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Draxxin Injectable Solution (Canada)

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Draxxin Injectable Solution

This treatment applies to the following species:
Manufacturer: Zoetis

tulathromycin sterile injectable solution

Veterinary Use Only

antibacterial

for cattle and swine

DIN 02285452

DESCRIPTION: Draxxin® Injectable Solution is a ready-to-use sterile parenteral preparation containing tulathromycin, a semi-synthetic macrolide antibiotic of the subclass triamilide. Each mL of Draxxin Injectable Solution contains 100 mg of tulathromycin as the free base in a propylene glycol vehicle.

Draxxin Injectable Solution consists of an equilibrated mixture of two isomeric forms of tulathromycin in a 9:1 ratio. Structures of the isomers are shown below:

Figure 1.

The chemical names of the isomers are (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) - 13 - [[2,6 - dideoxy - 3 - C - methyl - 3 - O - methyl - 4 - C - [(propylamino)methyl] - α - L - ribo - hexopyranosyl]oxy] - 2 - ethyl - 3,4,10 - trihydroxy - 3,5,8,10,12,14 - hexamethyl - 11 - [[3,4,6 - trideoxy - 3 - (dimethylamino) - β - D - xylo- hexopyranosyl]-oxy]-1-oxa-6-azacyclopentadecan-15-one and (2S,3S,6R,8R,9R,10S,11S,12R) - 11 - [[2,6 - dideoxy - 3 - C - methyl - 3 - O - methyl - 4 - C - [(propylamino)methyl] - α - L - ribo - hexopyranosyl]oxy] - 2 - [(1R,2R) - 1,2 - dihydroxy - 1 - methylbutyl] - 8 - hydroxy - 3,6,8,10,12 - pentamethyl - 9 - [[3,4,6 - trideoxy - 3 - (dimethylamino) - β - D - xylohexopyranosyl]oxy] - 1 - oxa - 4 - azacyclotridecan - 13 - one, respectively.

Draxxin Injectable Solution Indications

Cattle: Bovine respiratory disease (BRD): Draxxin Injectable Solution is indicated for the treatment of BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis and for the reduction of morbidity associated with BRD in feedlot calves caused by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis, during the first 14 days in the feedlot when administered at the time of arrival.

Infectious bovine keratoconjunctivitis (IBK): Draxxin Injectable Solution is indicated for the treatment of IBK associated with Moraxella bovis.

Foot Rot: Draxxin Injectable Solution is indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii.

Swine: Swine respiratory disease (SRD): Draxxin Injectable Solution is indicated for the treatment of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida and Mycoplasma hyopneumoniae and for the control of SRD caused by Actinobacillus pleuropneumoniae, Pasteurella multocida and Mycoplasma hyopneumoniae in groups of pigs where SRD has been diagnosed.

Dosage and Administration

Cattle: Inject subcutaneously in the neck, a single dose of 2.5 mg/kg body weight (1.25 mL/50 kg). Care should be taken to dose accurately. Do not inject more than 10 mL per injection site. Most animals will respond to treatment within 3 to 5 days. If no improvement is observed, the diagnosis should be re-evaluated.

On Arrival Treatment:

Note: To limit the potential development of antimicrobial resistance, Draxxin Injectable Solution should only be used as an arrival treatment when: 1) BRD has been diagnosed and 2) calves are at “high risk” of developing BRD. One or more of the following factors typically characterizes calves at “high risk” of developing BRD. Cattle are from multiple farm origins, and/or cattle have extended transport times (that may have included few if any rest stops), and/or ambient temperature change(s) from origin to arrival of 17°C or more, and/or animals have had continued exposure to extremely wet and cold weather conditions, and/or cattle have experienced excessive shrink or stressful processing procedures such as castration and dehorning.

Table 1. Draxxin Injectable Solution Cattle Dosing Guide

Animal Weight (kg)

Dose Volume (mL)

50

1.25

100

2.5

200

5.0

300

7.5

400

10.0

500

12.5

600

15.0

Swine: With the use of an automatic dosing syringe, inject intramuscularly in the neck, a single dose of 2.5 mg/kg body weight (0.25 mL/10 kg). Do not inject more than 2.5 mL per injection site. Most animals will respond to treatment within 3 to 5 days. If no improvement is observed, the diagnosis should be re-evaluated.

Note: To limit the development of antimicrobial resistance, Draxxin Injectable Solution should only be used for control of SRD when segregation and treatment of individual sick animals is unlikely to control the disease outbreak. Veterinarians should make treatment decision by considering among others overall farm management and outbreak associated factors.

