pasteurella multocida and Actinobacillus pleuropneumoniae may complicate enzootic pneumonia and require specific medication.

For treatment of porcine proliferative enteropathy (ileitis)

The dose is 4.25 mg tylvalosin per kg bodyweight per day in-feed for 10 consecutive da­ys.

For treatment and metaphylaxis of swine dysentery

The dose is 4.25 mg tylvalosin per kg bodyweight per day in-feed for 10 consecutive da­ys.

Important : these inclusion rates assume a pig eats the equivalent of 5% bodyweight per day.

In older pigs, or in pigs with reduced appetite, or on restricted feed intake, inclusion levels may need to be increased to achieve target dose. Where feed intake is reduced, use the following formula:

Dose rate (mg/kg bodyweight) x bodyweight (kg) Daily feed intake (kg) x Premix strength (mg/g)

As an adjunct to medication, good management and hygiene practices should be introduced in order to reduce the risk of infection and to control the build-up of resistance.

A horizontal ribbon mixer should be used to incorporate the product into the feeding stuff. It is recommended that Aivlosin is first mixed into 10 kg of the feeding stuff, followed by the rest of the feeding stuff and mixed well. Medicated feed may then be pelleted. Pelleting conditions involve a single pre-conditioning step with steam for 5 minutes and pelleting at not more than 70 °C under normal conditions.

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

No signs of intolerance have been observed in growing pigs at up to 10 times the recommended dose.

• 4.11 Withdrawal period(s)

Meat and offal: 2 days.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA92.

5.1 Pharmacodynamic properties

Tylvalosin tartrate is a macrolide antibiotic that has antibacterial activity against Gram-positive, some Gram-negative organisms and mycoplasma. It acts by inhibiting protein synthesis in the bacterial cell.

Macrolide antibiotics are metabolites or semi-synthetic derivatives of metabolites of soil organisms obtained by fermentation. They have differently sized lactone rings and are basic due to the dimethylamino group. Tylvalosin has a sixteen-membered ring.

Macrolides interfere with protein synthesis by reversibly binding to the 50S ribosome subunit. They bind to the donor site and prevent the translocation necessary for keeping the peptide chain growing. Their effect is essentially confined to rapidly dividing organisms. Macrolides are generally considered bacteriostatic and mycoplasmastatic.

It is considered that there are multiple mechanisms responsible for resistance development to macrolide compounds, namely alteration of the ribosomal target site, utilisation of active efflux mechanisms and production of inactivating enzymes.

Resistance to tylvalosin by Mycoplasma hyopneumoniae and Lawsonia intracellularis has not been reported or found in the field to date. No breakpoint for Brachyspira hyodysenteriae has been established.

Generally, strains of B. hyodysenteriae have higher MIC values in cases of resistance against other macrolides, such as tylosin. The clinical relevance of this reduced susceptibility is not fully explored. Cross-resistance between tylvalosin and other macrolide antibiotics cannot be excluded.

• 5.2 Pharmacoki­netic particulars

Tylvalosin tartrate is rapidly absorbed after oral administration of Aivlosin.

After administration of the recommended dose, lung concentrations of 0.060–0.066 ^g/ml were found at 2 and 12 hours post-treatment. The parent compound is widely distributed in the tissues with the highest concentrations found in the lungs, bile, intestinal mucosa, spleen, kidney and liver.

There is evidence that the concentration of macrolides is higher at the site of infection than in plasma, in particular in neutrophils, alveolar macrophages and alveolar epithelial cells.

In vitro metabolism studies have confirmed that the parent compound is rapidly metabolised to 3-O-acetyltylosin. In a trial with 14C-labeled Aivlosin administered at 2.125 mg/kg to pigs for 7 days, over 70% of the dose was excreted in the faeces, with urinary excretion accounting for 3 to 4% of the dose.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Hydrated magnesium silicate (sepiolite)

Wheat flour

Hydroxypropyl cellulose

Non-fat soyabean powder

6.2 Major 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: 3 years.

Shelf life after first opening of the immediate packaging: use immediately. Opened bags should not be stored.

Shelf life after incorporation into feed: 1 month in meal or pellets.

6.4 Special precautions for storage

Store below 30 °C.

Keep the container tightly closed.

Store in the original container.

• 6.5 Nature and composition of immediate packaging

One aluminium foil/polyester laminated bag containing 5 or 20 kg.

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

ECO Animal Health Europe Limited

6th Floor, South Bank House

Barrow Street

Dublin 4

D04 TR29

IRELAND

8. MARKETING AUTHORISATION NUMBERS

EU/2/04/044/001 – 20 kg

EU/2/04/044/002 – 5 kg

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 September 2004.

Date of last renewal: 9 September 2014.

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

Consideration should be given to official guidance on the incorporation of medicated premixes in final feed.

