NATIONAL PROCEDURE PUBLICLY AVAILABLE ASSESSMENT REPORT FOR A VETERINARY MEDICINAL PRODUCT Tylocure (tylosin tartrate) Asp No. 2015-0856 Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se E-mail: registrator@mpa.se Template version 2014-09-04
MODULE 1 PRODUCT SUMMARY Asp no 2015-0856 Name, strength and pharmaceutical form Applicant Active substance(s) Tylocure 910 mg/g Granules for use in drinking water Biovet ApS Kongevejen 66 DK-3480 Fredensborg Denmark tylosin tartrate ATC Vetcode QJ 01 FA 90 Target species Indication for use Pigs Infektioner orsakade av mikroorganismer känsliga för tylosin, tex porcin proliferativ enteropati (porcin intestinal adrnomatos, proliferativ hemorragisk enteropati, ileit) orsakat av Lawsonia intracellularis. Behandling av kliniska symptom av enzootisk pneumoni (SEP hos svin orsakad av mycoplasma hyopneumoniae.
MODULE 2 The Summary of Product Characteristics (SPC) for this product is available on the Medical Products Agency s website (http://www.lakemedelsverket.se/english/).
MODULE 3 PUBLIC ASSESSMENT REPORT Legal basis of original application Date of completion of the original national procedure Article 13a, Well established veterinary use, in accordance with Directive 2001/82/EC 2016-07-14 Date product first authorised 2016-07-14 I. SCIENTIFIC OVERVIEW The product is produced and controlled using validated methods and tests, which ensure the consistency of the product released on the market. It has been shown that the product can be safely used in the target species. The product is safe for the user, the consumer of foodstuffs from treated animals and for the environment, when used as recommended. Suitable warnings and precautions are indicated in the SPC. The efficacy of the product was demonstrated according to the claims made in the SPC. The overall risk/benefit analysis is in favour of granting a marketing authorisation. II. QUALITY ASPECTS A. Drug Substance The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described. The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies confirm the retest period. B. Medicinal Product The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics. The manufacturing process has been sufficiently described and critical steps identified.
The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4. III. SAFETY AND RESIDUES ASSESSMENT (PHARMACO-TOXICOLOGICAL) The Applicant referred to publications which in general fulfilled the requirements for safety and residue testing of a veterinary medicinal product intended for use in food-producing animals. The information provided was in line with the information in the CVMP MRL summary report on tylosin (EMEA/MRL/205/97-FINAL, April 1997). According to Directive 2001/82/EC a CVMP MRL summary report may be used as literature reference in an appropriate manner, particularly for the safety tests, for an application of a veterinary medicinal product with active substances demonstrated, in accordance with Article 13 a, to have been in well-established veterinary use within the Community for at least ten years. The information provided is summarised below. III.A Safety Testing Pharmacological Studies Tylosin is a macrolide and a bacteriostatic antibiotic that reversibly binds to the 23S rrna in the 50S ribosome subunit and inhibit mrna-directed protein synthesis. Tylosin also stimulates the dissociation of peptidyl-trna from ribosomes during translocation. Tylosin is active against grampositive bacteria, certain gramnegative bacteria and mycoplasma. For more details, see Part IV. Tylosin is rapidly absorbed and eliminated in rats following single oral administration of 20 to 100 mg/kg bw as tartrate or phosphate with peak serum concentrations obtained at 2-6 hours after administration. During 10 days administration of a commercially available preparation of tylosin base in drinking water (71 mg/ml) to rats, tylosin was not detected in plasma (< 0.1 µg/ml) but in lung tissues (3.93-18.14 µg/g). Plasma elimination half-life and body clearance in rats following i.v. administration has been reported to 0.40 h and 86 ml/min/kg, respectively. In rats, tylosin was shown to be mainly excreted in faeces (99% in faeces and 1% in urine); the excreted residues consisted predominantly of tylosin A, tylosin D and dihydrodesmycosin. The pharmacokinetics of tylosin in dogs was similar to that in rats. Peak plasma concentrations were attained 1-2 hours after oral administration. Oral bioavailability in rats and dogs were lower than in pigs (estimated to around 22.5%). Significant biliary secretion was reported both in rats and dogs. For pharmacokinetics in pigs, see Part IV. Toxicological Studies Single Dose Toxicity Oral LD 50 for tylosin base, tartrate and phosphate has been reported to > 5000, > 6200 and > 6200 mg/kg b.w., respectively, in both rats and mice. Intravenous LD 50 for tylosin tartrate was reported to be lower, i.e. 695 mg/kg b.w. in rats and up to 400 mg/kg b.w. in mice.
