Summary Additional Techniques for SC Injection of EXCEDE ® in Beef and Dairy Cattle February 2012 • Two additional techniques were recently approved for SC injection of EXCEDE ® Sterile Suspension at the base of the ear (BOE) of cattle. # EXCEDE can now be administered SC at the BOE in a rostral direction, toward the eye on the same side of the head as the ear. # EXCEDE can also now be administered SC at the BOE in a ventral direction. • Both additional EXCEDE administration techniques are approved for use in all classes of cattle. • Both additional BOE injection techniques are approved for use in lactating dairy cows and are preferred in these animals relative to the previously approved ‘opposite-eye’ method. • Research has demonstrated that the rostral and ventral BOE injection techniques are safe, well-tolerated, and readily accomplished using normal equipment and restraint. • The rostral and ventral BOE techniques provide injection outcomes similar to those observed using the previously approved opposite-eye technique. Pfizer Animal Health Pfizer Inc. Madison, NJ 07940 EXD12002 Two additional EXCEDE ® injection techniques provide more options for treating beef and lactating dairy cattle. XCEDE ® Sterile Suspension (ceftiofur crystalline free acid) is the potent single- dose treatment for bovine respiratory disease and foot rot that provides the demonstrated efficacy of ceftiofur in a convenient extended- therapy formulation. EXCEDE is intended for subcutaneous (SC) administration at a dose of 3 mg ceftiofur equivalents (CE) per lb body weight (BW) (or 1.5 mL EXCEDE/100 lb BW). An indication for acute post-partum metritis was recently approved for lactating dairy cows when a 2-dose regimen of EXCEDE is adminis- tered 3 days apart. Previously, EXCEDE was approved for SC injection of cattle (including lactating dairy cows) in the posterior aspect of the ear where it attaches to the head (base of the ear, or ‘BOE’), angled toward the opposite eye. In addition, EXCEDE could be administered in the middle third of the posterior aspect of the ear in beef and non-lactating dairy cattle (not in lactating dairy cows). E
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Summary
Additional Techniques for SC Injectionof EXCEDE® in Beef and Dairy Cattle
February 2012
• Two additional techniques were recently approved for SC injection of EXCEDE® Sterile
Suspension at the base of the ear (BOE) of cattle.
# EXCEDE can now be administered SC at the BOE in a rostral direction, toward the
eye on the same side of the head as the ear.
# EXCEDE can also now be administered SC at the BOE in a ventral direction.
• Both additional EXCEDE administration techniques are approved for use in all classes
of cattle.
• Both additional BOE injection techniques are approved for use in lactating dairy cows
and are preferred in these animals relative to the previously approved ‘opposite-eye’
method.
• Research has demonstrated that the rostral and ventral BOE injection techniques are
safe, well-tolerated, and readily accomplished using normal equipment and restraint.
• The rostral and ventral BOE techniques provide injection outcomes similar to those
observed using the previously approved opposite-eye technique.
Pfizer Animal HealthPfizer Inc. Madison, NJ 07940
EXD12002
Two additional
EXCEDE ® injection
techniques provide
more options for
treating beef and
lactating dairy
cattle.XCEDE® Sterile Suspension (ceftiofur
crystalline free acid) is the potent single-
dose treatment for bovine respiratory disease
and foot rot that provides the demonstrated
efficacy of ceftiofur in a convenient extended-
therapy formulation. EXCEDE is intended for
subcutaneous (SC) administration at a dose of 3
mg ceftiofur equivalents (CE) per lb body
weight (BW) (or 1.5 mL EXCEDE/100 lb BW).
An indication for acute post-partum metritis
was recently approved for lactating dairy cows
when a 2-dose regimen of EXCEDE is adminis-
tered 3 days apart.
Previously, EXCEDE was approved for SC
injection of cattle (including lactating dairy
cows) in the posterior aspect of the ear where it
attaches to the head (base of the ear, or
‘BOE’), angled toward the opposite eye. In
addition, EXCEDE could be administered in the
middle third of the posterior aspect of the ear in
beef and non-lactating dairy cattle (not in
lactating dairy cows).
E
2
Research by Pfizer scientists has resulted in
recent FDA approval of two additional BOE
injection techniques for EXCEDE, and more
specific BOE use instructions for lactating
dairy cows. The two additional BOE techniques
are:
• Rostral direction (toward the eye on the
same side of the head);
• Ventral direction (pointing ventrally toward
the base of the ear).
These two additional BOE techniques are
potentially safer and are the preferred methods
for using EXCEDE in lactating dairy cows
relative to the previously approved opposite-
eye technique. The rostral technique (toward
the same eye) is particularly useful for many
dairy cattle operations. However, because head
catches are almost always used for restraint of
beef cattle, the rostral method can be problem-
atic when animals pull backwards against the
vertical bars of the head catch. Thus, the
ventrally directed technique offers a dosing
method espe cially useful for treatment of beef
animals.
Figure 1 summarizes the SC injection options
for use of EXCEDE, depending on the class and
status of cattle being treated. In lactating dairy
cattle, SC injection at the BOE can be made
using the preferred rostral (Figures 2 and 3) or
ventral (Figure 4) injection techniques. For beef
and non-lactating dairy cattle, SC injection can
accomplished using the rostral, ventral, or
opposite-eye (Figure 5) BOE techniques in
addition to the middle-third of the ear option
(Figure 6).
