Contents

Active substance / Generic: Tylvalosin

Scientific discussion

This medicine is approved for use in the European Union
Aivlosin is a veterinary medicinal product containing the macrolide antibiotic tylvalosin (previous name: acetylisovaleryltylosin) as active substance. The target species are pigs, chickens and pheasants.

The product is presented for pigs as a premix for medicated feedingstuff to be incorporated into meal feed or pelleted feed or as an oral powder to be added to meal feed. The oral powder is to be used in individual pigs on farms where only a small number of pigs are to receive the medicine while large groups of animals would be medicated with medicated feedingstuff containing the premix. In pigs, chickens and pheasants, the product is available as granules for use in drinking water. The granules are either 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.

In pigs, Aivlosin is indicated for the treatment and prevention of Swine Enzootic Pneumonia at a dosage of 2.125 mg tylvalosin per kg bodyweight per day in-feed for 7 consecutive days. The product has also been authorised for the treatment of Porcine Proliferative Enteropathy and for the treatment and prevention of Swine Dysentery at a dosage of 4.25 mg tylvalosin per kg bodyweight per day in-feed for 10 consecutive days. The product is also authorised for the treatment and prevention of Porcine Proliferative Enteropathy at a dose rate of 5 mg tylvalosin per kg bodyweight per day in drinking water for 5 consecutive days.

In chickens, Aivlosin is indicated for the treatment and prevention of respiratory disease associated with Mycoplasma gallisepticum at a dosage of 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days. When used as an aid in the prevention strategy (where infection in ovum with Mycoplasma gallisepticum is likely), chicks are to be medicated in their first three days of life and this is to be repeated 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).

In pheasants, Aivlosin is indicated for the treatment of respiratory disease associated with Mycoplasma gallisepticum at a dosage of 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days.

The withdrawal period is 2 days for meat and offal (pigs, chickens and pheasants); however, for the granules for use in drinking water for pigs, the withdrawal period for meat and offal is one (1) day. Aivlosin is not authorised for birds laying eggs for human consumption and should, therefore, not be used in laying birds or in the two weeks before birds are likely to start laying eggs for human consumption.

No side effects in pigs, chickens or pheasants have been reported during the clinical trials.

Due to the skin-sensitising potential of tylvalosin in laboratory animals, the product literature includes a user warning for people with known hypersensitivity to tylvalosin tartrate.

Aivlosin: Quality Assessment

Composition of the veterinary medicinal product

Aivlosin as a premix for medicated feeding stuff contains 42.5 mg/g or 8.5 mg/g of tylvalosin (as tylvalosin tartrate) as the active substance, in a carrier of wheat feed flour and magnesium trisilicate along with other conventional pharmaceutical excipients. The oral powder presentations are identical to the 8.5 mg/g and 42.5 mg/g premix for medicated feeding stuff presentations, containing 8.5 mg/g and 42.5 mg/g of tylvalosin, respectively.

The granules for use in drinking water for pigs, chickens and pheasants are identical and contain 625 mg/g tylvalosin (as tylvalosin tartrate) as the active substance and lactose monohydrate as excipient.

Clinical Trial Formula

Clinical trials in pigs have been conducted using the premix formulation containing 42.5 mg/g tylvalosin. For chickens, pigs and pheasants, clinical trials have been conducted using granules for use in drinking water, containing 625 mg/g tylvalosin.

Development pharmaceutics

Data on the development of the intermediate product (which is used to prepare the 8.5 mg/g premix and oral powder presentations) have been presented. The selection of the excipients and the granulation method are explained. Intra-bag homogeneity of the intermediate product has been examined following transportation. The results indicate that there is no tendency for segregation to occur.

For the premix, inert carriers, wheat feed flour and magnesium trisilicate are used as the diluents. Intra-bag homogeneity of the premix has also been examined following transportation. The results indicate that no segregation occurred in the bags. Dust studies demonstrated that the 42.5 mg/g premix and 8.5 mg/g premix were both classified as being of medium dustiness.

