Hymatil (Canada)

Tilmicosin is produced semi-synthetically and is a member of the macrolide class of antibiotics.

Activity: Hymatil has an in vitro antibacterial spectrum that is predominantly Gram positive with activity against certain Gram negative microorganisms. Activity against several mycoplasma species has also been detected.

One hundred thirty-four of 139 (96.4%) Mannheimia (Pasteurella) haemolytica isolates tested were inhibited by less than or equal to 3.12 µg/mL tilmicosin.

With Pasteurella multocida Carter Type A of bovine origin, 53/54 (98.2%) isolates tested were inhibited by less than or equal to 12.5 µg/mL tilmicosin and 39/54 (72.2%) by less than or equal to 6.25 µg/mL.

In addition to its direct antibacterial action, tilmicosin may exert an anti-inflammatory effect in the lung by increasing neutrophil apoptosis and reducing the release of pro-inflammatory mediators. However, the clinical significance of this effect is unknown. In clinical trials, BRD treatment success with tilmicosin was usually characterized by rapid reduction in body temperatures, less severity of clinical signs, better weight gains and reduced mortality.

Toxicology: The cardiovascular system appears to be the target of toxicity in laboratory animals and domestic livestock administered tilmicosin by oral or parenteral routes. The primary cardiac effects are increased heart rate (tachycardia) and decreased contractility (negative inotropy).

Cardiovascular toxicity may be due to calcium channel blockade. Upon injection subcutaneously, the acute median lethal dose (mLD) of tilmicosin in mice is 97 mg of activity per kg and in rats is 185 mg/kg of body weight. Given orally, the mLD of tilmicosin is 800 mg/kg and 2250 mg/kg in fasted and nonfasted rats respectively. No compound-related lesions were found at necropsy.

In dogs, intravenous calcium offset tilmicosin-induced tachycardia and negative inotropy, restoring arterial pulse pressure within approximately 20 minutes. Dobutamine dose-dependently partially offset the negative inotropic effects induced by tilmicosin in dogs, but did not have an effect on the increased heart rate caused by tilmicosin. β-adrenergic antagonists, such as propranolol, exacerbated the negative inotropy of tilmicosin in dogs.

In monkeys, a single intramuscular dose of tilmicosin at 10 mg/kg caused no signs of toxicity. A single dose of tilmicosin at 20 mg/kg caused vomiting and 30 mg/kg caused the death of the only monkey tested.

In swine, intramuscular injection of tilmicosin at 10 mg/kg caused increased respiration, emesis and a convulsion, 20 mg/kg resulted in mortality in 3 of 4 pigs and 30 mg/kg caused the death of all 4 pigs tested. Injection of tilmicosin at 4.5 and 5.6 mg/kg intravenously followed by epinephrine, 1 mL (1:1000) intravenously 2 to 6 times, resulted in death of all pigs injected. All pigs given 4.5 mg/kg and 5.6 mg/kg tilmicosin intravenously with no epinephrine survived. These results suggest intravenous epinephrine may be contraindicated. Results of genetic toxicology studies were all negative. Results of teratology and reproduction studies in rats were negative. The no effect level in dogs after daily oral doses of tilmicosin for up to one year is 4 mg/kg of body weight.

In cattle, subcutaneous doses of tilmicosin at 10, 30 and 50 mg/kg of body weight, each injected at 72 hour intervals for three times, did not cause any deaths. As expected, edema at the site of injection was noted. In cattle, the only lesion observed at necropsy was minimal myocardial necrosis in the 50 mg/kg tilmicosin group. Subcutaneous doses of tilmicosin at 150 mg/kg injected at 72 hour intervals resulted in deaths. Edema was marked at the site of injection. Minimal myocardial necrosis was the only lesion observed at necropsy. Deaths of cattle have been observed with a single intravenous dose of tilmicosin at 5 mg/kg of body weight.

In lambs, single subcutaneous doses of tilmicosin up to 150 mg/kg of body weight did not cause death. Deaths of lambs have been observed with a single intravenous dose of 7.5 mg/kg body weight.

Pharmacokinetics: A single subcutaneous injection of tilmicosin at 10 mg/kg of body weight in cattle resulted in peak tilmicosin levels within one hour and detectable levels (0.07 µg/mL) in serum beyond 3 days. However, lung concentrations of tilmicosin remained above the tilmicosin MIC (95% of 3.12 µg/mL) for Mannheimia (Pasteurella) haemolytica for at least three days following the single injection. Serum tilmicosin levels are a poor indicator of total body tilmicosin. The lung/serum tilmicosin ratio in favour of lung tissue appeared to equilibrate by three days post injection at approximately 60. In a study with radioactive tilmicosin, 24% and 68% of the dose was recovered from urine and feces respectively over 21 days.

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Manufactured for: Modern Veterinary Therapeutics, LLC, Miami, Florida 33186 - USA

www.modernveterinarytherapeutics.com

info@modernveterinarytherapeutics.com

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Revision date: 01 June 2020

CPN: 1354009.4