The rostral and ventralinjection techniqueshave been approvedfor lactating dairy cattle as well as beefand non-lactating dairyanimals.
Figure 2 – BOE injections. Injection location for SC administration ofEXCEDE in the posterior aspect of the ear where it attaches tothe head (BOE).
Figure 1 – SC injection technique options foradministration of EXCEDE.
�
�
�
�
B
B
B
M
OE: Rostral
OE: Ventral
OE: Opposite eye
iddle-third of ear
Class of cattle:
�
�
�
BOE: Rostral
BOE: Ventral
BOE: Opposite eye
*
*
Dairy Beef
Non-LactatingLactating
*Preferred technique
Dairy Beef
Non-LactatingLactating
Previously approvedinjection techniques(middle-third of the earor BOE toward theopposite eye) offerother options for beef and non-la ctatingdairy cattle.
3
Figure 3 – Rostral technique (additional). Direction for SC injection ofEXCEDE administered rostrally toward the eye on the same sideof the head into the loose skin in the caudal aspect of the BOE.
Directions:
• Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the direction of an imaginary line thatwould pass through the head toward the eye on the same side ofthe head (Figures 2 and 3).
• Insert the needle through the loose skin in the posterior aspect ofthe ear where it attaches to the head (BOE) while maintaining theneedle position (Figure 3).
BOE – rostral (toward the same eye) technique
4
Figure 4 – Ventral technique (additional). Location and direction for SCinjection of EXCEDE administered ventrally into the loose skin inthe caudal aspect of the BOE.
Directions:
• Hold the syringe and needle above the ear to be dosed so that the needle and syringe are pointing ventrally toward the base of theear. The needle will be inserted into the loose skin in the posterioraspect of the ear where it attaches to the head (BOE) while pointing ventrally. Care should be taken to not insert the needlethrough the cartilage of the ear (Figure 4).
• Insert the needle through the loose skin in the posterior aspect ofthe ear where it attaches to the head (BOE) while maintaining needle position (Figure 4).
BOE – ventral technique
5
Figure 5 – Toward the opposite eye technique. SC injection of EXCEDE inthe posterior aspect of the ear where it attaches to the head(BOE) (previously approved technique).
Directions:
• Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the direction of an imaginary line thatwould pass through the head toward the animal’s opposite eye(Figures 2 and 5).
• Insert the needle through the loose skin in the posterior aspect ofthe ear where it attaches to the head (BOE) while maintaining thisangle (Figure 5).
BOE – toward the opposite eye technique
6
Figure 6 – Middle-third of the ear technique. SC injection of EXCEDE in themiddle third of the posterior aspect of the ear (previouslyapproved technique).
Directions:
• Deposit as a single SC injection in the middle third of the posterioraspect of the ear, avoiding all blood vessels (Figure 6).
• Adjust the needle insertion point to avoid any blood vessels, previous implants, ear tags, or ear-tag holes. Do not administerintra-arterially.
• When administered correctly, a subcutaneous bleb of EXCEDE willappear.
• When withdrawing the needle, apply pressure to the needle insertion point, and massage toward the base of the ear.
Middle-third of the ear technique
7
This study demonstrated that BOE administra-
tion of EXCEDE using the additional rostral or
ventral SC injection techniques was safe, well-
tolerated, and readily accomplished in lactating
dairy cows using normal equipment and
restraint. Injection outcomes were similar to
those observed using the previously approved
‘opposite-eye’ technique.
Feedlot heifersA similar field study involving 199 feedlot
heifers (750 lb BW) evaluated injection
procedures and site reactions for BOE injec-
tions of EXCEDE performed using the ventral
technique.2 Healthy cattle were enrolled in the
study at a commercial feedlot and treated with
EXCEDE at the approved dose of 3 mg CE/lb
BW. Ventrally directed BOE injections were
administered by 2 different people using 5/8-
or 1-inch needle lengths. At administration,
animals were scored for restraint, injection
procedure, and post-injection problems. Cattle
were observed for injection site reactions on
days 14 and 28 post-injection.
Study results show that few problems were
observed relative to restraint, re-injection,
leak-back, or excessive bleeding (Table 2). By
day 28, 92.5% of injection sites were scored as
normal using the ventral technique. Needle
length did not affect injection procedures or site
reactions.
This study demonstrated that BOE administra-
tion of EXCEDE using the ventrally directed
SC injection technique was safe, well-tolerated,
and readily accomplished in feedlot cattle using
normal equipment and restraint.
Injection Technique Field StudiesTwo field studies were conducted to gain expe-
rience on the practicality and acceptability of
the additional rostral and ventral BOE injection
techniques in dairy and beef cattle.
Lactating dairy cowsA field study involving 197 lactating dairy
cows compared injection procedures and site
reactions for BOE injections of EXCEDE
directed toward the opposite eye with those
directed either rostrally or ventrally.1 Healthy
lactating cows were enrolled in the study across
2 commercial dairy sites. The rostral and oppo-
site-eye techniques were compared at one site
(4 different treatment administrators, consistent
needle length), while the rostral and ventral
routes were used at the other site (2 different
treatment administrators, 5/8- or 1-inch needle
lengths). All cows received a single SC injec-
tion of EXCEDE at the approved dose of 3 mg
CE/lb BW. At administration, animals were
scored for restraint, injection procedure, and
post-injection problems. Cows were observed
for injection site reactions on days 14 and 28
post-injection.