Table 2. Draxxin Injectable Solution Swine Dosing Guide

Animal Weight (kg)

Dose Volume (mL)

8

0.2

12

0.3

16

0.4

24

0.6

32

0.8

40

1.0

48

1.2

56

1.4

64

1.6

72

1.8

80

2.0

88

2.2

100

2.5

120

3.0

140

3.5

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 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.

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

2Nightingale, 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 2.5 mg/kg body weight, 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 body weight to 5.0 mg/kg body weight. No pharmacokinetic differences are observed in castrated male versus female calves.

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

Swine: Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg body weight, 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: Draxxin Injectable Solution is primarily bacteriostatic but may be bactericidal against some pathogens. It acts by binding to bacterial ribosomal sub-unit thereby inhibiting protein synthesis.

Cattle: In vitro activity of tulathromycin has been demonstrated against commonly isolated bacterial and mycoplasma pathogens involving BRD including Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis; for Moraxella bovis associated with IBK; and for Fusobacterium necrophorum and Porphyromonas levii associated with Foot Rot.

Table 3. The minimum inhibitory concentrations (MICs) of Draxxin Injectable Solution were determined from natural BRD infections for isolates obtained from animals enrolled in field studies in the U.S. during 1999; for Moraxella bovis associated with IBK in clinical studies in the U.S. during 2004; and from natural foot rot infections for isolates obtained from animals in field studies in Canada and the U.S. in 2007.

Organism

No. Isolates

MIC50* (µg/mL)

MIC90* (µg/mL)

Histophilus somni

36

4

4

Mannheimia haemolytica

642

2

2

Pasteurella multocida

221

0.5

1

Mycoplasma bovis

43

0.125

1

Moraxella bovis

55

0.5

0.5

Fusobacterium necrophorum

116

2

64

Porphyromonas levii

103

8

128

* The minimum inhibitory concentration for 50% and 90% of the isolates

The bacterial name Porphyromonas levii comes from the taxonomic reclassification of Bacteroides melaninogenicus subspecies levii.

Swine: In vitro activity of tulathromycin has been demonstrated against commonly isolated bacterial and mycoplasma pathogens involved in SRD including Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Bordetella bronchiseptica, Haemophilus parasuis, Streptococcus suis and Arcanobacterium (Actinomyces) pyogenes.

Table 4. The MICs of tulathromycin were determined for isolates obtained from swine enrolled in SRD field studies in the U.S. and Canada during 2000 through 2002 and during 2007-2008.

Organism

Date Isolated

No. Isolates

MIC50* (µg/mL)

MIC90* (µg/mL)

Actinobacillus pleuropneumoniae

2000-2002

135

16

32

2007-2008

89

16

16

Pasteurella multocida

2000-2002

55

1

2

2007-2008

40

1

2

Mycoplasma hyopneumoniae

2000-2002

30

8

>32

2007-2008

46

>64

>64

* The minimum inhibitory concentration for 50% and 90% of the isolates

EFFICACY:

Cattle: BRD - In a multi-location field study conducted in the U.S., 314 calves with naturally occurring BRD were treated with Draxxin Injectable Solution and 160 were treated with saline. Responses to treatment were compared to saline-treated controls. A cure was defined as a calf with ≤ 40°C on Day 14. The cure rate was significantly higher (P≤ 0.05) in Draxxin Injectable Solution-treated calves (78%) compared to saline-treated calves (23.8%). There were two BRD-related deaths in the 314 Draxxin Injectable Solution-treated calves compared to nine BRD-related deaths in the 160 saline-treated calves.

In another U.S. multi-location field study with calves at high risk of developing BRD, administration of Draxxin Injectable Solution resulted in a significantly reduced incidence of BRD (13.3%, 53 of 399 treated calves) compared to saline-treated calves (58.7%, 236 of 402 treated calves). Effectiveness evaluation was based on scored clinical signs of normal attitude/activity, normal respiration, and a rectal temperature of ≤ 40°C on Day 14. There were no BRD-related deaths in the 399 Draxxin Injectable Solution-treated calves compared to two BRD-related deaths in the 402 saline-treated calves.

