Draxxin 25

Zoetis Inc.

Draxxin 25 (tulathromycin) Injectable Solution

FULL PRESCRIBING INFORMATION: CONTENTS*

• DRAXXIN 25 DESCRIPTION
• INDICATIONS
  • Swine
• DRAXXIN 25 DOSAGE AND ADMINISTRATION
  • Swine
• DRAXXIN 25 CONTRAINDICATIONS
• WARNINGS
• RESIDUE WARNINGS
  • Swine
• PRECAUTIONS
  • Swine
• DRAXXIN 25 ADVERSE REACTIONS
  • Swine
• CLINICAL PHARMACOLOGY
  • Swine
  • Comparative Bioavailability Summary
• MICROBIOLOGY
  • Swine
• EFFECTIVENESS
  • Swine
• ANIMAL SAFETY
  • Swine
• STORAGE CONDITIONS:
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL - 50 mL Vial Label
• PRINCIPAL DISPLAY PANEL - 50 mL Vial Carton
• PRINCIPAL DISPLAY PANEL - 100 mL Vial Label
• PRINCIPAL DISPLAY PANEL - 100 mL Vial Carton
• PRINCIPAL DISPLAY PANEL - 250 mL Vial Label
• PRINCIPAL DISPLAY PANEL - 250 mL Vial Carton

FULL PRESCRIBING INFORMATION

Antibiotic
25 mg of tulathromycin/mL
For intramuscular injection in swine only.

CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

DRAXXIN 25 DESCRIPTION

DRAXXIN 25 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 25 contains 25 mg of tulathromycin as the free base in a 50% propylene glycol vehicle, monothioglycerol (5 mg/mL), citric acid (4.8 mg/mL) with hydrochloric acid and sodium hydroxide added to adjust pH.

DRAXXIN 25 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-Ο-methyl-4-C-[(propylamino) methyl]-α-L-ribo-hexopyrano-syl]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 (2R,3R,6R, 8R,9R,10S,11S,12R)-11-[[2,6-dideoxy-3-C-methyl-3-Ο-methyl-4-C-[(propylamino)methyl]-α-L-ribo-hexopyrano-syl]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-xylo-hexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13-one, respectively.

INDICATIONS

Swine

DRAXXIN 25 Injectable Solution is indicated for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae; and for the control of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae in groups of pigs where SRD has been diagnosed.

DRAXXIN 25 DOSAGE AND ADMINISTRATION

Swine

Inject intramuscularly as a single dose in the neck at a dosage of 2.5 mg/kg (1 mL/22 lb) Body Weight (BW). Do not inject more than 4 mL per injection site.

DRAXXIN 25 CONTRAINDICATIONS

The use of DRAXXIN 25 Injectable Solution is contraindicated in animals previously found to be hypersensitive to the drug.

WARNINGS

FOR USE IN ANIMALS ONLY.

NOT FOR HUMAN USE.

KEEP OUT OF REACH OF CHILDREN.

NOT FOR USE IN CHICKENS OR TURKEYS.

RESIDUE WARNINGS

Swine

Swine intended for human consumption must not be slaughtered within 5 days from the last treatment.

PRECAUTIONS

Swine

The effects of DRAXXIN 25 on porcine reproductive performance, pregnancy, and lactation have not been determined. Intramuscular injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter.

DRAXXIN 25 ADVERSE REACTIONS

Swine

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

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. Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32. 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. Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443. 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.

Swine

Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (T_max ~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 (CL_systemic = 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.

Comparative Bioavailability Summary

A single intramuscular dose of 2.5 mg tulathromycin/kg Body Weight (BW) of either DRAXXIN Injectable Solution (100 mg/mL) or DRAXXIN 25 Injectable Solution (25 mg/mL) resulted in comparable tulathromycin concentrations in swine plasma. Summary statistics for PK parameters per treatment group are shown in Table 2.

The ratio of the means between DRAXXIN Injectable Solution (100 mg/mL) and DRAXXIN 25 Injectable Solution (25 mg/mL) was contained within the 90% confidence limits of 0.80 – 1.25 for AUC_0-LOQ and 0.70 – 1.43 for C_max. As a result, DRAXXIN 25 Injectable Solution is considered pharmacologically equivalent to DRAXXIN Injectable Solution when administered to swine by IM injection at a dose rate of 2.5 mg tulathromycin/kg BW.

MICROBIOLOGY

Swine

In vitro activity of tulathromycin has been demonstrated against Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae.

The MICs of tulathromycin against indicated SRD pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A and M31-A3). MICs for Haemophilus parasuis were determined using Veterinary Fastidious Medium and were incubated up to 48 hours at 35 to 37°C in a CO₂-enriched atmosphere. All MIC values were determined using the 9:1 isomer ratio of this compound. Isolates obtained in 2000 and 2002 were from lung samples from saline-treated pigs and non-treated sentinel pigs enrolled in Treatment of SRD field studies in the U.S. and Canada. Isolates obtained in 2007 and 2008 were from lung samples from saline-treated and DRAXXIN-treated pigs enrolled in the Control of SRD field study in the U.S. and Canada. The results are shown in Table 3.

Table 3. Tulathromycin minimum inhibitory concentration (MIC) valuesThe correlation between in vitro susceptibility data and clinical effectiveness is unknown. for indicated pathogens isolated from field studies evaluating SRD in the U.S. and Canada.

