Macrosyn: Product Information (Page 2 of 4)

ADVERSE REACTIONS

Cattle

In one BRD field study, two calves treated with tulathromycin injection at 2.5 mg/kg BW exhibited transient hypersalivation. One of these calves also exhibited transient dyspnea, which may have been related to pneumonia.

Swine

In one field study, one out of 40 pigs treated with tulathromycin injection at 2.5 mg/kg BW exhibited mild salivation that resolved in less than four hours.

POST APPROVAL EXPERIENCE

The following adverse events are based on post approval adverse drug experience reporting. Not all adverse events are reported to the FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The following adverse events are listed in decreasing order of reporting frequency in cattle: Injection site reactions and anaphylaxis/anaphylactoid reactions. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae.

CLINICAL PHARMACOLOGY

At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to the plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined.

Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE.

Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.

1 Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.

2 Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.

Cattle

Following subcutaneous administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulathromycin is rapidly and nearly completely absorbed. Peak plasma concentrations generally occur within 15 minutes after dosing and product relative bioavailability exceeds 90%. Total systemic clearance is approximately 170 mL/hr/kg. Tulathromycin distributes extensively into body tissues, as evidenced by volume of distribution values of approximately 11 L/kg in healthy ruminating calves.3 This extensive volume of distribution is largely responsible for the long elimination half-life of this compound [approximately 2.75 days in the plasma (based on quantifiable terminal plasma drug concentrations) versus 8.75 days for total lung concentrations (based on data from healthy animals)]. Linear pharmacokinetics are observed with subcutaneous doses ranging from 1.27 mg/kg BW to 5.0 mg/kg BW. No pharmacokinetic differences are observed in castrated male versus female calves.

3 Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either subcutaneous or intravenous injection.

Swine

Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (Tmax ~0.25 hour). Subsequently, the drug rapidly distributes into body tissues, achieving a volume of distribution exceeding 15 L/kg. The free drug is rapidly cleared from the systemic circulation (CLsystemic = 187 mL/hr/kg). However, it has a long terminal elimination half-life (60 to 90 hours) owing to its extensive volume of distribution. Although pulmonary tulathromycin concentrations are substantially higher than concentrations observed in the plasma, the clinical significance of these findings is undetermined. There are no gender differences in swine tulathromycin pharmacokinetics.

MICROBIOLOGY

Cattle

Tulathromycin has demonstrated in vitro activity against Mannheimia haemolytica , Pasteurella multocida , Histophilus somni , and Mycoplasma bovis , four pathogens associated with BRD; against Moraxella bovis associated with IBK; and against Fusobacterium necrophorum and Porphyromonas levii associated with bovine foot rot.

The MICs of tulathromycin against indicated BRD and IBK pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A2). The MICs against foot rot pathogens were also determined using methods recommended by the CLSI (M11-A6). All MIC values were determined using the 9:1 isomer ratio of this compound.

BRD — The MICs of tulathromycin were determined for BRD isolates obtained from calves enrolled in therapeutic and at-risk field studies in the U.S. in 1999. In the therapeutic studies, isolates were obtained from pre-treatment nasopharyngeal swabs from all study calves, and from lung swabs or lung tissue of saline-treated calves that died. In the at-risk studies, isolates were obtained from nasopharyngeal swabs of saline-treated non-responders, and from lung swabs or lung tissue of saline-treated calves that died. The results are shown in Table 3.

IBK — The MICs of tulathromycin were determined for Moraxella bovis isolates obtained from calves enrolled in IBK field studies in the U.S. in 2004. Isolates were obtained from pre-treatment conjunctival swabs of calves with clinical signs of IBK enrolled in the tulathromycin injection and saline-treated groups. The results are shown in Table 3.

Foot Rot — The MICs of tulathromycin were determined for Fusobacterium necrophorum and Porphyromonas levii obtained from cattle enrolled in foot rot field studies in the U.S. and Canada in 2007. Isolates were obtained from pretreatment interdigital biopsies and swabs of cattle with clinical signs of foot rot enrolled in the tulathromycin injection and saline-treated groups. The results are shown in Table 3.

Table 3. Tulathromycin minimum inhibitory concentration (MIC) values * for indicated pathogens isolated from field studies evaluating BRD and IBK in the U.S. and from foot rot field studies in the U.S and Canada.

Indicated pathogen

Date isolated

No. of isolates

MIC 50
(μg/mL)

MIC 90
(μg/mL)

MIC range (μg/mL)

Mannheimia haemolytica

1999

642

2

2

0.5 to 64

Pasteurella multocida

1999

221

0.5

1

0.25 to 64

Histophilus somni

1999

36

4

4

1 to 4

Mycoplasma bovis

1999

43

0.125

1

≤ 0.063 to > 64

Moraxella bovis

2004

55

0.5

0.5

0.25 to 1

Fusobacterium necrophorum

2007

116

2

64

≤ 0.25 to > 128

Porphyromonas levii

2007

103

8

128

≤ 0.25 to > 128

* The correlation between in vitro susceptibility data and clinical effectiveness is unknown.

† The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.

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