Two experimentally-induced infection model studies using Mycoplasma bovis pathogenic strains were conducted to confirm the efficacy of tulathromycin in the treatment of BRD associated with M. bovis. The efficacy was evaluated based on pneumonic lung lesions and on clinical signs of respiratory disease such as pyrexia, abnormal respiration and depression. In both studies, calves treated with Draxxin Injectable Solution had significantly less percentage of pneumonic lung lesions than the saline-treated calves (11.3% vs. 28.9%, P= 0.0001 and 15% vs. 30.7%, P<0.0001). Treatment with Draxxin Injectable Solution did not eliminate Mycoplasma bovis from infected lungs. The clinical significance of this finding, as it relates to potential relapses and/or persistent subclinical infections, is unknown.

IBK - Two field efficacy studies were conducted evaluating Draxxin Injectable Solution for the treatment of infectious bovine keratoconjunctivitis (IBK) associated with Moraxella bovis in calves. The primary clinical endpoint of these studies was cure rate as assessed on Days 5, 9, 13, 17 and 21. The secondary clinical endpoint of the studies was time to improvement. At all timepoints, in both studies, the cure rate was significantly higher (P<0.05) for Draxxin Injectable Solution-treated calves compared to saline-treated calves. Additionally, time to improvement was significantly greater (P<0.05) in the saline-treated calves than in the Draxxin Injectable Solution-treated calves. There were no suspect adverse product experiences observed in either study.

Foot Rot - The effectiveness of a single dose of Draxxin Injectable Solution for the treatment of bovine foot rot was evaluated in two field studies. In both studies the cattle were clinically evaluated on day 7 and treatment success was determined based on defined decreases in lesion, swelling and lameness scores. In one of the studies 4 of the 50 (8%) saline-treated cattle met the success criteria while 30 of 50 (60%) of the Draxxin Injectable Solution-treated cattle met the success criteria. The treatment success rate for the Draxxin Injectable Solution-treated group was significantly greater P < 0.0001 compared to the saline-treated group. In the second study 17 of the 34 (50%) saline-treated cattle met the success criteria while 30 of 36 (83.3%) of the Draxxin Injectable Solution-treated cattle met the success criteria. The treatment success rate for the Draxxin Injectable Solution-treated group was significantly greater P=0.0088 compared to the saline-treated group.

Swine: A total of 266 pigs with naturally occurring SRD were treated with Draxxin Injectable Solution in a multi-location field study (5 United States, 1 Canada). Responses to treatment were compared to 267 saline-treated controls. Success was defined as a pig with normal attitude, normal respiration, and a rectal temperature of ≤ 40°C on day 7. The treatment success rate was significantly greater (P≤0.05) in Draxxin Injectable Solution-treated pigs (71.1%) compared to saline-treated pigs (46.4%). Mortality rates were 2.6% (7 of 266) in the Draxxin Injectable Solution-treated pigs compared to 9.0% (24 of 267) in the saline-treated controls.

The efficacy of tulathromycin in the treatment of SRD associated with Mycoplasma hyopneumoniae was confirmed in two experimentally-induced infection model studies using M. hyopneumoniae strains with MIC of tulathromycin > 64 µg/mL. In each study, 36 pigs were administered saline intramuscularly (IM) at a dosage of 0.025 mL/kg body weight and 36 pigs were administered tulathromycin IM at a dosage of 2.5 mg/kg body weight. Treatments were administered ten days after the first M. hyopneumoniae inoculation. All pigs were weighed, euthanized and necropsied on Study Day 10. For each pig, the percent of gross pneumonic lesions by lobe was determined. The primary clinical endpoint to determine the efficacy of tulathromycin was the difference in lung lesions scores between treatment groups. The percentage of gross pneumonic lesions was significantly less (P<0.0001) for tulathromycin-treated pigs than for saline-treated pigs in both studies (8.52% vs. 23.62% and 11.31% vs. 26.42%). Treatment with Draxxin Injectable Solution did not eliminate Mycoplasma hyopneumoniae from infected lungs. The clinical significance of this finding, as it relates to potential relapses and/or persistent subclinical infections, is unknown.

In another multi-location field study to evaluate the control of SRD (5 United States, 1 Canada), 226 pigs exposed to naturally occurring SRD were administered Draxxin Injectable Solution. Treatment was initiated when at least 15% of the pigs in the pen expressed clinical signs associated with SRD (rectal temperature ≥ 40°C and at least moderate distress in breathing and at least moderate depression). Draxxin Injectable Solution-treated pigs had a significant (P<0.05) higher treatment success rate (59%) compared to saline-treated pigs (41%). An animal was classified as a Treatment Success on Study Day 7, if it was alive, and had a respiration score of ≤ 1 (scale of 0 to 3 where 0 is normal), and had a rectal temperature of < 40°C. Failure to meet any one of the criteria classified the animal as a Treatment Failure.