Results summarized in Table 1 indicate that no
relevant differences were observed in restraint,
re-injection, leak-back, or excessive bleeding
between the 3 techniques. By day 28, 73% of
injection sites were scored as normal using the
rostral technique, compared to 87.8% using the
ventral technique and 64.6% using the oppo-
site-eye technique. Needle length did not affect
injection procedures or site reactions.
Parameter Rostral Ventral Opposite
Number of cows 100 49 48
No added restraint (%) 98.0 89.8 100.0
No re-injection (%) 97.0 87.8 100.0
No leak back (%) 99.0 100.0 100.0
No excessive bleeding (%) 99.0 100.0 100.0
Day 14 normal sites (%) 32.0 46.9 47.9
Day 28 normal sites (%) 73.0 87.8 64.6
Parameter Ventral
Number of heifers 199
No added restraint (%) 95.5
No re-injection (%) 93.5
No leak back (%) 99.0
No excessive bleeding (%) 100.0
Day 14 normal sites (%) 65.3
Day 28 normal sites (%) 92.5
Table 1 – Injection parameters and site outcomes in lactating dairy cows after BOE injection ofEXCEDE using rostral, ventral, or opposite-eyeSC techniques.
Table 2 – Injection parameters andsite outcomes in beefheifers after ventrallydirected BOE injection.
No relevant differences were
observed betweenBOE techniques
(restraint, re-injection,leak-back, bleeding,
site reactions).
Important Safety Information: As with all
drugs, the use of EXCEDE Sterile Suspension is
contraindicated in animals previously found to
be hypersensitive to the drug. Though safe in
cattle when properly administered, inadvertent
intra-arterial injection in the ear is possible and
is fatal. EXCEDE has a pre-slaughter with -
drawal period of 13 days.
ConclusionsEXCEDE can be administered SC at the BOE
CAUTIONdairy cattle. Not for use in calves to be processed for veal.the ear where it attaches to the head (base of the ear) in beef and non-lactating
the posterior middle third of in the to the head (base of the ear) in lactating dairy cattle. For subcutaneous injectionFor subcutaneous injection in the posterior aspect of the ear where it attaches
Federal (USA) law restricts this drug to use by or on the order of a licensed
Sterile Suspensionystalline Freetiofur CrryCef((C
dairy cattle. Not for use in calves to be processed for veal.the ear where it attaches to the head (base of the ear) in beef and non-lactating
posterior aspect ofor in the aspect of the ear to the head (base of the ear) in lactating dairy cattle. For subcutaneous injection
posterior aspect of the ear where it at
Federal (USA) law restricts this drug to use by or on the order of a licensed
Sterile Suspension)idd)e Acci
massage toward the base of the ear.
the ear where it attaches to the head (base of the ear) in beef and non-lactatingposterior aspect of
to the head (base of the ear) in lactating dairy cattle. For subcutaneous injectionttaches
Federal (USA) law restricts this drug to use by or on the order of a licensed
middle third of the posterior aspect of the ear.Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the
massage toward the base of the ear.
middle third of the posterior aspect of the ear.Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the
Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the skin in the caudal aspect of the base of the ear.administered rostrally toward the eye on the same side of the head into the looseFigure 6. Diagram of head showing the direction for the base of ear injections
skin in the caudal aspect of the base of the ear.administered rostrally toward the eye on the same side of the head into the looseFigure 6. Diagram of head showing the direction for the base of ear injections
skin in the caudal aspect of the base of the ear.administered rostrally toward the eye on the same side of the head into the looseFigure 6. Diagram of head showing the direction for the base of ear injections
administered rostrally toward the eye on the same side of the head into the loose
Figure 6. Diagram of head showing the direction for the base of ear injections
DESCRIPTIONveterinarian.
against Gram-
broad a is which ceftiofur, of acid free
EXCEDE Sterile Suspension is a ready-to-use formulation that contains the crystalline
strains. Like other
positive and Gram-negative bacteria including ß-lactamase-producing
inhibition of cell wall synthesis.
cephalosporins, ceftiofur is bactericidal,
Figure 1. Structure of ceftiofur crystalline free acid:cottonseed oil based suspension.