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance :

Tylvalosin (as tylvalosin tartrate) 625 mg/g.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Granules for use in drinking water.

White granules.

4. CLINICAL PARTICULARS4.1 Target species

Pigs

• 4.2 Indications for use, specifying the target species

Treatment and metaphylaxis of porcine proliferative enteropathy (ileitis) caused by Lawsonia intracellularis.

Treatment and metaphylaxis of swine enzootic pneumonia caused by susceptible strains of Mycoplasma hyopneumoniae.

The presence of the disease in the group must be established before metaphylaxis.

4.3 Contraindications

None.

• 4.4 Special warnings for each target species

In severely diseased pigs, if water intake is reduced, pigs should be treated with a suitable injectable veterinary medicinal product prescribed by a veterinarian.

At the recommended dose, lung lesions and clinical signs are reduced but infection with Mycoplasma hyopneumoniae is not eliminated.

• 4.5 Special precautions for use

Special precautions for use in animals

Official, national and regional antimicrobial policies should be taken into account when the product is used.

Good management and hygiene practices should be followed to reduce the risk of re-infection.

It is sound clinical practice to base treatment on susceptibility testing of the bacteria isolated from the animal. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of target bacteria.

Use of the veterinary medicinal product deviating from the instructions in the SPC may increase the risk of development and selection of resistant bacteria and decrease the effectiveness of treatment with other macrolides due to the potential for cross-resistance.

An antibacterial with a lower risk of antimicrobial resistance selection, if available for the same indication, should be used for first line treatment where susceptibility testing suggests the likely efficacy of this approach.

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

Tylvalosin has been shown to cause hypersensitivity (allergic) reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin should avoid contact with this product.

When mixing the veterinary medicinal product and handling the medicated water, direct contact with eyes, skin and mucous membranes should be avoided. Personal protective equipment consisting of impervious gloves and a half-mask respirator conforming to European Standard EN 149 or a nondisposable respirator conforming to European Standard EN 140 with a filter conforming to European Standard EN 143 should be worn when mixing the product. Wash contaminated skin.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation in pigs. Use only in accordance with benefit-risk assessment by the responsible veterinarian.

Laboratory studies in animals have not produced any evidence of a teratogenic effect. Maternal toxicity in rodents has been observed at doses of 400 mg tylvalosin per kg bodyweight and above. In mice, a slight reduction in the foetal bodyweight was seen at doses causing maternal toxicity.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

• 4.9 Amounts to be administered and administration route

For use in drinking water.

To ensure a correct dosage, bodyweight should be determined as accurately as possible. Water consumption should be monitored, and the concentration of the product adjusted if needed to avoid underdosing.

The product should be added to a volume of water that the pigs will consume in one day. No other source of drinking water should be available during treatment.

Porcine proliferative enteropathy (ileitis) caused by Lawsonia intracellularis

The dose is 5 mg tylvalosin per kg bodyweight per day in drinking water for 5 consecutive days.

Calculate the total amount of product required with the following formula:

Total weight of product in grams = total bodyweight of the heaviest pig to be treated in kg x number of pigs x 5/ 625.

Select the correct number of sachets according to the amount of product required.

The 40 g sachet is sufficient to treat a total of 5,000 kg of pigs (e.g. 250 pigs with the heaviest pig weighing 20 kg) for one day.

The 160 g sachet is sufficient to treat a total of 20,000 kg of pigs (e.g. 400 pigs with the heaviest pig weighing 50 kg) for one day.

The 400 g sachet is sufficient to treat a total of 50,000 kg of pigs (e.g. 1000 pigs with the heaviest pig weighing 50 kg) for one day.

Swine enzootic pneumonia caused by susceptible strains of Mycoplasma hyopneumoniae

The dose is 10 mg tylvalosin per kg bodyweight per day in drinking water for 5 consecutive days.

Calculate the total amount of product required with the following formula:

Total weight of product in grams = total bodyweight of the heaviest pig to be treated in kg x number of pigs to be treated x 10 / 625.

Select the correct number of sachets according to the amount of product required.

The 40 g sachet is sufficient to treat a total of 2,500 kg of pigs (e.g. 125 pigs with the heaviest pig weighing 20 kg) for one day.

The 160 g sachet is sufficient to treat a total of 10,000 kg of pigs (e.g. 200 pigs with the heaviest pig weighing 50 kg) for one day.

The 400 g sachet is sufficient to treat a total of 25,000 kg of pigs (e.g. 500 pigs with the heaviest pig weighing 50 kg) for one day.

Mixing instructions:

In order to achieve a correct dose, accurate and properly calibrated equipment should be used for weighing out the required amount of product.

The veterinary medicinal product may be mixed directly into the drinking water system or first mixed as a stock solution into a smaller amount of water, which is then added into the drinking water system.

