For subcutaneous use in beef cattle.
Not for use in cattle intended for dairy production or in calves to be processed for veal.
Federal law prohibits the extra-label use of this drug in food-producing animals.
Each mL contains 180 mg of danofloxacin as the mesylate
salt, 200 mg 2-pyrrolidone, 50 mg polyvinyl pyrrolidone, 20.3 mg heavy
magnesium oxide, 2.5 mg phenol, 5 mg monothioglycerol, hydrochloric acid
or sodium hydroxide as needed to adjust pH, nitrogen headspace and
water for injection, q.s.
INDICATIONS: For the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida in beef cattle and for the control of BRD in beef cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida.
DOSAGE AND ADMINISTRATION: Care should be taken to dose accurately. Administered dose volume should not exceed 15 mL per injection site.
Single-Dose Therapy (BRD Treatment and Control in Cattle at High Risk): Administer subcutaneously at 8 mg/kg of body weight (2 mL/100 lb) as a one-time injection.
Multi-Day Therapy (BRD Treatment):
Administer subcutaneously at 6 mg/kg of body weight (1.5 mL/100 lb) with
this treatment repeated once approximately 48 hours following the first
injection.
ADVOCIN Dosage and Treatment Schedule
Cattle Weight (lb)
|
Dose Volume (mL)
|
6 mg/kg, given twice, 48 hours apart (treatment)
|
8 mg/kg given once (treatment and control in cattle at high risk)
|
50
|
0.75
|
1
|
100
|
1.5
|
2
|
150
|
2.25
|
3
|
200
|
3
|
4
|
250
|
3.75
|
5
|
300
|
4.5
|
6
|
400
|
6
|
8
|
500
|
7.5
|
10
|
600
|
9
|
12
|
700
|
10.5
|
14
|
800
|
12
|
16*
|
900
|
13.5
|
18*
|
1000
|
15
|
20*
|
* Administered dose volume should not exceed 15 mL per injection site.
Clinical field studies indicate that ADVOCIN
(danofloxacin injection) Sterile Injectable Solution is effective for
the control of respiratory disease in beef cattle at high risk of developing BRD. Cattle at high risk of developing BRD typically experience one or more of the following risk factors:
•
Commingling from multiple sale barns/sources
•
Extended transport times and shrink
•
Exposure to wet or cold weather conditions or wide temperature swings
•
Stressful arrival processing procedures (such as castration, dehorning, or branding)
•
Recent weaning or poor vaccination history
|
RESIDUE WARNINGS: Animals intended
for human consumption must not be slaughtered within 4 days from the
last treatment. Do not use in cattle intended for dairy production. A
withdrawal period has not been established for this product in
preruminating calves. Do not use in calves to be processed for veal.
|
|
ANTIBACTERIAL WARNINGS: Use of
antibacterial drugs in the absence of a susceptible bacterial infection
is unlikely to provide benefit to treated animals and may increase the
risk of the development of drug-resistant bacteria.
HUMAN WARNINGS: For use in animals only. Keep out of reach of children.
Avoid contact with eyes. In case of contact, immediately flush eyes
with copious amounts of water for 15 minutes. In case of dermal contact,
wash skin with soap and water. Consult a physician if irritation
persists following ocular or dermal exposures. Individuals with a
history of hypersensitivity to quinolones should avoid this product. In
humans, there is a risk of user photosensitization within a few hours
after excessive exposure to quinolones. If excessive accidental exposure
occurs, avoid direct sunlight. To report adverse reactions or to obtain
a copy of the Material Safety Data Sheet (MSDS), call 1-888-963-8471.
PRECAUTIONS: The effects of danofloxacin on bovine reproductive performance, pregnancy, and lactation have not been determined.
Subcutaneous injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter.
Quinolone-class drugs should be used with caution in
animals with known or suspected central nervous system (CNS) disorders.
In such animals, quinolones have, in rare instances, been associated
with CNS stimulation, which may lead to convulsive seizures.
Quinolone-class drugs have been shown to produce
erosions of cartilage of weight-bearing joints and other signs of
arthropathy in immature, rapidly growing animals of various species.
Refer to Animal Safety for information specific to danofloxacin.
ADVERSE REACTIONS: A
hypersensitivity reaction was noted in 2 healthy calves treated with
ADVOCIN in a laboratory study. In one location of a multi-site field
trial, one out of the 41 calves treated with 6 mg/kg q 48 hours showed
lameness on Day 6 only. In this same field trial location one of 38
calves treated with 8 mg/kg once became lame 4 days after treatment and
remained lame on the last day of the study (Day 10). Another calf in the
same treatment group developed lameness on the last day of the study.