acid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyo
Each mL of this ready-to-use sterile suspension contains ceftiofur crystalline free
Federal (USA) law restricts this drug to use by or on the order of a licensed
antibiotic cephalosporin spectrum broad
EXCEDE Sterile Suspension is a ready-to-use formulation that contains the crystalline
positive and Gram-negative bacteria including ß-lactamase-producing
, resulting fromin vitrocephalosporins, ceftiofur is bactericidal,
Figure 1. Structure of ceftiofur crystalline free acid:
acid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyo
Each mL of this ready-to-use sterile suspension contains ceftiofur crystalline free
activeantibiotic
EXCEDE Sterile Suspension is a ready-to-use formulation that contains the crystalline
positive and Gram-negative bacteria including ß-lactamase-producing
, resulting from
and)®lacid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyo
Each mL of this ready-to-use sterile suspension contains ceftiofur crystalline free
of EXCEDE Sterile Suspension into ear arteries is likely to be fatal.posterior ear and the recommended needle insertion locations. AdministrationFigure 3. Diagram of the approximate locations of the major arteries of the
of EXCEDE Sterile Suspension into ear arteries is likely to be fatal.posterior ear and the recommended needle insertion locations. AdministrationFigure 3. Diagram of the approximate locations of the major arteries of the
of EXCEDE Sterile Suspension into ear arteries is likely to be fatal.posterior ear and the recommended needle insertion locations. AdministrationFigure 3. Diagram of the approximate locations of the major arteries of the
Administration for Base of the Ear: Ventral Technique
inserted into the loose skin in the posterior aspect of the ear where it attaches to
syringe are pointing ventrally toward the base of the ear. The needle will be
Administration for Base of the Ear: Ventral Technique
inserted into the loose skin in the posterior aspect of the ear where it attaches to
syringe are pointing ventrally toward the base of the ear. The needle will be
Administration for Base of the Ear: Ventral Technique
inserted into the loose skin in the posterior aspect of the ear where it attaches to
syringe are pointing ventrally toward the base of the ear. The needle will be
inserted into the loose skin in the posterior aspect of the ear where it attaches to
syringe are pointing ventrally toward the base of the ear. The needle will be
skin exposure, wash with soap and water. Remove contaminated clothing. If allergic
In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental
report any adverse event please call 1-800-366-5288.
information. To obtain a material safety data sheet please call 1-800-733-5500. To
The material safety data sheet contains more detailed occupational safetyposterior aspect of the ear where it attaches to the head (base of the ear).Figure 4. Subcutaneous administration of EXCEDE Sterile Suspension in the
KEEP OUT OF REACH OF CHILDREN.FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE.
clothing. Sensitization of the skin may be avoided by wearing protective gloves.
to sensitization. Avoid direct contact of the product with the skin, eyes, mouth and
individuals. Repeated allergic reactions in some
Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe
Penicillins and cephalosporins can cause allergic reactions in sensitized individuals.
exposure to this product.
Persons with a known hypersensitivity to penicillin or cephalosporins should avoid
(EXCEDE Sterile Suspension) is metabolized rapidly to desfuroylceftiofur, the primary
, for generallysomni) for the labeled BRD pathogens,
metabolites in plasma above the lowest minimum inhibitory concentration to
of ceftiofur and desfuroylceftiofur-related
BOE) of beef, non-lactating dairy, and lactating dairy cattle,
non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the
andbeef of MOE)
metabolite. Subcutaneous administration of ceftiofur crystalline free acid, either in the
The pharmacokinetic parameters for the two subcutaneous locations of injection
Table 4. Ceftiofur minimum inhibitory concentration (MIC) values* of indicated
Indicated Year of Number ofpathogen isolation isolates
Mannheimia haemolytica 1996 to 1997 75
Pasteurella multocida 1996 to 1997 43
Histophilus somni 1996 to 1997 11
Fusobacterium necrophorum 2006 to 2007 148
Porphyromonas levii 2006 to 2007 141
susceptibility data and clinical effectiveness is unknown.in vitroThe correlation between
Table 4. Ceftiofur minimum inhibitory concentration (MIC) values* of indicated
Number of **50MIC **90MIC MIC range(μg/mL) (μg/mL) (μg/mL)
0.008 0.015 0.001 to 0.015
0.004 0.004 0.001 to 0.015
0.004 0.004 0.002 to 0.015
0.25≤ 0.5 0.25 to >128≤
0.25≤ 2.0 5 to 160.2≤
susceptibility data and clinical effectiveness is unknown.
arterial injection of
injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-
Since intra-arterial injection was confirmed in three animals that died following
Two heifers (body weight
EXCEDE Sterile Suspension were investigated in feeder cattle.
CE/kg) BW bolus dose of mg (6.6
proximately 225 kg) were given a single 3.0 mg CE/lbap
result in death and must be avoided.
minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will
artery. Both heifers collapsed immediately and died within approximately eight
intravenous
Since subcutaneous injection in the ear may potentially result in inadvertent
Three heifers and three steers (body weight range 197-223 kg) were given a single
Sterile EXCEDE of injection intravenous
administration of an injectable product, the consequences of purposeful
injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-
Since intra-arterial injection was confirmed in three animals that died following
EXCEDE Sterile Suspension were investigated in feeder cattle.
proximately 225 kg) were given a single 3.0 mg CE/lb
result in death and must be avoided.
minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will
artery. Both heifers collapsed immediately and died within approximately eight
EXCEDE Sterile Suspension in the middle auricular
Since subcutaneous injection in the ear may potentially result in inadvertent
Three heifers and three steers (body weight range 197-223 kg) were given a single
feeder in investigated were Suspension Sterile
administration of an injectable product, the consequences of purposeful
injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-
Since intra-arterial injection was confirmed in three animals that died following
EXCEDE Sterile Suspension were investigated in feeder cattle.
proximately 225 kg) were given a single 3.0 mg CE/lb
minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will
artery. Both heifers collapsed immediately and died within approximately eight
EXCEDE Sterile Suspension in the middle auricular
Since subcutaneous injection in the ear may potentially result in inadvertent
Three heifers and three steers (body weight range 197-223 kg) were given a single
cattle.feeder
administration of an injectable product, the consequences of purposeful
in lactating dairy cattle.of the ear (BOE Cattle) in beef cattle as well into the base of the ear (BOE Lactating)of two different locations of the ear, middle third of the ear (MOE Cattle) and baseSuspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous injection into onedesfuroylceftiofur-related metabolites after administration of EXCEDE SterileFigure 8. Average (n=12/group) plasma concentrations of ceftiofur and
equivalent.