When mixing the product directly into the drinking water system, the contents of the sachet should be sprinkled onto the surface of the water and mixed thoroughly until a clear solution is produced (usually within 3 minutes).

When preparing a stock solution, the maximum concentration should be 40 g of product per 1,500 ml, 160 g of product per 6,000 ml or 400 g of product per 15,000 ml water and it is necessary to mix the solution for 10 minutes. After this time, any remaining cloudiness will not affect the efficacy of the veterinary medicinal product.

Only a sufficient amount of medicated drinking water should be prepared to cover the daily requirements.

Medicated drinking water should be replaced every 24 hours.

After end of the medication period, the water supply system should be cleaned appropriately to avoid intake of subtherapeutic amounts of the active substance.

As an adjunct to medication, good management and hygiene practices should be introduced in order to reduce the risk of infection and to control the build-up of resistance.

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

No signs of intolerance have been observed in pigs at up to 100 mg tylvalosin per kg bodyweight per day for 5 days.

• 4.11 Withdrawal period(s)

Meat and offal: 2 days.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA92.

5.1 Pharmacodynamic properties

Tylvalosin is a macrolide antibiotic. Macrolides are metabolites or derivatives of metabolites of soil organisms obtained by fermentation. They interfere with protein synthesis by reversibly binding to the 50S ribosome subunit. They are generally considered bacteriostatic.

Tylvalosin has activity against pathogenic organisms isolated from a range of animal species-mainly Gram-positive organisms and mycoplasma but also some Gram-negative organisms, including Lawsonia intracellularis. At concentrations above MIC, in vitro studies have shown a bactericidal effect of tylvalosin against Mycoplasma hyopneumoniae strains.

Bacteria can develop resistance to antimicrobial substances. There are multiple mechanisms responsible for resistance development to macrolide compounds. The mechanisms involve the alteration of the ribosomal target site (e.g. encoded by erm genes), the utilization of active efflux mechanism (e.g. due to mef, msr genes) and the production of inactivating enzymes (e.g. caused by mph genes). Bacterial resistance to macrolides may be chromosomal or plasmid-encoded and may be transferable if associated with transposons or plasmids. In Mycoplasmas, resistance may be transferable if associated with mobile genetic elements. Cross-resistance within the macrolide group of antibiotics cannot be excluded.

Scientific evidence suggests that macrolides act synergistically with the host immune system. Macrolides appear to enhance phagocyte killing bacteria.

In addition to their antimicrobial properties, immunomodulating and anti-inflammatory effects have been described for some macrolides in experimental studies. Tylvalosin has been shown to induce apoptosis of porcine neutrophils and macrophages, promote efferocytosis and inhibit pro-inflammatory CXCL-8, ILla and LTB4 production, while inducing the release of pro-resolving Lipoxin A4 and Resolvin D1 in vitro”.

• 5.2 Pharmacoki­netic particulars

Tylvalosin tartrate is rapidly absorbed after oral administration of the veterinary medicinal product. Tylvalosin is widely distributed in tissues, with the highest concentrations found in the respiratory tissues, bile, intestinal mucosa, spleen, kidney and liver. The tmax for tylvalosin is about 2.2 hours; the terminal half-life for the elimination is approximately 2.2 hours.

Tylvalosin has been shown to concentrate in phagocytic cells and gut epithelial cells. Concentrations (up to 12 times) were achieved in the cells (intracellular), compared to the extracellular concentration. In vivo studies have shown tylvalosin to be present in higher concentrations in the mucous lining of the respiratory and gut tissues compared to the plasma.

The major metabolite of tylvalosin is 3-acetyltylosin (3-AT), which is also microbiologically active.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

6.2 Major 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:

40 g sachet – 3 years.

160 g sachet – 2 years.

400 g sachet – 2 years.

Shelf life after first opening of the immediate packaging: 5 weeks.

Shelf life of the medicated drinking water: 24 hours.

6.4. Special precautions for storage

Do not store above 25 °C.

• 6.5 Nature and composition of immediate packaging

Aluminium foil laminated sachet containing 40 g, 160 g or 400 g of granules.

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 product should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

ECO Animal Health Europe Limited

6th Floor, South Bank House

Barrow Street

Dublin 4

D04 TR29

IRELAND

8. MARKETING AUTHORISATION NUMBERS

EU/2/04/044/009 – 40 g

EU/2/04/044/010 – 160 g

EU/2/04/044/017 – 400 g

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 September 2004.

Date of last renewal: 9 September 2014.

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Tylvalosin (as tylvalosin tartrate) 625 mg/g.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Granules for use in drinking water.

White granules.

4. CLINICAL PARTICULARS4.1 Target species

Pheasants

• 4.2 Indications for use, specifying the target species

Treatment of respiratory disease associated with Mycoplasma gallisepticum in pheasants.