The 8.5 mg/g oral powder formulation is identical to the 8.5 mg/g premix formulation. No special development studies were originally performed but in response to questions the bulk density of the powder: tapped/un-tapped and pre/post transport have been examined. The differences observed were acceptable.

For the granules for use in drinking water, the selection of the excipient, the granulation method and the need for moisture resistant packaging are explained.

The dustiness and friability of the product was not evaluated, but since the complete sachet of the granules for use in drinking water will be used at once without measuring out, the absence of such data is acceptable.

Manufacturing Process

The 8.5 mg/g premix and oral powder formulations are manufactured via the intermediate product Aivlosin 17% Granules. Manufacturing formulae for the intermediate product and the final premix and oral powder are presented. The intermediate product is produced using a roller compaction granulation process. A conventional blending procedure is then employed to dilute the intermediate product. The 42.5 mg/g premix is manufactured by blending all of the formulation ingredients and then granulating the blend by roller compaction to produce the final product.

For the granules for use in drinking water, tylvalosin tartrate and lactose monohydrate are blended together and then transferred to a granulation system which uses a roller compaction process.

Satisfactory flow diagrams and detailed descriptions of the method of manufacture, including in-process controls, are presented for the all presentations of Aivlosin.

All of the above manufacturing processes have been validated.

Active substance

Tylvalosin tartrate is a white to light yellow powder and is not described in any pharmacopoeia. The specification for tylvalosin tartrate is based upon the monograph for this substance as set out in “The minimum requirements for pharmaceutical products not requiring approval for veterinary use in Japan”. Manufacture is via fermentation, using a genetically modified strain of Streptomyces thermotolerans. Tylvalosin is isolated from the fermentation broth and the tartrate salt is formed with the final material being spray dried. No organic solvents are employed during the manufacturing process.

In-process controls, their limits and methods, as performed during the fermentation, purification and spray drying stages are fully documented. Comprehensive specifications and linked test methods, and an indication of which tests are conducted on receipt, are presented for each of the materials used during production.

Satisfactory process validation data of the active substance are provided. The in-process results at various stages of manufacture of the active substance show consistency between batches. The final batch results demonstrate compliance with the authorised specification.

Stability data are presented according to CVMP-VICH guidelines on a number of batches of the active substance. A 9-month re-test period for the active substance was accepted.

Packaging

The intermediate product is packed in four-layer aluminium laminated bags with an innermost layer of polyethylene. The 42.5 mg/g premix is packed in laminated bags (laminate composed of polyester, aluminium and low density polyethylene) containing 5 or 20 kg. The 8.5 mg/g premix and oral powder presentations are packed in polyethylene lined paper bags containing 5 or 20 kg for premix and 1 kg or 3 kg bags for the oral powder. Full specifications have been provided for the packaging.

For the oral powder presentation, polystyrene measuring scoops of 5 ml, 10 ml and 25 ml (for 8.5 mg/g) and 1 ml and 5 ml (for 42.5 mg/g) are supplied with each pack. The suitability of the scoops for food contact applications has been confirmed. Scoop accuracy and precision were satisfactory.

The granules for use in drinking water are packed in single, laminated sachets (laminate composed of polyester, aluminium and low density polyethylene).

For chicken, pack sizes of 40 g and 400 g are available, which would allow the treatment of a total of 1,000 kg or 10,000 kg bodyweight of chickens per sachet, respectively (e.g. 20,000 birds with average bodyweight of 50 g or 500 g, respectively). For pheasants, pack sizes of 16 g and 40 g are available, which would allow the treatment of a total of 400 kg or 1,000 kg bodyweight of pheasants per sachet, respectively (e.g. 1000 birds with an average bodyweight of 400 g or 20,000 birds with a bodyweight of 50 g, respectively). For pigs, pack sizes of 40 g and 160 g are available, which would allow the treatment of a total of 5,000 or 20,000 kg bodyweight of pigs per sachet, respectively (e.g. 250 pigs with an average bodyweight of 20 kg or 400 pigs with an average bodyweight of 50 kg, respectively). For treatment of smaller flocks or animal numbers, the preparation of a stock solution is required.