subcutaneous injection sites (MOE and BOE) demonstrate that they are therapeutically
(MOE and BOE) are found in Table 2. Statistical analyses of the data from these two
The pharmacokinetic parameters for the two subcutaneous locations of injection
its
met
abol
ites
(μg/
mL)
Conc
entr
atio
n of
cef
tiof
ur a
nd
of the ear (BOE Cattle) in beef cattle as well into the base of the ear (BOE Lactating)of two different locations of the ear, middle third of the ear (MOE Cattle) and baseSuspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous injection into onedesfuroylceftiofur-related metabolites after administration of EXCEDE SterileFigure 8. Average (n=12/group) plasma concentrations of ceftiofur and
subcutaneous injection sites (MOE and BOE) demonstrate that they are therapeutically
(MOE and BOE) are found in Table 2. Statistical analyses of the data from these two
The pharmacokinetic parameters for the two subcutaneous locations of injection
*
**
The correlation between
respiratory 5. Table
data, the following breakpoints are recommended for BRD pathogens by CLSI.
single administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility
Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a
The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.
Pathogen
Mannheimia haemolyticaPasteurella multocida
of the ear (BOE Cattle) in beef cattle as well into the base of the ear (BOE Lactating)of two different locations of the ear, middle third of the ear (MOE Cattle) and baseSuspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous injection into onedesfuroylceftiofur-related metabolites after administration of EXCEDE SterileFigure 8. Average (n=12/group) plasma concentrations of ceftiofur and
subcutaneous injection sites (MOE and BOE) demonstrate that they are therapeutically
(MOE and BOE) are found in Table 2. Statistical analyses of the data from these two
The pharmacokinetic parameters for the two subcutaneous locations of injection
susceptibility data and clinical effectiveness is unknown.in vitroThe correlation between
respiratory criteria* interpretive CLSI-accepted
data, the following breakpoints are recommended for BRD pathogens by CLSI.
single administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility
Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a
The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.
pathogens.
Pathogen Disk Zone diameterpotency (mm)
S I
Mannheimia haemolyticaPasteurella multocida 30 μg ≥ 21 18 to 20
susceptibility data and clinical effectiveness is unknown.
against cattleceftiofur for criteria*
data, the following breakpoints are recommended for BRD pathogens by CLSI.
single administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility
Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a
The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.
Three heifers and three steers (body weight range 197-223 kg) were given a single
untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile
and one heifer had transient (2 to 5 minutes) increases in heart rate without any other
jugular vein and were monitored for adverse effects following injection.
Safety Studies in Beef CattleSuspension is an unacceptable route of administration.
Middle of the ear injection:
into the
when EXCEDE Sterile Suspension was administered as a single subcutaneous injection
A study was designed and conducted to specifically address tissue tolerance in cattle
material. Additional increases in thickness were observed through Day 14 after injection.
increase in thickness is attributed to the space required for the volume
cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial
EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of
(6.6 mg CE/kg) BW. Results from this study indicate that the subcutaneous injection of
posterior aspect of the ear of cattle at the recommended dose of 3.0 mg CE/lb
mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE
Three heifers and three steers (body weight range 197-223 kg) were given a single
untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile
and one heifer had transient (2 to 5 minutes) increases in heart rate without any other
jugular vein and were monitored for adverse effects following injection.
Sterile Suspension in the
Suspension is an unacceptable route of administration.
when EXCEDE Sterile Suspension was administered as a single subcutaneous injection
A study was designed and conducted to specifically address tissue tolerance in cattle
material. Additional increases in thickness were observed through Day 14 after injection.
increase in thickness is attributed to the space required for the volume
cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial
EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of
(6.6 mg CE/kg) BW. Results from this study indicate that the subcutaneous injection of
posterior aspect of the ear of cattle at the recommended dose of 3.0 mg CE/lb
Three heifers and three steers (body weight range 197-223 kg) were given a single
untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile
and one heifer had transient (2 to 5 minutes) increases in heart rate without any other
One steerjugular vein and were monitored for adverse effects following injection.
Sterile Suspension in the
when EXCEDE Sterile Suspension was administered as a single subcutaneous injection
A study was designed and conducted to specifically address tissue tolerance in cattle
material. Additional increases in thickness were observed through Day 14 after injection.
of injected
cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial
EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of
(6.6 mg CE/kg) BW. Results from this study indicate that the subcutaneous injection of
posterior aspect of the ear of cattle at the recommended dose of 3.0 mg CE/lb
administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension inand desfuroylceftiofur metabolites calculated after a single subcutaneousTable 2. Average (n = 12/group) pharmacokinetic parameters for ceftiofur
its
met
abol
ites
(μg/
mL)
Conc
entr
atio
n of
cef
tiof
ur a
nd
administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension inand desfuroylceftiofur metabolites calculated after a single subcutaneousTable 2. Average (n = 12/group) pharmacokinetic parameters for ceftiofur
Day
Histophilus somni
S – Susceptible
I – Intermediate
EFFECTIVENESS
have not been established.