4.3 Contraindications

None.

• 4.4 Special warnings for each target species

Treat as soon as possible after clinical signs suggestive of mycoplasmosis are observed.

Treat all the birds in the affected flock.

• 4.5 Special precautions for use

Special precautions for use in animals

Good management and hygiene practices should be introduced to reduce the risk of re-infection.

Use of the product should be based on susceptibility testing of the bacteria isolated from the animal. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of the target bacteria.

Use of the veterinary medicinal product deviating from the instructions may increase the risk of development and selection of resistant bacteria and decrease the effectiveness of treatment with other macrolides due to the potential for cross-resistance.

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

Tylvalosin has been shown to cause hypersensitivity (allergic) reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin should avoid contact with this product.

When mixing the veterinary medicinal product and handling the medicated water, direct contact with eyes, skin and mucous membranes should be avoided. Personal protective equipment consisting of impervious gloves and a half-mask respirator conforming to European Standard EN 149 or a nondisposable respirator conforming to European Standard EN 140 with a filter conforming to European Standard EN 143 should be worn when mixing the product. Wash contaminated skin.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during lay.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

• 4.9 Amounts to be administered and administration route

For use in drinking water.

The dose is 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days.

Determine the combined bodyweight (in kg) of all the birds to be treated. For example, one sachet of 40 g is sufficient to treat a total of 1,000 birds with an average bodyweight of 1 kg; one sachet of 400 g is sufficient to treat a total of 10,000 birds with an average bodyweight of 1 kg.

In order to achieve a correct dose, the preparation of a concentrated (stock) solution might be required (e.g. to treat a total of 500 kg total bird weight, only 50% of the prepared stock solution prepared from the 40 g sachet should be used).

The veterinary medicinal product should be added to a volume of water that the birds will consume in one day. The intake of medicated water depends on the clinical condition of the animals. In order to obtain the correct dose, the concentration of Aivlosin has to be adjusted accordingly.

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

Mixing instructions:

The veterinary medicinal product may be mixed directly into the drinking water system or first mixed as a stock solution into a smaller amount of water, which is then added into the drinking water system.

When mixing the veterinary medicinal product directly into the drinking water system, the contents of the sachet should be sprinkled onto the surface of the water and mixed thoroughly until a clear solution is produced (usually within 3 minutes).

When preparing a stock solution, the maximum concentration should be 40 g of product per 1,500 ml of water and it is necessary to mix the solution for 10 minutes. After this time, any remaining cloudiness will not affect efficacy of the product.

Only a sufficient amount of medicated drinking water should be prepared to cover the daily requirements.

Medicated drinking water should be replaced every 24 hours.

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

No signs of intolerance have been observed in poultry species at up to 150 mg tylvalosin per kg bodyweight per day for 5 days.

• 4.11 Withdrawal period(s)

Meat and offal: 2 days.

Do not release pheasants for at least two days after the end of medication.

Not for use in birds producing or intended to produce eggs for human consumption.

Do not use within 14 days of the start of the laying period.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA92.

5.1 Pharmacodynamic properties

Tylvalosin is a macrolide antibiotic. Macrolides are metabolites or derivatives of metabolites of soil organisms obtained by fermentation. They interfere with protein synthesis by reversibly binding to the 50S ribosome subunit. They are generally considered bacteriostatic.

Tylvalosin has activity against pathogenic organisms isolated from a range of animal species-mainly Gram-positive organisms and mycoplasma but also some Gram-negative organisms. Tylvalosin has activity against the following mycoplasma species found in poultry: Mycoplasma gallisepticum.

The minimum inhibitory concentration of tylvalosin for M. gallisepticum ranges from 0.007 to 0.25 ^g/ml. Macrolides (including tylvalosin) have been shown to have effects on the innate immune system, which may augment the direct effects of the antibiotic on the pathogen and aid the clinical situation.

Bacteria can develop resistance to antimicrobial substances. There are multiple mechanisms responsible for resistance development to macrolide compounds.

Cross-resistance within the macrolide group of antibiotics cannot be excluded. Reduced susceptibility for tylvalosin was generally noted in tylosin resistant strains.

• 5.2 Pharmacoki­netic particulars

Tylvalosin tartrate is rapidly absorbed after oral administration of the veterinary medicinal product. Tylvalosin is widely distributed in tissues with the highest concentrations found in the respiratory tissues, bile, intestinal mucosa, spleen, kidney and liver.

Tylvalosin has been shown to concentrate in phagocytic cells and gut epithelial cells. Concentrations (up to 12 times) were achieved in the cells (intracellular), compared to the extracellular concentration. In vivo studies have shown tylvalosin to be present in higher concentrations in the mucous lining of the respiratory and gut tissues compared to the plasma.

The major metabolite of tylvalosin is 3-acetyltylosin (3-AT), which is also microbiologically active.

