AIVLOSIN^®

DESCRIPTION: Aivlosin® Water Soluble Granules is a water soluble granular powder containing 62.5% w/w tylvalosin (as tylvalosin tartrate) for oral use by administration in the drinking water.

ANTIBIOTIC CLASSIFICATION: Tylvalosin, the active ingredient in Aivlosin® Water Soluble Granules, is a macrolide antibiotic.

INDICATIONS: For the treatment of Porcine Proliferative Enteropathy (PPE) associated with Lawsonia intracellularis in pigs. As an aid in reducing the severity of Swine Respiratory Disease (SRD) associated with Haemophilus parasuis, Pasteurella multocida, Streptococcus suis and Mycoplasma hyopneumoniae in groups of pigs experiencing an outbreak of SRD.

TARGET SPECIES: Pig

DOSAGE AND ADMINISTRATION: To reduce the development of antimicrobial resistance and maintain effectiveness, use this antibiotic prudently.

For use in drinking water of swine only.

Aivlosin® Water Soluble Granules sachet size	160 grams	400 grams
Tylvalosin content of sachet (grams)	100	250
Recommended volume of stock solution (US gallons)	4	10
Volume of drinking water (US gallons)	528	1320
Final Tylvalosin inclusion rate in drinking water	50 parts per million (ppm

Note: Based on theoretical daily water consumption rate of 10-20% body weight, 50 ppm tylvalosin in drinking water will provide a dose rate of 5-10 mg tylvalosin/kg body weight per day.

Administer continuously in drinking water. Medicated water should be the only source of drinking water during the treatment period. If improvement is not observed within 5 days, the diagnosis should be reconfirmed.

MIXING: Keep water supply equipment clean and in good operating condition. Clean water medication equipment before and after each use. Only a sufficient amount of medicated drinking water should be prepared to cover daily requirements. Do not mix or administer medicated water using equipment made of galvanized metal. Galvanized metal adversely affects the stability of tylvalosin in water and may reduce the effectiveness of the product. Prepare a fresh batch of medicated stock solution or medicated drinking water daily. Aivlosin® Water Soluble Granules may be mixed directly into the drinking water system or first mixed as a stock solution in a smaller amount of water, which is then added to the drinking water system, for example, using an automatic water proportioner.

Direct Mixing: Prepare a fresh batch of medicated drinking water daily. 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 slowly and thoroughly until a clear solution is produced (usually within 3 minutes).

Stock Solution: Prepare a fresh batch of medicated stock solution daily. When preparing a stock solution for an automatic water proportioner, the recommended maximum concentration is one-160 g sachet per 16 L (~4 US gallons) or one-400 g sachet per 40 L (~10 US gallons). Sprinkle contents onto the surface of the water and mix slowing and thoroughly for 10 minutes. After this time, any remaining cloudiness will not affect tylvalosin concentration. Use the stock solution for dilution into the drinking water system as soon as it is prepared. Add 32 mL of this stock solution per 4 L drinking water to provide a final concentration of 50 ppm. Prepare drinking water medicated with 50 parts per million tylvalosin.

Administer continuously in the drinking water for five (5) consecutive days. Based on a theoretical daily water consumption rate of 10-20% body weight, 50 ppm tylvalosin in drinking water will provide a dose rate of 5-10 mg tylvalosin/kg body weight per day.

CAUTIONS: Not for use in lactating or pregnant females, or males and females intended for breeding. The effects of tylvalosin on swine reproductive performance, pregnancy and lactation have not been determined.

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

WARNINGS: Treated swine must not be slaughtered for use in food for at least 24 hours after the latest treatment with this drug. Tylvalosin has been shown to cause hypersensitivity reactions in laboratory animals; therefore, people with known hypersensitivity to tylvalosin tartrate should avoid contact with this product. When mixing Aivlosin® Water Soluble Granules and handling the medicated water, avoid inhalation, oral exposure and direct contact with skin or eyes. Keep out of reach of children.

ADVERSE REACTIONS: No adverse reactions related to the drug were observed during clinical or target animal safety trials.

CLINICAL PHARMACOLOGY AND MICROBIOLOGY: Tylvalosin is a 16-membered semi-synthetic macrolide antibiotic. Macrolides are generally considered to be bacteriostatic agents that exert their antibiotic effect by reversibly binding to the 23S rRNA of the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. The spectrum of activity of most available macrolides used in veterinary medicine is primarily against Gram-positive bacteria and Mycoplasmas, with some activity against Gram-negative fastidious bacteria. These compounds have no activity against the naturally resistant Enterbacteriaceae including Escherichia coli and Salmonella spp. Minimal inhibitory concentration (MIC) data for Lawsonia intracellularis have been generated with the intracellular MIC value of 32 µg/mL for three tested strains (McOrist, 2012; Gebhart, 2000) and MIC of >64 µg/mL for another strain (Gebhart, 2000). All isolates of Bordetella bronchiseptica (n=38) from the pilot effectiveness study conducted in the USA in 2013 showed tylvalosin MIC values of >256 µg/mL. Use of antibacterial drugs in the absence of a susceptible bacterial infection is unlikely to provide benefit to treated animals and may increase the development of drug-resistant pathogenic bacteria. Typically macrolides achieve higher concentrations in tissues than in plasma.