Acute effects reported in female rats following i.v. administration of tylosin included tremor, clonic convulsions, leg weaknesses and poor grooming. For single dose toxicity in pigs, see Part IV. Repeated Dose Toxicity In rats, offspring from parents fed tylosin before mating, during gestation and lactation and fed diet with up to 1.0% tylosin base (equivalent to 1000 mg/kg b.w. per day) for up to one year no effects on mortality, growth, food consumption, organ weights, or pathology were reported. There was a dose-related increase in lymphocyte count and decrease in neutrophils, significantly only in females from 0.5% (500 mg/kg b.w.). Trends of increased blood glucose levels were also noted. Based on these results a NOEL of 0.1%, approximately 50 mg/kg b.w., was set. A 2-year study in the dog reported vomiting and diarrhoea from oral doses of 200 mg/kg b.w. and above. Mild renal effects (nephrosis and pyelonephritis) were also seen (in 1 of 4 dogs at 200 and 400 mg/kg b.w.). Based on these results a NOEL of 100 mg/kg b.w. was set for dogs. Reproductive Toxicity, including Teratogenicity: No reproductive or teratogenic effects were reported in mice or rats treated with oral doses up 1000 mg/kg/day (days 7-12 of gestation) and 4800 mg/kg per day (days 1-20 of gestation), respectively. Delayed ossification of foetuses, slightly decreased pup weights and a slight decrease in growth of offspring were reported in rats at the highest studied dose level of 4800 mg/kg per day given in feed. Mutagenicity Based on the available information (3 in vitro assays; mouse L5178Y TK+/- lymphoma, gene mutation assay at the HGPRT+ locus in Chinese hamster ovary (CHO) cells, chromosome aberration in CHO cells, 1 in vivo assay; mouse bone marrow micronucleus) no genotoxic potential was indicated for tylosin. Carcinogenicity (if necessary): Based on the available information from 2 carcinogenicity studies in rats fed with up to 1% tylosin in the diet (equivalent to approximately 1000 mg/kg/day) no carcinogenic potential was indicated for tylosin. Other Studies Based on studies in guinea pigs and rabbits tylosin appear to have a mild sensitization potential, a slight and slight to moderate potential to cause irritation to the skin and the eyes, respectively. Observations in Humans There are several reports on contact dermatitis caused by tylosin in animal feed workers. Tylosin thus appears to have a potential to cause skin reactions. Microbiological Studies In the application erm-genes are described as the most widespread mechanism for resistance and that these genes causes cross-resistance to macrolides, lincosamides and streptogramin B. The human health consequences with macrolide-resistant Campylobacter spp. and possible treatment failures are discussed.
In humans, macrolides are mostly used for infections caused by bacteria which are not transmitted via food, except for campylobacteriosis and sometimes for salmonellosis. According to the opinion of CVMP (EMA/CVMP/SAGAM/741087/2009), results from risk assessment on the impact of macrolide-resistant Campylobacter on public health are equivocal. However, even if the bacteria causing human infections are not directly linked to food of animal origin they may acquire resistance determinants from animal bacteria. This said, because tylosin is already approved for treatment of pigs in Sweden an approval of the current application would have no or marginal consequences for human health, despite the importance of macrolides in human medicine. It is not likely that the total consumption of tylosin for pigs would increase because of another approved product. User Safety A user risk assessment broadly in accordance with the CVMP Guideline on User Safety for Pharmaceutical Veterinary Medicinal Products (EMEA/CVMP/543/03-Rev.1) was performed Main identified risks are qualitative and include potential allergic reactions and irritation to the respiratory tract following inhalation of the powder during preparation of the medicated water, and to the skin and the eyes following accidental spillage of powder or medicated water on the skin or splashes of the medical water in the in the eyes. These risks are mitigated by the proposed precautionary measures in SPC section 4.5 Special precautions to be taken by the person administering the veterinary medicinal product to animals which are identical to those for the product with granules of tylosin tartrate for use in drinking water currently approved in Sweden and thus acceptable. Environmental Risk Assessment Phase I The PEC soil values calculated for Tylocure and a maximum treatment duration of 7 days were above the trigger value of 100 µg/kg for Phase II studies. In order to stop the ERA in Phase I based on degradation in manure a literature study of degradation of tylosin in pig manure was provided. This study together with another literature study are considered sufficient to meet the requirement of degradation of tylosin in pig manure with respect to tylosin A, B and D but not for an unknown degradate whereas it did not allow estimation of the level of an in manure after 30 days. The level of the unknown degradate was approximately 30% of added tylosin or lower at 72 hours of incubation, and it was indicated to, together with tylosin B and tylosin D, represent approximately 1% of added tylosin after 8 months. This information, together with the intermittent treatment and the national regulation regarding storage and spreading of pig manure, was considered sufficient to stop the ERA in Phase I. Conclusion Based on the data provided, the ERA can stop at Phase I. The product is not expected to pose an unacceptable risk for the environment when used according to the SPC. A note that national regulation regarding storage and spreading of pig manure should be followed was included.