The terminal half-lives for the elimination of tylvalosin and its active metabolite 3-AT range from 1 to 1.45 hours. Six hours after treatment, the concentration of tylvalosin in the gastrointestinal tract mucosa has a mean concentration of 133 ng/g and in the gastrointestinal contents of 1,040 ng/g. The active metabolite 3-AT has a mean concentration of 57.9 ng/g and 441 ng/g, respectively.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

6.2 Major 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:

40 g sachet – 3 years.

400 g sachet – 2 years.

Shelf life after first opening the immediate packaging: 5 weeks.

Shelf life of the medicated drinking water: 24 hours.

6.4. Special precautions for storage

40 g sachet: do not store above 25 °C.

400 g sachet: do not store above 25 °C.

• 6.5 Nature and composition of immediate packaging

Aluminium foil laminated sachets containing 40 g or 400 g granules.

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

7. MARKETING AUTHORISATION HOLDER

ECO Animal Health Europe Limited

6th Floor, South Bank House

Barrow Street

Dublin 4

D04 TR29

IRELAND

8. MARKETING AUTHORISATION NUMBERS

EU/2/04/044/012 – 40 g

EU/2/04/044/014 – 400 g

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 September 2004.

Date of last renewal: 9 September 2014.

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Tylvalosin (as tylvalosin tartrate) 42.5 mg/g.

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Oral powder.

A beige granular powder.

4. CLINICAL PARTICULARS4.1 Target species

Pigs

• 4.2 Indications for use, specifying the target species

• • Treatment and metaphylaxis of swine enzootic pneumonia caused by susceptible strains of Mycoplasma hyopneumoniae in pigs. At the recommended dose, lung lesions and weight loss are reduced but infection with Mycoplasma hyopneumoniae is not eliminated.
• • Treatment of porcine proliferative enteropathy caused by Lawsonia intracellularis in herds where there is a diagnosis based on clinical history, post-mortem findings and clinical pathology results.
• • Treatment and metaphylaxis of swine dysentery, caused by Brachyspira hyodysenteriae in herds where the disease has been diagnosed.

4.3 Contraindications

None.

• 4.4 Special warnings for each target species

Acute cases and severely diseased pigs with reduced food and water intake should be treated with a suitable injectable veterinary medicinal product.

Generally, strains of B. hyodysenteriae have higher minimal inhibitory concentration (MIC) values in cases of resistance against other macrolides such as tylosin. The clinical relevance of this reduced susceptibility is not fully explored. Cross-resistance between tylvalosin and other macrolides cannot be excluded.

• 4.5 Special precautions for use

Special precautions for use in animals

It is sound clinical practice to base treatment on susceptibility testing of the bacteria isolated from the animal. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of target bacteria.

Use of the veterinary medicinal product deviating from the instructions in the SPC may increase the risk of development and selection of resistant bacteria and decrease the effectiveness of treatment with other macrolides due to the potential for cross-resistance.

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

Tylvalosin has been shown to cause hypersensitivity (allergic) reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin should avoid contact with this product.

When mixing the veterinary medicinal product and handling the medicated oral powder, direct contact with eyes, skin and mucous membranes should be avoided. Personal protective equipment consisting of impervious gloves and a half-mask respirator conforming to European Standard EN 149 or a nondisposable respirator conforming to European Standard EN 140 with a filter conforming to European Standard EN 143 should be worn when mixing the product. Wash contaminated skin.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy and lactation Use only in accordance with benefit-risk assessment by the responsible veterinarian.

Laboratory studies in animals have not produced any evidence of a teratogenic effect. Maternal toxicity in rodents has been observed at doses of 400 mg tylvalosin per kg bodyweight and above. In mice, a slight reduction in the foetal bodyweight was seen at doses causing maternal toxicity.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

• 4.9 Amounts to be administered and administration route

For use in individual pigs on farms where only a small number of pigs are to receive the treatment. Larger groups should be treated with medicated feeding stuff containing the premix.

For treatment and metaphylaxis of swine enzootic pneumonia

The dose is 2.125 mg tylvalosin per kg bodyweight per day for 7 consecutive days. Secondary infection by organisms such as Pasteurella multocida and Actinobacillus pleuropneumoniae may complicate enzootic pneumonia and require specific medication.

For treatment of porcine proliferative enteropathy (ileitis)

The dose is 4.25 mg tylvalosin per kg bodyweight per day for 10 consecutive da­ys.

For treatment and metaphylaxis of swine dysentery

The dose is 4.25 mg tylvalosin per kg bodyweight per day for 10 consecutive da­ys.

This is achieved by thoroughly mixing Aivlosin into approximately 200–500 g of feed and then thoroughly mixing this pre-mixture into the remainder of the daily ration.