Indicated pathogen	Date isolated	No. of isolates	MIC50 The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. (μg/mL)	MIC90 The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. (μg/mL)	MIC range (μg/mL)
Actinobacillus pleuropneumoniae	2000-2002 2007-2008	135 88	16 16	32 16	16 to 32 4 to 32
Haemophilus parasuis	2000-2002	31	1	2	0.25 to > 64
Pasteurella multocida	2000-2002 2007-2008	55 40	1 1	2 2	0.5 to > 64 ≤ 0.03 to 2
Bordetella bronchiseptica	2000-2002	42	4	8	2 to 8

EFFECTIVENESS

Swine

Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution or as DRAXXIN 25 Injectable Solution were demonstrated to be pharmacologically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution support the effectiveness for DRAXXIN 25 Injectable Solution.

In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with DRAXXIN. Responses to treatment were compared to saline-treated controls. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104°F on Day 7. The treatment success rate was significantly greater (P ≤ 0.05) in DRAXXIN-treated pigs (70.5%) compared to saline-treated pigs (46.1%). M. hyopneumoniae was isolated from 106 saline-treated and non-treated sentinel pigs in this study. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN against M. hyopneumoniae. Ten days after inoculation intranasally and intratracheally with a field strain of M. hyopneumoniae, 144 pigs were treated with either DRAXXIN (2.5 mg/kg BW) intramuscularly or an equivalent volume of saline. Pigs were euthanized and necropsied 10 days post-treatment. The mean percentage of gross pneumonic lung lesions was statistically significantly lower (P < 0.0001) for DRAXXIN-treated pigs than for saline-treated pigs in both studies (8.52% vs. 23.62% and 11.31% vs. 26.42%).

The effectiveness of DRAXXIN for the control of SRD was evaluated in a multi-location natural infection field study. When at least 15% of the study candidates showed clinical signs of SRD, all pigs were enrolled and treated with DRAXXIN (226 pigs) or saline (227 pigs). Responses to treatment were evaluated on Day 7. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104°F. The treatment success rate was significantly greater (P < 0.05) in DRAXXIN-treated pigs compared to saline-treated pigs (59.2% vs. 41.2%).

ANIMAL SAFETY

Swine

Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution or as DRAXXIN 25 Injectable Solution were demonstrated to be pharmacologically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore systemic target animal safety studies conducted with DRAXXIN Injectable Solution support the systemic safety for DRAXXIN 25 Injectable Solution.

Safety studies were conducted in pigs receiving a single intramuscular dose of 25 mg/kg BW, or 3 weekly intramuscular doses of 2.5, 7.5, or 12.5 mg/kg BW (both studies utilized DRAXXIN Injectable Solution). 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 BW. Discoloration 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.

Sixteen growing pigs were injected with either saline or DRAXXIN 25 as a single injection of 4 mL. Injection site observations included two instances of erythema in the DRAXXIN 25-treated group on Day 1 post-injection. No heat, sensitivity, firmness, necrosis, drainage, or swelling was observed at any injection sites in either treatment group. The gross and microscopic findings in the DRAXXIN 25-treated group were consistent with inflammatory changes induced by injections and were considered to be mild or moderate with progression to macroscopic resolution by Day 28 post-injection and microscopic resolution by Day 42 post-injection.

STORAGE CONDITIONS:

Store at or below 25°C (77°F). Use within 90 days of first vial puncture.

HOW SUPPLIED

DRAXXIN 25 Injectable Solution is available in the following package sizes:

50 mL vial; 100 mL vial; 250 mL vial

NADA 141-349, Approved by FDA

Distributed by:
Zoetis Inc.
Kalamazoo, MI 49007

To report a suspected adverse reaction or to request a material safety data sheet call 1-888-963-8471. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

For additional DRAXXIN 25 product information call:

1-888-DRAXXIN or go to www.DRAXXIN.com

060003
8208000
Made in Brazil
Revised: September 2013

PRINCIPAL DISPLAY PANEL - 50 mL Vial Label

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL
For intramuscular injection in
swine only. CAUTION: Federal
(USA) law restricts this drug to
use by or on the order of a
licensed veterinarian.

zoetis

Net Contents: 50 mL
NADA 141-349, Approved by FDA

PRINCIPAL DISPLAY PANEL - 50 mL Vial Carton

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL

For intramuscular injection in swine only.

CAUTION: Federal (USA) law restricts
this drug to use by or on the order of
a licensed veterinarian.

Net Contents: 50 mL

zoetis

NADA 141-349, Approved by FDA

PRINCIPAL DISPLAY PANEL - 100 mL Vial Label

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL
For intramuscular injection in
swine only. CAUTION: Federal
(USA) law restricts this drug to
use by or on the order of a
licensed veterinarian.

zoetis

Net Contents: 100 mL
NADA 141-349, Approved by FDA

PRINCIPAL DISPLAY PANEL - 100 mL Vial Carton

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL

For intramuscular injection in swine only.

CAUTION: Federal (USA) law restricts
this drug to use by or on the order of
a licensed veterinarian.

Net Contents: 100 mL

zoetis

NADA 141-349, Approved by FDA

PRINCIPAL DISPLAY PANEL - 250 mL Vial Label

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL
For intramuscular injection in swine only.
CAUTION: Federal (USA) law restricts
this drug to use by or on the order of a
licensed veterinarian.

Net Contents: 250 mL
NADA 141-349, Approved by FDA

zoetis

PRINCIPAL DISPLAY PANEL - 250 mL Vial Carton

Draxxin ^® 25
(tulathromycin)

Injectable Solution
Antibiotic

25 mg of tulathromycin/mL

For intramuscular injection in swine only.

CAUTION: Federal (USA) law restricts
this drug to use by or on the order of
a licensed veterinarian.

Net Contents: 250 mL

zoetis

NADA 141-349, Approved by FDA