CLINICAL PHARMACOLOGY:
(a) Pharmacokinetics: Danofloxacin
distributes extensively throughout the body, as evidenced by a steady
state volume of distribution (VDss) in cattle exceeding 1 L/kg.
Danofloxacin concentrations in the lung homogenates markedly exceed
those observed in plasma, further suggesting extensive distribution to
the indicated site of infection. Danofloxacin is rapidly eliminated from
the body (apparent terminal elimination T1/2 ranging from 3-6 hours),
and negligible accumulation was observed when animals were dosed twice,
48 hours apart.
Danofloxacin is rapidly absorbed and is highly
bioavailable when administered as a subcutaneous injection in the neck.
Linear pharmacokinetics has been demonstrated when danofloxacin is
administered to cattle by subcutaneous injection at doses between 1.25
to 10 mg/kg. No statistically significant gender difference was observed
in peak or total systemic exposure following a single subcutaneous
administration of danofloxacin to heifers and steers at a dose of 6
mg/kg body weight (Table 1).
Table 1. Danofloxacin
pharmacokinetic values in male and female cattle (n=6/group) after a
single subcutaneous injection into the lateral neck region at a dose of 6
mg danofloxacin/kg body weight
|
Steers
|
Heifers
|
Mean
|
%CVe
|
Mean
|
%CV
|
a AUC0-24
|
µg x hr/mL
|
9.4
|
10
|
8.8
|
9
|
b F%
|
|
92
|
5
|
87
|
3
|
a Cmax
|
µg/mL
|
1.25
|
16
|
1.27
|
13
|
a,c Tmax
|
hr
|
3.2
|
42
|
1.7
|
31
|
d CL
|
L/hr
|
0.54
|
12
|
0.62
|
9
|
d VDss
|
L/kg
|
2.7
|
7
|
2.6
|
4
|
a T1/2
|
hr
|
4.8
|
18
|
4.2
|
7
|
a AUC0-24 = area under the plasma concentration versus time curve from hr zero to hr 24 postdose. Cmax = maximum observed concentration. Tmax = time to Cmax.
b Bioavailability (F%) =
extent of drug absorption following subcutaneous administration. Within
subject F values were determined as the ratio of AUC0-inf values estimated following a 6 mg/kg dose administered by either a subcutaneous or intravenous injection.
c Statistically significant differences in Tmax were detected between genders. Given the similarity in Cmax values, these differences are not expected to have any clinical relevance.
d Clearance (CL) and
Volume of distribution at steady state (VDss) were determined from data
obtained after intravenous administration of a 6 mg/kg dose.
e Coefficient of variation %
(b) Microbiology: Danofloxacin
exerts its activity by inhibiting the bacterial DNA gyrase enzyme,
thereby blocking DNA replication. Inhibition of DNA gyrase is lethal to
bacteria and danofloxacin has been shown to be rapidly bactericidal.
Danofloxacin is active against gram-negative and gram-positive bacteria.
The Minimum Inhibitory Concentrations (MIC) of
danofloxacin for pathogens isolated in natural infections from various
clinical studies in North America, 1996-1997, were determined using the
standardized microdilution technique (SENSITITRE/ALAMAR, Accumed
International), and are shown in Table 2.
Table 2. Danofloxacin minimum
inhibitory concentration (MIC) values* of indicated pathogens isolated
from 1996-1997 pivotal BRD treatment field studies in the U.S.
Indicated Pathogen
|
Number of Isolates
|
MIC50** (µg/mL)
|
MIC90** µg/mL
|
MIC Range µg/mL
|
Mannheimia haemolytica
|
106
|
0.06
|
0.06
|
≤0.015 to 0.12
|
Pasteurella multocida
|
94
|
≤0.015
|
0.06
|
≤0.015 to 0.12
|
* 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.
Table 3. Danofloxacin minimum
inhibitory concentration (MIC) values* of indicated pathogens isolated
from 2013 pivotal field studies in the U.S. and Canada for the control
of BRD in cattle at high risk of developing BRD.
Indicated Pathogen
|
Number of Isolates
|
MIC50** (µg/mL)
|
MIC90** µg/mL
|
MIC Range µg/mL
|
Mannheimia haemolytica
|
507
|
0.03
|
0.06
|
≤0.008 to >8
|
Pasteurella multocida
|
324
|
≤0.008
|
0.12
|
≤0.008 to 1.0
|
* 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.
EFFECTIVENESS: The effectiveness of 8
mg/kg administered once and the 6 mg/kg BW alternate day regimen was
confirmed in 4 well-controlled studies of naturally acquired bacterial
respiratory infections in feedlot age cattle. These studies were
conducted under commercial conditions at 4 locations in North America.