EFFECTIVENESS:

Control of Porcine Proliferative Enteropathy (PPE):

A multi-location challenge model study was conducted to confirm the effectiveness of Aivlosin® Water Soluble Granules for the control of PPE associated with Lawsonia intracellularis. Pigs were challenged by intragastric gavage with a mucosal homogenate containing a North American isolate of Lawsonia intracellularis isolated in 2005 that induces representative disease in challenged pigs. When at least 15% of the study pigs were showing signs of infection based on abnormal fecal scores, pigs were provided with water containing tylvalosin at an inclusion rate of 50 ppm for five consecutive days, or were provided non-medicated water. Effectiveness was evaluated using clinical scores (pig demeanor score, abdominal appearance score, and fecal score) and clinically-validated gross PPE lesion scores. A conclusion of the effectiveness of 50 ppm tylvalosin for the control of PPE was determined based on a statistically significant (p=0.0103) improvement in the clinically-validated gross PPE lesion scores in the 50 ppm tylvalosin-treated group compared to the non-medicated group.

Control of Swine Respiratory Disease (SRD):

The effectiveness of Aivlosin® Water Soluble Granules for the control of Swine Respiratory Disease (SRD) associated with Bordetella bronchiseptica, Haemophilus parasuis, Pasteurella multocida, Streptococcus suis and Mycoplasma hyopneumoniae was investigated in a natural field infection study conducted in the United States (three study sites) and Canada (one study site). Day 0 was defined when at least 15% of the candidate pigs were deemed clinically affected with SRD (moderate or severe respiratory score, moderate or severe depression score, and rectal temperature greater than or equal to 104.0oF). On Day 0 a total of 980 pigs were enrolled and randomly assigned to a tylvalosin-treated group (50 ppm tylvalosin in drinking water for 5 consecutive days) or a non-medicated control group. Treatment success was evaluated on Day 7 and was defined as a pig with normal or mild respiratory score, normal or mild depression score, and rectal temperature less than 104.0oF. The proportion of pigs meeting the definition of treatment success was numerically higher in the tylvalosin-treated group (48.5%) compared to the proportion of pigs meeting the definition of treatment success in the nonmedicated group (41.6%), and the observed difference was statistically significant (p=0.0353). To confirm the presence of M. hyopneumoniae, lung samples from pigs in the field study were screened with a quantitative polymerase chain reaction (qPCR) test and microbiological culture. Of the 976 samples tested, 185 (19%) were qPCR positive and 9 cultures were positive for M. hyopneumoniae. The data from both the multicentric field study and the experimentally-induced infection model study described below demonstrates that tylvalosin is effective as an aid in reducing the severity of SRD associated with M. hyopneumoniae. Additional data to demonstrate the effectiveness of Aivlosin® Water Soluble Granules for the control of SRD associated with Mycoplasma hyopneumoniae was obtained in an experimentally-induced infection model study. Two hundred and forty (240) commercial crossbred pigs were challenged endotracheally with a representative isolate of M. hyopneumoniae. One hundred and ninety-two (192) study pigs were randomly assigned to either a tylvalosin-treated group (50 ppm tylvalosin in drinking water for 5 consecutive days) or a non-medicated control group. Treatment was started when at least four of eight randomly pre-selected sentinel pigs exhibited a minimum of 3% weighted gross lung lesions consistent with M. hyopneumoniae infection. After a 5-day treatment period and a 5-day post-treatment period, study pigs were euthanized and necropsy performed to determine lung lesion scores. There was a statistically significant (p<0.0001) improvement in pen mean. M. hyopneumoniae lung lesion scores in 50 ppm tylvalosin-treated pigs (5.1%) compared to negative control (10.9%).

 Animal Safety

Margin of safety: Aivlosin® Water Soluble Granules given orally in drinking water at 0, 50, 150 and 250 ppm tylvalosin (0, 1X, 3X and 5X the labelled dose, respectively) to 8 healthy pigs per treatment group over 15 days (3X the labelled duration) did not result in drug-induced clinical signs, gross pathologic lesions, histopathologic lesions or clinically-relevant clinical pathology abnormalities.