used to determine antimicrobial susceptibility. Interpretive criteria for bovine foot rot pathogens
* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are
bacterial component of BRD under field conditions. All treatments were administered
single doses of 2.0 and 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) BW for the treatment of the
A field dose confirmation study for the treatment of BRD evaluated the effectiveness of
administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension inand desfuroylceftiofur metabolites calculated after a single subcutaneousTable 2. Average (n = 12/group) pharmacokinetic parameters for ceftiofur
Histophilus somni
S – Susceptible
I – Intermediate
EFFECTIVENESS
have not been established.
used to determine antimicrobial susceptibility. Interpretive criteria for bovine foot rot pathogens
* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are
Suspension administered subcutaneously in the middle third of the poste
single dose of EXCEDE Sterile
incidence of clinical BRD within 28 days
negative control.or BWmg CE/kg)
at high risk for BRD were assigned to one of four arrival treatments, including EXCEDE
3911) considered to ben=addition to standard processing on arrival at feedlots, cattle (
BRD in feedlot cattle was evaluated in a nine-location field effectiveness study. In
The effectiveness of a single dose of EXCEDE Sterile Suspension for the control of
negativeto compared processing
of the ear at arrival processing significantly reduced the incidence of BRD in high-risk
rior aspect
Base of the ear administration (beef and non-lactating dairy cattle) and middle third of
EXCEDE
implants was well tolerated by cattle and did not
Suspension in the posterior aspect of the ear
bred steers. The administration of EXCEDE Sterile207 Angus and Angus cross-
promoting implant growth implant, promoting
Sterile Suspension alone, EXCEDE Sterile Suspension with a growth
the boundaries of the middle third of the ear in some within
administered after EXCEDE Sterile Suspension may need to be adjusted slightly
performance. Based upon the results of this study, the location of
Base of the ear injection:
Suspension Sterile EXCEDE of ear
to ear the of tolerance local The
2926 beef cattle. Normal restraint was adequate for adminis
Suspension for 99.8% of cattle. No post injection problems (exces
leak back) were observed in 99.8% of cattle. On Days 28 and 56 post-injec
and 98.9% of the cattle had “normal” (no observed swelling) ears.
In a residue study, 72 beef cattle were injected in the
implants was well tolerated by cattle and did not
with or without growth promotingSuspension in the posterior aspect of the ear
bred steers. The administration of EXCEDE Sterile
product, in or neither alone, promoting implant
Sterile Suspension alone, EXCEDE Sterile Suspension with a growth
the boundaries of the middle third of the ear in some
administered after EXCEDE Sterile Suspension may need to be adjusted slightly
performance. Based upon the results of this study, the location of
affect feedlot cattleadversely
animals.
was Suspension
base the at injection subcutaneoussingle a
2926 beef cattle. Normal restraint was adequate for adminis
field multi-location a in evaluated
Suspension for 99.8% of cattle. No post injection problems (exces
tration of EXCEDE Sterile
leak back) were observed in 99.8% of cattle. On Days 28 and 56 post-injec
sive bleeding or
and 98.9% of the cattle had “normal” (no observed swelling) ears.
tion,
base of the ear with EXCEDEIn a residue study, 72 beef cattle were injected in the
with or without growth promoting
bred steers. The administration of EXCEDE Sterile
a total ofproduct, in
Sterile Suspension alone, EXCEDE Sterile Suspension with a growth
administered after EXCEDE Sterile Suspension may need to be adjusted slightly
implantsperformance. Based upon the results of this study, the location of
affect feedlot cattle
theof base
instudy field
tration of EXCEDE Sterile
sive bleeding or
97.8%tion,
base of the ear with EXCEDE
gTwo-Dose Regimen
the 2-dose regimen are provided in Table 3.
shown is cows regimen in 12
ceftiofur for profile time vs.
for the treatment of acute metritis in lactating cows. The mean plasma concentration
A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required
(μg CE/mL)maxC =
(h)maxt
maximum plasma concentration (in μg CE/mL).
=
0-LOQAUC
the time after injection when C
(h)model>0.2,t
to the limit of quantitation of the assay (0.15 μg CE/mL).
=
(h)>0.2, nca t
estimated using compartmental pharmacokinetic techniques.
the time plasma concentrations remain above 0.2 μ
=
(h)1/2t
estimated using noncompartmental pharmacokinetic techniques.
the time plasma concentrations remain above 0.2 μg CE/mL (in hours),
=
NE
terminal phase biological half life (in hours)
= Not estimated
the 2-dose regimen are provided in Table 3.
pharmacokinetic The below. 9 Figure in shown
metabolites desfuroylceftiofur-related and
for the treatment of acute metritis in lactating cows. The mean plasma concentration
A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required
maximum plasma concentration (in μg CE/mL).
occurs (in hours).maxthe time after injection when C
to the limit of quantitation of the assay (0.15 μg CE/mL).
estimated using compartmental pharmacokinetic techniques.
the time plasma concentrations remain above 0.2 μ
estimated using noncompartmental pharmacokinetic techniques.
the time plasma concentrations remain above 0.2 μg CE/mL (in hours),
terminal phase biological half life (in hours)
Not estimated
forparameters pharmacokinetic
2-dosethe for metabolites
for the treatment of acute metritis in lactating cows. The mean plasma concentration
A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required
pharmacokiear
administration (lactating dairy cattle) were compared to the middle third of thethe ear
therapeutically equivalent.
EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%).