Bacterial pathogens isolated in the clinical field trial are provided in
the Microbiology section.
The effectiveness of ADVOCIN for the control of BRD in cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida
was demonstrated in a multi-site study conducted in North America. The
study enrolled a total of 1,480 commercial, crossbred-beef, Holstein and
Holstein-cross steer calves at high risk of developing BRD associated
with M. haemolytica and P. multocida.
At enrollment, calves were randomly administered a one-time
subcutaneous injection of either ADVOCIN at a dosage rate of 8 mg/kg of
body weight or an equivalent volume of sterile saline. Cattle were
observed daily for clinical signs of BRD and were evaluated for clinical
success on Day 10 post-treatment. The treatment success rate of
ADVOCIN-treated calves (86.0%) was statistically significantly
(p=0.0068) greater than that of saline-treated calves (76.3%) (based on
back-transformed least squares means). No adverse events associated with
ADVOCIN administration were reported in the study.
ANIMAL SAFETY: Safety studies were
conducted in feeder calves using single doses of 10, 20, or 30 mg/kg for
6 consecutive days and 18, 24, or 60 mg/kg for 3 consecutive days. No
clinical signs of toxicity were observed at doses of 10 and 20 mg/kg
when administered for 6 days, nor at doses of 18 and 24 mg/kg when
administered for 3 days. Articular cartilage lesions, consistent with
fluoroquinolone chondropathy, were observed after examination of joints
from animals as follows: one of 5 animals administered 18 mg/kg for 3
days; one of 6 animals administered 20 mg/kg for 6 days; 5 of 6 animals
administered 30 mg/kg for 6 days; and in all 4 animals administered 60
mg/kg for 3 days. Clinical signs of inappetence, transient lameness
(2/6), ataxia (2/6), tremors (2/6), nystagmus (1/6), exophthalmos (1/6),
and recumbency (2/6) were observed when a dose of 30 mg/kg was
administered for 6 consecutive days. Recumbency and depression were seen
in one out of 4 animals administered 60 mg/kg for 3 days. Swelling at
the injection site was noted at each dose level.
Safety was also evaluated in 21-day-old calves. In one
group, these immature animals were given injections of 6 mg/kg on study
days 0, 2, 3, 5, 6, and 8. A second group of animals received injections
of 18 mg/kg for a total of 2 injections 48 hours apart. The only
treatment-related sign was erythema of the nasal pad in 3 of 6 calves
that received 18 mg/kg. One calf in the 6 mg/kg group had pre-treatment
scleral erythema, and developed nasal erythema after treatment that may
or may not have been treatment-related. No changes in clinical pathology
parameters were observed. No articular cartilage lesions were observed
in the joints at any dosage.
An injection site study conducted in feeder calves
demonstrated that the product can induce a transient local reaction in
the subcutaneous tissue and underlying tissue.
TOXICOLOGY: Ninety-day oral toxicity
studies in dogs and rats established a no observable effect level
(NOEL) of 2.5 mg/kg bw/day and 2.4 mg/kg bw/day, respectively. Higher
doses in juvenile dogs produced arthropathy, a typical
quinolone-associated side effect. In chronic rodent bioassays, no
evidence of carcinogenicity was associated with long-term danofloxacin
administration in rats and mice. No teratogenic effects were observed in
rodents at doses up to 50 mg/kg bw/day (mice) or 100 mg/kg bw/day
(rats) or in rabbits at the highest dose tested of 15 mg/kg bw/day. A
three-generation rat reproductive toxicity study established a NOEL of
6.25 mg/kg bw/day. Microbial safety analyses indicate that danofloxacin
residues present in edible tissues of treated animals under the current
use conditions would most likely not cause adverse effects on the human
intestinal microflora of the consumer.
STORAGE INFORMATION: Store at or
below 30°C (86°F). Protect from light. Protect from freezing. The color
is yellow to amber and does not affect potency.
HOW SUPPLIED: ADVOCIN (180 mg danofloxacin/mL) is supplied in 100- and 250-mL, amber-glass, sterile, multi-dose vials.
NADA #141-207, Approved by FDA
Distributed by: Zoetis Inc., Kalamazoo, MI 49007
Use Only as Directed
CONTACT INFORMATION: To report
suspected adverse effects and/or obtain a copy of the MSDS or for
technical assistance, call Zoetis Inc. at 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
https://www.fda.gov/AnimalVeterinary/SafetyHealth.
Revised: May 2014
Made in France
Net Contents:
|
|
100 mL
|
8713833
|
250 mL
|
8713843
|
CPN: 3690271.3