III.B Residues documentation Residue Studies For pharmacokinetics in pigs except excretion, see Part IV. In pigs, tylosin was reported to be mainly excreted in faeces (94-99% in faeces and 1-6% in urine). The principal components of the excreted residues (expressed as % of total 14 C- residues) were tylosin D (33-56%), tylosin (6%) and dihydrodesmycosin (6-44%). Low tylosin A levels (around 30 µg/kg) below the MRL of 100 mg/kg were reported to be detected in the liver and the kidney of pigs at 6 hours after 10 days administration of tylosin in drinking water at a dose level approximately 2.5-fold the maximum dose of 10 mg/kg b.w. per day recommended for Tylocure. In another study no tylosin residues were reported to be found in edible tissue at 0 to 5 days after 5 days treatment with tylosin tartrate in drinking water at doses corresponding to approximately 0, 24 and 49 mg/kg b.w. per day. No further information on analytical methods in addition to what was provided in the references was provided which is considered acceptable. MRLs Tylosin is included in Table 1 of the Annex to Commission Regulation (EU) No 37/2010 as follows: Pharmacologically active substance Marker residue Animal species Tylosin Tylosin A All food producing species MRLs 100 µg/kg 100 µg/kg 100 µg/kg 100 µg/kg 50 µg/kg 200 µg/kg Target tissues Muscle* fat** Liver Kidney Milk Eggs Other provisions Therapeutic classification It was estimated that extending the MRLs to all food producing species, as proposed above, would result in a consumer intake not exceeding 80% of the microbiological ADI (360 µg/person) *For fin fish this MRL relates to muscle and skin in natural proportions **For porcine and poultry species this MRL relates to skin and fat in natural proportions Withdrawal Periods Based on the results of the referred depletion studies and a withdrawal period of 1 day for similar products a withdrawal period of 1 day in meat for Tylocure and a maximum treatment period of 7 days is considered justified. IV. CLINICAL ASSESSMENT (EFFICACY) IV.A Pre-Clinical Studies Pharmacology Some susceptibility for L intracellularis was presented. It was concluded that there are currently no standards for susceptibility testing of L intracellularis and susceptibility data is scant. Published data demonstrate high variability indicating that reduced susceptibility may
occur. However, the clinical relevance of MIC data is regarded to be unclear. Thus, justification of a claim for L intracellularis was regarded to be dependent on the outcome of clinical studies. The applicant provided published data to support that tylosin is a lipid-soluble organic base with 40 % protein binding, a high degree of lipid solubility and a low degree of ionization for which reason it is widely distributed throughout tissues and body fluids. Apparent median volume distribution and steady-state volume distribution after iv administration to pigs is 14.6 and 9.7 l/kg, respectively. The total body clearance and the elimination half-life of tylosin calculated after iv administration is 31.3 ml(min x kg) and 4.5 hours, respectively. Tolerance in the Target Species of Animals The publications provided presented outcome of clinical and experimental trials where pigs of varying age were provided different doses of tylosin for varying periods of time and via different administration routes. In submitted publication where pigs had been provided substantially higher oral doses of tylosin (22.8 mg/kg and 50 mg/kg body weight daily) than proposed for the current application (5-10 mg/kg body weight daily) adverse events were either rare or absent. Furthermore, it was acknowledged that tylosin as tartrate has been authorized for decades in Sweden and other European countries and clinical experience with regard to safety is well known from this long time use. The dose regimen is similar to previously authorized oral tylosin formulation for use in swine. The adverse events mentioned in the proposed product information are in line with what was noted in the studies submitted. The published information presented together with the fact that oral tylosin formulations has been authorised for use in swine during many year with acceptable safety profile and similar safety specifications, was regarded to provide sufficient support for tolerance. Resistance The potential for development of resistance against tylosin and cross-resistance against other macrolides for different swine