Scoops of 2 sizes are provided for measuring the correct amount of Aivlosin for mixing with the daily ration, according to the schedule below. The feed containing the oral powder should be provided as the sole ration for the periods recommended above.

The pig to be treated should be weighed and the amount of feed that the pig is likely to consume should be estimated, based on a daily feed intake equivalent to 5% of bodyweight. Consideration must be given to pigs whose daily feed intake is reduced or restricted. The correct quantity of Aivlosin should be added to the estimated quantity of daily ration for each pig, in a bucket or similar receptacle, and thoroughly mixed.

The veterinary medicinal product should only be added to dry non-pelleted feed.

NB: A level scoop of the product should be measured

As an adjunct to medication, good management and hygiene practices should be introduced in order to reduce the risk of infection and to control the potential build-up of resistance.

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

No signs of intolerance have been observed in growing pigs at up to 10 times the recommended dose.

• 4.11 Withdrawal period(s)

Meat and offal: 2 days.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA92.

5.1 Pharmacodynamic properties

Tylvalosin tartrate is a macrolide antibiotic that has antibacterial activity against Gram-positive, some Gram-negative organisms and mycoplasma. It acts by inhibiting protein synthesis in bacteria cells.

Macrolide antibiotics are metabolites or semi-synthetic derivatives of metabolites of soil organisms obtained by fermentation. They have differently sized lactone rings and are basic due to the dimethylamino group. Tylvalosin has a sixteen-membered ring.

Macrolides interfere with protein synthesis by reversibly binding to the 50S ribosome subunit. They bind to the donor site and prevent the translocation necessary for keeping the peptide chain growing. Their effect is essentially confined to rapidly dividing organisms. Macrolides are generally considered bacteriostatic and mycoplasmastatic.

It is considered that there are multiple mechanisms responsible for resistance development to macrolide compounds, namely alteration of the ribosomal target site, utilisation of active efflux mechanism and production of inactivating enzymes.

Resistance to tylvalosin by Mycoplasma hyopneumoniae and Lawsonia intracellularis has not been reported or found in the field to date. No breakpoint for Brachyspira hyodysenteriae has been established. Generally, strains of B. hyodysenteriae have higher MIC values in cases of resistance against other macrolides, such as tylosin. The clinical relevance of this reduced susceptibility is not fully explored.

Cross-resistance between tylvalosin and other macrolide antibiotics cannot be excluded.

• 5.2 Pharmacoki­netic particulars

Tylvalosin tartrate is rapidly absorbed after oral administration of Aivlosin.

After administration of the recommended dose lung concentrations of 0.060–0.066 ^g/ml were found at 2 and 12 hours post-treatment. The parent compound is widely distributed in the tissues with the highest concentrations found in the lungs, bile, intestinal mucosa, spleen, kidney and liver.

There is evidence that the concentration of macrolides is higher at the site of infection than in plasma, in particular in neutrophils, alveolar macrophages and alveolar epithelial cells.

In vitro metabolism studies have confirmed that the parent compound is rapidly metabolised to 3-O -acetyltylosin. In a trial with 14C-Aivlosin administered at 2.125 mg/kg to pigs for 7 days, over 70% of the dose was excreted in the faeces, with urinary excretion accounting for 3 to 4% of the dose.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Hydrated magnesium silicate (sepiolite)

Wheat flour

Hydroxypropyl cellulose

Non-fat soyabean powder

6.2 Major 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: 3 years.

Shelf life after first opening of the immediate packaging: 4 weeks.

Feed to which the oral powder has been added should be replaced if not consumed within 24 hours.

6.4 Special precautions for storage

Store below 30 °C.

Keep the container tightly closed.

Store in the original container.

• 6.5 Nature and composition of immediate packaging

One aluminium foil/polyester laminated bag containing 500 g. Scoops of 1 ml and 5 ml are attached.

• 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

ECO Animal Health Europe Limited

6th Floor, South Bank House

Barrow Street

Dublin 4

D04 TR29

IRELAND

8. MARKETING AUTHORISATION NUMBERS

EU/2/04/044/013

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 September 2004.

Date of last renewal: 9 September 2014.

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance:

Tylvalosin (as tylvalosin tartrate) 625 mg/g.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Granules for use in drinking water.

White granules.

4. CLINICAL PARTICULARS4.1 Target species

Chicken and turkeys.

• 4.2 Indications for use, specifying the target species

Chicken

Treatment and metaphylaxis of respiratory infections caused by Mycoplasma gallisepticum in chicken. The presence of the disease in the flock should be established before metaphylactic treatment.

As an aid in reducing the development of clinical signs and mortality from respiratory disease in flocks, where infection in ovum with Mycoplasma gallisepticum is likely because the disease is known to exist in the parent generation.

Turkeys

Treatment of respiratory disease associated with tylvalosin sensitive strains of Ornithobacterium rhinotracheale in turkeys.