There analysis.
swelling and lameness scores. A total of 169 beef and dairy cattle were included in the
post-treatment
or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days
injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg
were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous
evaluated in a six-location field effectiveness study. Cattle diagnosed with bovine foot rot
effectiveness of EXCEDE Sterile Suspension for the The
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
discharge and a rectal temperature of ≥
evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal
The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was
estimated using compartmental pharmacokinetic techniques.
g CE/mL (in hours),
estimated using noncompartmental pharmacokinetic techniques.
the time plasma concentrations remain above 0.2 μg CE/mL (in hours),
pharmacoki
administration (lactating dairy cattle) were compared to the middle third of the
therapeutically equivalent.
non-lactating and beef for data netic
EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%).
significant difference statistically a was There
swelling and lameness scores. A total of 169 beef and dairy cattle were included in the
based was which success, treatment for post-treatment
or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days
injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg
were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous
evaluated in a six-location field effectiveness study. Cattle diagnosed with bovine foot rot
effectiveness of EXCEDE Sterile Suspension for the
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
°F were enrolled in the study and treated with 103 discharge and a rectal temperature of ≥
evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal
The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was
administration (lactating dairy cattle) were compared to the middle third of the
Base of the ear administration (beef and non-lactating dairy cattle) and middle third of
beto found were and cattle dairy non-lactating
EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%).
forsuccess treatment in 0.0054) = (p
swelling and lameness scores. A total of 169 beef and dairy cattle were included in the
lesion,in decreases defined on based
or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days
BWE/kg) Cinjection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg
were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous
evaluated in a six-location field effectiveness study. Cattle diagnosed with bovine foot rot
foot rot wastreatment of bovine effectiveness of EXCEDE Sterile Suspension for the
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
°F were enrolled in the study and treated with
evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal
The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was
inflammation (hemorrhage, conges
the animals showed ear drooping. At necropsy, signs ofanimals. None of 72
site swelling during the study; swelling resolved prior to euthanasia in 23 of
trimming procedures similar to slaughterhouse practices. All animals had injection
swelling and drooping, and evaluated grossly at necropsy, using skin
were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for
Sterile Suspension at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW
In a residue study, 72 beef cattle were injected in the
post-injection, gross lesions were found in the
material were seen in the area around the injection site and on the carcass. At 13 days
in all 18 animals, and in the exposed carcass tissue in 11 of 18 animals.
Injection site scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28,
injection technique. Normal restraint was adequate for 95.5% of animals in the study.
Suspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral
study in 200 beef cattle. Each animal received a single injection of EXCEDE Sterile
The ventral base of the ear injection technique was evaluated in a conditions of use
inflammation (hemorrhage, conges
the animals showed ear drooping. At necropsy, signs of
site swelling during the study; swelling resolved prior to euthanasia in 23 of
trimming procedures similar to slaughterhouse practices. All animals had injection
swelling and drooping, and evaluated grossly at necropsy, using skin
were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for
. Injection sitesSterile Suspension at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW
base of the ear with EXCEDEIn a residue study, 72 beef cattle were injected in the
post-injection, gross lesions were found in the
material were seen in the area around the injection site and on the carcass. At 13 days
and firmness of tissue) and presence of drugtion,
in all 18 animals, and in the exposed carcass tissue in 11 of 18 animals.
inedible portions of the base of the ear
Injection site scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28,
injection technique. Normal restraint was adequate for 95.5% of animals in the study.
Suspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral
study in 200 beef cattle. Each animal received a single injection of EXCEDE Sterile
The ventral base of the ear injection technique was evaluated in a conditions of use
the animals showed ear drooping. At necropsy, signs of
site swelling during the study; swelling resolved prior to euthanasia in 23 of
trimming procedures similar to slaughterhouse practices. All animals had injection
ning andswelling and drooping, and evaluated grossly at necropsy, using skin
were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for
. Injection sites
base of the ear with EXCEDE
material were seen in the area around the injection site and on the carcass. At 13 days
and firmness of tissue) and presence of drug
inedible portions of the base of the ear
Injection site scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28,
injection technique. Normal restraint was adequate for 95.5% of animals in the study.
Suspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral
study in 200 beef cattle. Each animal received a single injection of EXCEDE Sterile
The ventral base of the ear injection technique was evaluated in a conditions of use
(6.6 mg CE/kg) BW in 12 lactating cows.Subcutaneous Injections of EXCEDE 72 hours apart at a Dose of 3.0 mg CE/lbFigure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two
the 2-dose regimen are provided in Table 3.
its
met
abol
ites
(μg/
mL)
Conc
entr
atio
n of
cef
tiof
ur a
nd
(6.6 mg CE/kg) BW in 12 lactating cows.Subcutaneous Injections of EXCEDE 72 hours apart at a Dose of 3.0 mg CE/lbFigure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two
Subcutaneous Injections of EXCEDE 72 hours apart at a Dose of 3.0 mg CE/lbFigure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two
Systemic Safety StudiesANIMAL SAFETY
determined the probable cause of death to be intra-arterial injection.
cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings
in EXCEDE-treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One
observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001)
temperature < 103 °F, and that did not require alternate (“escape”) therapy during the
and vaginal discharge score were recorded. Cows with a non-fetid discharge, and a rectal
post-treatment, each cow remaining in the study was examined and rectal temperature
control, administered approximately 72 hours apart at the base of opposite ears. At 14
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
tolerance study conducted with ceftiofur sodium in normal feeder calves indicated
to evaluate the systemic safety of EXCEDE Sterile
desfuroylceftiofur. Therefore, studies
Suspension), ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to
After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile
Systemic Safety StudiesANIMAL SAFETY
determined the probable cause of death to be intra-arterial injection.
cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings
in EXCEDE-treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One
observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001)
temperature < 103 °F, and that did not require alternate (“escape”) therapy during the
and vaginal discharge score were recorded. Cows with a non-fetid discharge, and a rectal
post-treatment, each cow remaining in the study was examined and rectal temperature
control, administered approximately 72 hours apart at the base of opposite ears. At 14
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
tolerance study conducted with ceftiofur sodium in normal feeder calves indicated
Suspension. Results from a five-dayto evaluate the systemic safety of EXCEDE Sterile
conducted with ceftiofur sodium are adequatedesfuroylceftiofur. Therefore, studies
Suspension), ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to
After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile
determined the probable cause of death to be intra-arterial injection.
cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings
in EXCEDE-treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One
observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001)
14_day temperature < 103 °F, and that did not require alternate (“escape”) therapy during the
and vaginal discharge score were recorded. Cows with a non-fetid discharge, and a rectal
post-treatment, each cow remaining in the study was examined and rectal temperature
days control, administered approximately 72 hours apart at the base of opposite ears. At 14
either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle
tolerance study conducted with ceftiofur sodium in normal feeder calves indicated
Suspension. Results from a five-day
conducted with ceftiofur sodium are adequate
Suspension), ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to
After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile
Safety Studies in Lactating Dairy Cattlesize comparable to other study animals by Day 14.
unusually an animal had respectively. One
The local tolerance of the ear to a single subcutaneous injec
of cattle using nor
cattle. Successful injection in the base of the ear was achieved in 97.4%adult dairy
Sterile Suspension was evaluated in a multi-location field study in 114ear of EXCEDE
bleeding was observed fol
facilities and restraint equipment. No leak back or excessivemal
as normal with no injection site swelling.
Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed
ranging from 15 to 30 mL. On Days 28 and 56 following injection of EXCEDE Sterile
lowing injection for 99.1% of cattle, with injection volumes
days after injection. At necropsy, all six cows showed evidence of injection site10
the injection site at all observation times after treatment. Cows were slaughtered
drooping ears at any time after treatment but all animals had
of BW CE/kg) mg (6.6 CE/lb mg 3.0
In a residue study, six dairy cows were injected in the base of the ear at a dose rate of
Safety Studies in Lactating Dairy Cattlesize comparable to other study animals by Day 14.
reduced which large swelling on Day 7 unusually
The local tolerance of the ear to a single subcutaneous injec
cattle. Successful injection in the base of the ear was achieved in 97.4%
Sterile Suspension was evaluated in a multi-location field study in 114
tion at the base of the
facilities and restraint equipment. No leak back or excessive
as normal with no injection site swelling.
Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed
ranging from 15 to 30 mL. On Days 28 and 56 following injection of EXCEDE Sterile
lowing injection for 99.1% of cattle, with injection volumes
days after injection. At necropsy, all six cows showed evidence of injection site
the injection site at all observation times after treatment. Cows were slaughtered
signs of swelling atdrooping ears at any time after treatment but all animals had
animals No Suspension. Sterile EXCEDE of
In a residue study, six dairy cows were injected in the base of the ear at a dose rate of
ato reduced
cattle. Successful injection in the base of the ear was achieved in 97.4%
Sterile Suspension was evaluated in a multi-location field study in 114
tion at the base of the
facilities and restraint equipment. No leak back or excessive
Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed
ranging from 15 to 30 mL. On Days 28 and 56 following injection of EXCEDE Sterile
lowing injection for 99.1% of cattle, with injection volumes
days after injection. At necropsy, all six cows showed evidence of injection site
the injection site at all observation times after treatment. Cows were slaughtered
signs of swelling at
exhibitedanimals
In a residue study, six dairy cows were injected in the base of the ear at a dose rate of
at a 72 Hour Interval.of EXCEDE Sterile Injections
Table 3. Average (n = 12) Pharmacokinetic Parameters Following Two Subcutaneous
PK Parameter
0-LOQAUC
(h)½t
(h)0.2t>
(h)maxT
Conc
entr
atio
n of
cef
tiof
ur a
nd
mg CE/lb (6.6 a Dose 3.0 Suspension at of EXCEDE Sterile Table 3. Average (n = 12) Pharmacokinetic Parameters Following Two Subcutaneous
Mean ± Standard Deviation
55.7 ± 4.84
341 ± 34.0
77.1 ± 33.4
imately 8 times the approved dose of EXCEDE Sterile
that ceftiofur was well tolerated at 25 mg CE/lb/day for five con
tolerance study conducted with ceftiofur sodium in normal feeder calves indicated
CE/kg) BW. Ceftiofur administered parenterally had no adverse systemic effects.
In a 15-day safety/toxicity study, five steer and five heifer calves per group were admin
is
calves. Local tissue tolerance to
that ceftiofur has a wide margin of safety when injected intramuscularly into feeder
mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, indicating3.0
thus, evaluating up to 3.3 times the approved dose of EXCEDE Sterile Suspension of