pathogens was demonstrated in submitted studies, as would be expected. This is in line with the characteristics of this substance presented in the Reflection Paper EMA/CVMP/SAGAM/741087/2009. With regard to L intracellularis the fact that no standards for susceptibility testing are available implies that there is lack of relevant data to assess current resistance situation. From clinical data there is currently no indication of resistance that would hamper effectiveness during treatment of infection with L intracellularis. IV.B Clinical Studies Laboratory Trials A challenge study including Lawsonia intracellularis was submitted to support the proposed dosing regimen. Pigs were administered tylosin tartrate in drinking water by mixing a tylosin tartrate soluble powder into the water to a concentration of 83.3 mg/l. According the recorded daily water disappearance per pig and assuming a wastage factor of 40 % the daily dose provided was 8.7 mg/kg body weight. This dose is also used in several other publications for the treatment of gastrointestinal infections and 5-10 mg/kg body weight daily for seven days is the recommended dose for an oral powder for drinking water previously authorized in Sweden. The treatment was connected to clinically relevant and statistically significant improvement as compared to untreated animals in clinical and post mortem parameters after L intracellularis inoculation. Thus the proposed dose interval 5-10 mg/kg body weight was considered to be sufficiently supported for the treatment of L intracellularis. Field Trials The applicant provided data from some experimental and clinical field studies to further support the clinical efficacy of tylosin for the treatment of L intracellularis. Furthermore, it was acknowledged that 5-10 mg/kg body weight given for 7 days is the recommended dose for a
tylosin tartrate formulation for drinking water already authorized in Sweden. It was further noted that for oral tylosin formulations for drinking water authorised in other European countries a similar dosing strategy is given. In view of the clinical data provided and of the fact that oral tylosin formulations have been on the market for decades and the dosing strategy has not been challenged, clinical efficacy for the treatment of L intracellularis with the proposed dose was regarded sufficiently supported. V. OVERALL CONCLUSION AND BENEFIT RISK ASSESSMENT A positive effect of treatment of porcine proliferative enteropathy caused by Lawsonia intracellularis with the proposed dosing regimen is sufficiently supported by data. Similarly, the safety of the product when used in clinical setting with the proposed dosing regimen is regarded adequately supported through the data submitted. Regarding risks for resistance transmission from animals to humans, the product information contains information in line with the risk mitigation measures recommended in reflection paper EMA/CVMP/SAGAM/741087/2009. Given that tylosin in the same presentation as Tylocure is already approved for treatment of enteric disease in pigs in Sweden approval of the current application would have no or marginal consequences for human health The safety of users and consumers and risk for the environment are considered acceptable when used in accordance with the recommendations given in the SPC. To conclude, the data submitted in the dossier demonstrate that when the product is used in accordance with the Summary of Product Characteristics, the risk benefit profile for the target species is favourable and the quality and safety of the product for humans and the environment is acceptable.
MODULE 4 POST-AUTHORISATION ASSESSMENTS The SPC and package leaflet may be updated to include new information on the quality, safety and efficacy of the veterinary medicinal product. The current SPC is available on the Medical Products Agency s website (http://www.lakemedelsverket.se/english/). This section contains information on significant changes which have been made after the original procedure which are important for the quality, safety or efficacy of the product. Quality changes Summary of change (Application number) <Example: Change to active substance specification> (MS/V/XXX/X/IB/XX) Section updated in Module 3 N/A Approval date Safety/efficacy changes Summary of change (Type; application number) <Example: Addition of target species - pigs> (MS/V/XXX/X/II/XX) Section updated in Module 3 <IIIA> <IIIB> <IV> Approval date