4.3 Contraindications

None.

• 4.4 Special warnings for each target species

In field studies investigating the effect of treatment and metaphylaxis on mycoplasmosis, all birds (approximately 3 weeks old) received the product when clinical signs were evident in 2–5% of the flock. At 14 days after initiation of treatment, 16.7–25.0% morbidity and 0.3–3.9% mortality were observed in the treated group in comparison to 50.0–53.3% morbidity and 0.3–4.5% mortality in an untreated group.

In further field studies, chicks from parent stock with evidence of Mycoplasma gallisepticum infection were administered Aivlosin for the first three days of life followed by a second course at 16–19 days of age (a period of management stress). By 34 days after the initiation of treatment, 17.5–20.0% morbidity and 1.5–2.3% mortality were observed in the treated groups in comparison to 50.0–53.3% morbidity and 2.5–4.8% mortality in the untreated groups.

The strategy for Mycoplasma gallisepticum infection should include efforts to eliminate the pathogen from the parent generation.

Infection with Mycoplasma gallisepticum is reduced but not eliminated at the recommended dose.

Medication should only be used for short-term amelioration of clinical signs in breeder flocks whilst awaiting confirmation of diagnosis of Mycoplasma gallisepticum infection.

• 4.5 Special precautions for use

Special precautions for use in animals

Good management and hygiene practices should be introduced to reduce the risk of re-infection.

It is sound clinical practice to base treatment on susceptibility testing of the bacteria isolated from the animal. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of target bacteria.

Use of the veterinary medicinal product deviating from the instructions may increase the risk of development and selection of resistant bacteria and decrease the effectiveness of treatment with other macrolides due to potential for cross-resistance.

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

Tylvalosin has been shown to cause hypersensitivity (allergic) reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin should avoid contact with this product.

When mixing the veterinary medicinal product and handling the medicated water, direct contact with eyes, skin and mucous membranes should be avoided. Personal protective equipment consisting of impervious gloves and a half-mask respirator conforming to European Standard EN 149 or a nondisposable respirator conforming to European Standard EN 140 with a filter conforming to European Standard EN 143 should be worn when mixing the product. Wash contaminated skin.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

None known.

• 4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during lay in turkeys.

The product can be used in chickens laying eggs for human consumption and breeding birds producing eggs for hatching broiler stock or replacement layers.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

• 4.9 Amounts to be administered and administration route

For use in drinking water.

Chickens

For treatment of respiratory disease associated with Mycoplasma gallisepticum:

The dose is 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days.

When used as an aid in reducing the development of clinical signs and mortality (where infection in ovum with Mycoplasma gallisepticum is likely):

The dose is 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days at 1 day old. This is followed by a second treatment with 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days at the period of risk, i.e. at times of management stress such as administration of vaccines (typically when birds are 2–3 weeks old).

Determine the combined bodyweight (in kg) of all the chickens to be treated. Select the correct number of sachets according to the amount of product required.

One sachet of 40 g is sufficient to treat a total of 1,000 kg of chicken (e.g. 20,000 birds with an average bodyweight of 50 g).

One sachet of 400 g is sufficient to treat a total of 10,000 kg of chicken (e.g. 20,000 birds with an average bodyweight of 500 g).

In order to achieve a correct dose, the preparation of a concentrated (stock) solution might be required (e.g. to treat a total of 500 kg total bird weight, only 50% of the prepared stock solution prepared from the 40 g sachet should be used).

The product should be added to a volume of water that the chicken will consume in one day. No other source of drinking water should be available during the medication period.

Turkeys

For treatment of respiratory disease associated with Ornithobacterium rhinotracheale:

The dose is 25 mg tylvalosin per kg bodyweight per day in drinking water for 5 consecutive days.

Determine the combined bodyweight (in kg) of all the turkeys to be treated. Select the correct number of sachets according to the amount of product required.

One sachet of 40 g is sufficient to treat a total of 1,000 kg of turkeys (e.g. 10,000 birds with an average bodyweight of 100 g).

One sachet of 400 g is sufficient to treat a total of 10,000 kg of turkeys (e.g. 10,000 birds with an average bodyweight of 1 kg).

In order to achieve a correct dose, the preparation of a concentrated (stock) solution might be required (e.g. to treat a total of 500 kg total bird weight, only 50% of the prepared stock solution prepared from the 40 g sachet should be used).

The product should be added to a volume of water that the turkeys will consume in one day. No other source of drinking water should be available during the medication period.

Mixing instructions:

The veterinary medicinal product may be mixed directly into the drinking water system or first mixed as a stock solution into a smaller amount of water, which is then added into the drinking water system.

When mixing the product directly into the drinking water system, the contents of the sachet should be sprinkled onto the surface of the water and mixed thoroughly until a clear solution is produced (usually within 3 minutes).