Overall Conclusion On Quality

The active substance is suitably controlled using validated methods. The specification limits for individual impurities have been justified in terms of batch data, stability data and safety.

The method of manufacture for the 42.5 mg/g premix is well defined. The premix is suitably controlled using validated methods. The shelf-life Finished Product Specification includes limits for four named degradation products and for total impurities and these limits have also been suitably justified in terms of batch data, stability data and safety.

Stability data are presented which confirm: the shelf-life for the intermediate product (24 months), the shelf-life for the 42.5 mg/g premix (18 months) and the in-feed shelf-life (1 month).

It has been demonstrated that the premix can be homogeneously incorporated into pig feed to give an in-feed concentration of 42.5 mg tylvalosin/kg feed. A specification was proposed for feed medicated with the premix.

The inclusion rate of the 42.5 mg premix in feed will be 0.1%. Since inclusion rates of less than 0.5% are not permitted in some EU Member States, an appropriate recommendation was included in the SPC and the product information: “Consideration should be given to official guidance on the incorporation of medicated premixes in final feeds.” In addition, the applicant confirmed to submit an application for a new presentation with a lower strength resulting in an inclusion rate of 0.5%.

The data presented subsequently for the lower strength premix (8.5 mg/g) premix are comprehensive. The 8.5 mg/g premix is prepared using an intermediate product unlike the 42.5 mg/g premix, which is prepared directly from its constituent ingredients. The intermediate product is simply subjected to a dilution step in order to produce the 8.5 mg/g premix. The data submitted for the 8.5 mg/g premix results in higher inclusion rate for the 8.5 mg/g premix in feed is in accordance with recommendations in the European Pharmacopoeia and national legislation in the EU concerning the medication of feed.

The 8.5 mg/g oral powder presentation is identical in formulation to the 8.5 mg/g premix presentation. However, as the oral powder is to be added to the feed of individual animals, the pack size is smaller and measuring scoops are supplied with each pack. Scoop accuracy and precision have been demonstrated. In view of the volumetric measurement of the dose, the bulk density of the oral powder is controlled.

An 18 month shelf life was initially agreed for the 8.5 mg/g premix and the oral powder when stored below 25°C; this was later extended to 3 years. The oral powder cannot be mixed thoroughly into pelleted feed; therefore, the use of the oral powder is restricted to dry, non-pelleted feed.

In 2006, the Marketing Authorisation Holder extended the indications to two further claims (Porcine Proliferative Enteropathy (ileitis) and Swine Dysentery) with a higher dosage resulting in higher inclusion rates for the premix in feed (85 mg/g tylvalosin/kg feed). Satisfactorily results from homogeneity and stability data were provided. However, low recoveries of the feed medicated with the premix which were attributed to the double pelleting process used by the feed mill resulted in slight changes in the wording of the SPC regarding the recommended pelleting conditions. Also, a new formula was introduced in the product literature to calculate the correct inclusion rate in feed. With regard to the oral powder presentation, an additional larger size scoop was requested.

In 2008, the marketing authorisation was extended to include a new pharmaceutical form, granules for use in drinking water for chickens. Satisfactory data were provided to demonstrate that the product is suitably formulated and quality-controlled. The solubility of the product has been investigated according to the relevant CVMP Guideline. In higher concentrations, presence of cloudiness was noted, which was demonstrated to be a very fine secondary precipitate without impact on the efficacy of the product. Appropriate instructions have therefore been included in the SPC. Stability studies have been presented confirming the proposed shelf-life of 3 years for the finished product. No stability data are provided for open sachets and opened sachets should not be stored. Sufficient data have been presented to demonstrate the stability of the diluted product in typical drinking water systems. In 2009, the marketing authorisation was further extended to allow the use of granules for use in drinking water for pigs and pheasants.