ANIMAL SAFETY:

Cattle: Safety studies were conducted in feeder calves receiving a single subcutaneous dose of 25 mg tulathromycin per kg body weight, or 3 weekly treatments of 2.5, 7.5 or 12.5 mg/kg body weight. In all groups, transient indications of pain after injection were seen, including head shaking and pawing at the ground. Injection site swelling, discolouration of the subcutaneous tissues at the injection site and corresponding histopathologic changes were seen in animals at all dosage groups. These lesions showed signs of resolving over time. No other drug-related lesions were observed macroscopically or microscopically.

An exploratory study was conducted in feeder calves receiving a single subcutaneous dose of 10, 12.5 or 15 mg tulathromycin per kg body weight. Macroscopically, no lesions were observed. Microscopically, minimal to mild myocardial degeneration was seen in one of six calves administered 12.5 mg/kg body weight once and two of six calves administered 15 mg/kg body weight.

A safety study was conducted in calves 13 to 27 days of age receiving 2.5 or 7.5 mg of tulathromycin per kg body weight once subcutaneously. With the exception of minimal to mild injection site reactions, no drug-related clinical signs or other lesions were observed macroscopically or microscopically.

An injection site study conducted in feeder calves using maximum injection volumes (10 mL) demonstrated that Draxxin Injectable Solution will induce transient reaction in the subcutaneous tissues.

Swine: Safety studies were conducted in pigs receiving a single intramuscular dose of 25 mg tulathromycin per kg body weight, or 3 weekly intramuscular doses of 2.5, 7.5 or 12.5 mg/kg body weight. In all groups, transient indications of pain after injection were seen, including restlessness and excessive vocalization. Tremors occurred briefly in one animal receiving 7.5 mg/kg body weight. Discolouration and edema of injection site tissues and corresponding histopathologic changes were seen in animals at all dosages and resolved over time. No other drug-related lesions were observed macroscopically or microscopically.

WARNINGS: Treated animals must not be slaughtered for use as food for at least 44 days in cattle and 8 days in swine, after the latest treatment with this drug. / Do not use in dairy cows 20 months of age and older. / Do not use in veal calves. The withdrawal period has not been established in pre-ruminating calves. / To limit the potential development of antimicrobial resistance, Draxxin Injectable Solution should only be used (1) as an arrival treatment in feedlot calves when BRD has been diagnosed and calves are at high risk of developing BRD, and (2) for control of SRD outbreak when groups of pigs are at high risk of developing SRD.

Keep out of reach of children.

Note: To reduce the possibility of excess trim at the injection site it is recommended that swine not be slaughtered for up to 35 days after the latest treatment with this drug.

CAUTIONS: The effects of Draxxin Injectable Solution on bovine and porcine reproductive performance, pregnancy and lactation have not been determined. Subcutaneous injection in cattle and intramuscular injection in swine can cause a local tissue reaction that may result in trim loss of edible tissue at slaughter. The safety of Draxxin Injectable Solution has not been demonstrated in pigs less than 4 weeks of age.

CONTRAINDICATION: Draxxin Injectable Solution is contraindicated in animals previously found to be hypersensitive to macrolide antibiotics.

ADVERSE REACTION: No systemic adverse drug reactions were observed during clinical field studies.

Storage

Store at a temperature between 15 and 30°C. Contents should be used within 28 days after the first dose is removed.

PRESENTATION: Draxxin Injectable Solution is available in 20 mL, 50 mL, 100 mL, 250 mL and 500 mL vials.

® Registered trademark of Pfizer Products Inc.; Pfizer Canada Inc., Licensee.

© Pfizer Canada Inc., 2009

Pfizer Animal Health, Pfizer Canada Inc., Kirkland QC H9J 2M5

Net

 

20 mL

 

50 mL

8189-09-1E

87 1146 4

100 mL

 

250 mL

 

500 mL

8176-09-0E

8713910

NAC No.: 11983314

ZOETIS CANADA
16,740 TRANS-CANADA HIGHWAY, KIRKLAND, QC, H9H 4M7
Order Desk:   800-663-8888
Technical Services Canada:   800-461-0917
Technical Services USA:   800-366-5288
Website:   www.zoetis.ca
Every effort has been made to ensure the accuracy of the Draxxin Injectable Solution information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the Canadian product label or package insert.

Copyright © 2014 North American Compendiums. Updated: 2014-09-05

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