When preparing a stock solution, the maximum concentration should be 40 g per 1,500 ml or 400 g of product per 15 litres water and it is necessary to mix the solution for 10 minutes. After this time, any remaining cloudiness will not affect efficacy of the product.

Only a sufficient amount of medicated drinking water should be prepared to cover the daily requirements. Medicated drinking water should be replaced every 24 hours.

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

No signs of intolerance have been observed in poultry species at up to 150 mg tylvalosin per kg bodyweight per day for 5 days.

No adverse effects on egg production, egg fertility, hatchability and chick viability were observed in broiler breeder stock administered 75 mg tylvalosin per kg bodyweight per day for 28 consecutive da­ys.

• 4.11 Withdrawal period(s)

Meat and offal: 2 days.

Eggs (chicken): zero days.

Turkeys: Not for use in birds producing or intended to produce eggs for human consumption.

Do not use within 21 days of the start of the laying period.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA92.

5.1 Pharmacodynamic properties

Tylvalosin is a macrolide antibiotic. Macrolides are metabolites or derivatives of metabolites of soil organisms obtained by fermentation. They interfere with protein synthesis by reversibly binding to the 50S ribosome subunit. They are generally considered bacteriostatic.

Tylvalosin has activity against pathogenic organisms isolated from a range of animal species, mainly Gram-positive organisms and mycoplasma but also some Gram-negative organisms.

Macrolides (including tylvalosin) have been shown to have effects on the innate immune system, which may augment the direct effects of the antibiotic on the pathogen and aid the clinical situation.

Chicken

Tylvalosin has activity against the following mycoplasma species found in chicken: Mycoplasma gallisepticum.

The minimal inhibitory concentration (MIC) of tylvalosin for M. gallisepticum ranges from 0.007 to 0.25 ^g/ml.

Turkeys

Tylvalosin has activity against Ornithobacterium rhinotracheale , a Gram-negative organism found in turkeys and chickens.

The MIC of tylvalosin for Ornithobacterium rhinotracheale ranges from 0.016 to 32 ^g/ml.

Efficacy of tylvalosin against O. rhinotracheale in turkeys was demonstrated in a challenge model using co-infection with avian metapneumovirus and a single strain of O. rhinotracheale under strictly controlled conditions. These studies demonstrated a modest but statistically significant reduction in the incidence of lower respiratory lesions (lung and air sac) and clinical signs in turkeys treated with tylvalosin compared with negative controls. Efficacy studies under field conditions have not been conducted.

Bacteria can develop resistance to antimicrobial substances. There are multiple mechanisms responsible for resistance development to macrolide compounds.

Cross-resistance within the macrolide group of antibiotics cannot be excluded. Reduced susceptibility for tylvalosin was generally noted in tylosin resistant strains.

• 5.2 Pharmacoki­netic particulars

Tylvalosin tartrate is rapidly absorbed after oral administration of the veterinary medicinal product. Tylvalosin is widely distributed in tissues, with the highest concentrations found in the respiratory tissues, bile, intestinal mucosa, spleen, kidney and liver.

Tylvalosin has been shown to concentrate in phagocytic cells and gut epithelial cells. Concentrations (up to 12 times) were achieved in the cells (intracellular), compared to the extracellular concentration. In vivo studies have shown tylvalosin to be present in higher concentrations in the mucous lining of the respiratory and gut tissues compared to the plasma.

The major metabolite of tylvalosin is 3-acetyltylosin (3-AT), which is also microbiologically active.

The terminal half-lives for the elimination of tylvalosin and its active metabolite 3-AT range from 1 to 1.45 hours in the chicken. Six hours after treatment, the concentration of tylvalosin in the gastrointestinal tract mucosa has a mean concentration of 133 ng/g and in the gastrointestinal contents of 1,040 ng/g. The active metabolite 3-AT has a mean concentration of 57.9 ng/g and 441 ng/g, respectively.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

6.2 Major 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:

40 g sachet – 3 years.

400 g sachet – 2 years.

Shelf life after first opening of the immediate packaging: 5 weeks.

Shelf life of the medicated drinking water: 24 hours.

6.4. Special precautions for storage

40 g sachet: do not store above 25 °C.

400 g sachet: do not store above 25 °C.

• 6.5 Nature and composition of immediate packaging

Aluminium foil laminated sachet containing 40 g or 400 g.

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

7. MARKETING AUTHORISATION HOLDER

ECO Animal Health Europe Limited

6th Floor, South Bank House

Barrow Street

Dublin 4

D04 TR29

IRELAND

8. MARKETING AUTHORISATION NUMBERS

Chickens and Turkeys

EU/2/04/044/018 – 40 g

EU/2/04/044/019 – 400 g

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 September 2004.

Date of last renewal: 9 September 2014.