In 2009, the marketing authorisation was extended to include a 42.5 mg/g oral powder for pigs that is identical to 42.5 mg/g Premix containing 42.5 mg/g. No additional development studies were performed. However, as the oral powder is to be added to the feed of individual animals, the pack size is small and measuring scoops are supplied with each pack. Scoop accuracy and precision have been demonstrated. In view of the volumetric measurement of the dose, the bulk density of the oral powder is controlled.

Tylvalosin: Efficacy Assessment

Pharmacodynamics

Tylvalosin is a macrolide, which is mainly active against Gram-positive bacteria and mycoplasma. No other major pharmacological effects are known. The mode of action is to inhibit protein synthesis by reversibly binding to the 50S ribosome subunit.

Tylvalosin showed activity towards various gram-positive strains

(e.g. Staphylococcus, Micrococcus, Microbacterium, Bacillus, Corynebacterium, Aerococcus, Arthrobacter and Streptococcus, Campylobacter, Enterococcus and Clostridia). The substance was not active against most of the gram-negative strains (including Escherichia coli, Serratia, Klebsiella, Proteus, Salmonella, Shigella and Pseudomonas). The main metabolite, 3-O-acetyltylosin (3-AT), showed similar antimicrobial activity.

Target animal safety

Pigs

Two tolerance studies were presented in pigs receiving up to 250 mg tylvalosin/kg feed (inclusion rate) over 10 days and in pigs receiving 500 mg tylvalosin/kg feed (inclusion rate) for 14 consecutive days (i.e. five-times the recommended dose for an extended treatment duration). Tylvalosin had no negative effect on the health of the pigs. There was no variation in food consumption between groups and no differences in body weight. No intolerance to the diet was observed. No necropsy findings could be attributable to tylvalosin administration.

It was concluded that tylvalosin administration via feed to growing pigs, was safe at up to five times the proposed dose.

In support of the extension application for granules for use in drinking water, the marketing authorisation holder provided in 2009 a new GLP-compliant target animal safety study in 6-week old pigs. The study was conducted in USA in 2006. As concentrations over 200 ppm cause palatability issues, most pigs were medicated by gavage. No adverse effects were observed and it was concluded that Aivlosin Granules for use in drinking water are safe when administered at up to 10 x the recommended dose level of 5 mg/kg for 3 x the recommended duration of treatment, and at up to 20 x the recommended dose level for the recommended duration of treatment.

Chickens

Groups of chickens were medicated with doses of 30 mg, 90 mg or 150 mg tylvalosin/kg bodyweight for three days, or with 30 mg/kg bodyweight for 15 days, i.e. 5 x the recommended duration. The results demonstrated that the administration of high doses of tylvalosin had no adverse effect on the birds. Similar observations were made in the clinical studies. The CVMP concluded, therefore, that tylvalosin has a wide safety margin and is considered to be safe when administered at the proposed dose regimen in chickens as young as 1 day old.

Pheasants

As the proposed dose rate in pheasants is the same as for chickens, the CVMP agreed that the findings in chickens could be extrapolated to the minor species pheasant and that no extra tolerance data in pheasants were required.

Aivlosin: Benefit Risk Assessment

Tylvalosin is a macrolide antibiotic with in vitro activity against Gram-positive bacteria, mycoplasma and some Gram-negative bacteria, including Lawsonia intracellularis.

Benefit Assessment

Direct benefits

Aivlosin in different formulations (premix for medicated feeding stuff, oral powder, granules for use in drinking water) has been shown to be efficacious in the treatment and / or prevention of a number of indications in pigs, i.e. enzootic pneumonia, porcine proliferative enteropathy and swine dysentery; and in respiratory disease associated withMycoplasma gallisepticum in chickens and pheasants.

Efficacy of the proposed dose and duration in the treatment of the respective diseases has been demonstrated in a number of pre-clinical and clinical studies.

Indirect benefits

The Committee noted that the inclusion rate of active substance in the 42.5 mg/g premix in feed would be 0.1%. Since inclusion rates of less than 0.5% are not permitted in some EU Member States, the lower strength premix (8.5 mg/g premix for medicated feeding stuff), introduced as an extension in 2005 achieved higher inclusion rates in feed, which are in accordance with recommendations in the European Pharmacopoeia and national legislation in the EU concerning the medication of feed.

Granules for use in drinking water have the advantage that even animals with reduced appetite due to illness might still drink and receive medication via drinking water. Also, the inclusion rate can be adjusted daily according to water intake to achieve the correct dose. The oral powders permit treatment of individual animals where necessary.

Risk Assessment

Tylvalosin has a wide therapeutic margin in target animal safety studies. This is supported by the clinical studies (no serious adverse reactions). The risk of adverse effects is low and no special warnings are required in the SPC.

Safety of the product has not been established in pregnant or lactating pigs; however, these animals are not at high risk of developing the disease and are unlikely to be treated with the product. An appropriate warning in section 4.7 of the SPC addresses any potential risk.

Tylvalosin is of low toxicity and poses low risk to users of the product. However, people may be exposed to tylvalosin via inhalation, by accidental ingestión or by skin contact and hypersensitivity reactions are a possible effect of contact with the product. However, satisfactory user warnings are included in the SPC and product literature explaining how to avoid such contact.

The environmental risk assessment has demonstrated that the risk for the soil and aquatic environments is acceptable and it is concluded that the product will not pose a risk for the environment when used according to the recommended posology for pigs, chickens and pheasants.

MRLs for tylvalosin for pigs and poultry have been included in Annex I of Council Regulation (EEC) No. 2377/90. Based on the data provided and taking into account a sufficient safety span, a withdrawal period of 2 days was considered acceptable for chickens and pheasants, as well as for the premix and oral powder formulations for pigs, and 1 day for the granules for use in drinking water formulation for pigs.

Consumer safety is assured by a withdrawal period for meat and offal of 1 to 2 days for chickens, pheasants and pigs (depending on the different presentations).

Resistance may be a hazard. Tylvalosin has no activity against Salmonella spp. and variable activity against Campylobacter spp., and concentrations reached in the ileum and colon of pigs may be sufficient to lead to selection for resistant strains, which could be transferred to humans. An appropriate warning has been added to the SPC and product literature. The indication for the product advises that the presence of disease should be established in a herd before preventive use.

Evaluation Of The Benefit – Risk Balance

The product is considered to be appropriately formulated. It is manufactured and controlled in accordance with relevant EU and VICH quality guidelines and current scientific knowledge.

The indications for Aivlosin represent serious diseases in terms of the effect they have on pig, chicken and pheasant welfare and production losses (mortalities and reduced feed efficiency).

Dose determination and confirmation studies demonstrated the efficacy of Aivlosin in the treatment of clinical signs, improving performance and reducing mortality. The product has been shown to be efficacious for a number of indications.

The therapeutic margin for the product is very good, with no adverse reactions at up to 5 x of the recommended daily dose. Residues also deplete quickly, leading to practicable withdrawal periods. Sufficient warnings have been included in the SPC and product literature in relation to mitigation against the risk of resistance development and risk for the user.

The overall benefit-risk evaluation is deemed positive with a sufficiently clear and complete SPC and product literature.

Overall Conclusions

Based on the original and subsequent data presented, the Committee concluded that the quality, safety and efficacy of Aivlosin were considered to be in accordance with the requirements of Council Directive 2001/82/EC, as amended.


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