Additional Techniques for SC Injection of EXCEDE in Beef ... · Summary Additional Techniques for...

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

of cattle by two additional options, directed

rostrally toward the eye on the same side of the

head, or directed ventrally. Both 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. For beef cattle and non-lactating

dairy animals, the additional rostral and ventral

BOE injection techniques join the previously

approved SC methods (middle-third of the ear

or BOE toward the opposite eye) as options for

administering EXCEDE.

8

9

(Ceftiofur Crystalline Free Acid)Sterile Suspension

ft

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


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


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


antibiotic cephalosporin spectrum broad



, 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


activeantibiotic



, resulting from

and)®lacid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyo


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









INDICATIONS

thio] methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene 2-carboxylic acid

7-[[2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetyl]amino]- 3-[[(2-furanylcarbonyl)

Chemical name of ceftiofur crystalline free acid:

cattle.

in Histophilus somniand multocida,(BRD, shipping fever, pneumonia) associated with

EXCEDE Sterile Suspension is indicated for treatment of bovine respiratory disease

thio] methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene 2-carboxylic acid


Chemical name of ceftiofur crystalline free acid:

lactating and dairy, beef, non-lactating

Pasteurella, haemolyticaMannheimia(BRD, shipping fever, pneumonia) associated with

EXCEDE Sterile Suspension is indicated for treatment of bovine respiratory disease


dairylactating

PasteurellaEXCEDE Sterile Suspension is indicated for treatment of bovine respiratory disease

base of the ear.when Figure 7. Diagram of head showing the direction of base of ear injections

insert the needle through the cartilage of the ear. See Figure 7.

the

attaches to the head (base of the ear) while maintaining needle position. See Figure

base of the ear.loose ventrally into the administered when

Figure 7. Diagram of head showing the direction of base of ear injections


pointing while ear) the of (base head the

attaches to the head (base of the ear) while maintaining needle position. See Figure

theaspect of caudal the skin in loose Figure 7. Diagram of head showing the direction of base of ear injections


notto taken be should Care ventrally. pointing

7.attaches to the head (base of the ear) while maintaining needle position. See Figure

not

7.

cattle.

and P. multocida,, haemolyticaM.with

beef and non-lactating dairy cattle which are at high risk of developing BRD associated

EXCEDE Sterile Suspension is also indicated for the control of respiratory disease in

in beef, non-lactating dairy, and lactating dairy cattle.Porphyromonas leviirot (interdigital necrobacillosis) associated with

also is Suspension Sterile EXCEDE

Treatment of BRD and bovine foot rot

DOSAGE

dairy cattle.

post-partum) associated with bacterial organisms susceptible to ceftiofur in lactating

EXCEDE Sterile Suspension is also indicated for treatment of acute metritis (0-10

where it

Administer as a single subcutaneous injection in the posterior aspect of the ear

100 lb BW).

equivalents (CE)/lb (6.6 mg CE/kg) body weight (BW)

of the ear) to cattle at a dosage of 3.0 mg ceftiofurattaches to the head (base

.H. somnibeef and non-lactating dairy cattle which are at high risk of developing BRD associated


in beef, non-lactating dairy, and lactating dairy cattle.

Fusobacterium necrophorumrot (interdigital necrobacillosis) associated with

bovine of treatment the for indicated also

Treatment of BRD and bovine foot rot


EXCEDE Sterile Suspension is also indicated for treatment of acute metritis (0-10


(1.5 mL sterile suspension perequivalents (CE)/lb (6.6 mg CE/kg) body weight (BW)

of the ear) to cattle at a dosage of 3.0 mg ceftiofur

beef and non-lactating dairy cattle which are at high risk of developing BRD associated


andFusobacterium necrophorumfootbovine


daysEXCEDE Sterile Suspension is also indicated for treatment of acute metritis (0-10


(1.5 mL sterile suspension per

of the ear) to cattle at a dosage of 3.0 mg ceftiofur

ADMINISTRATION FOR BASE OF THE EAR

be made by the rostral or ventral injection techniques.

in the posterior aspect of the ear where it attaches to the head (base of the ear) can

In lactating dairy cattle the injection techniques for subcutaneous (SC) injection

made by the rostral, ventral or toward the opposite eye injection techniques.

In beef and non-lactating dairy cattle the SC injection in the base of the ear can be

of the ear where it attaches to the head (base of the ear).

EXCEDE administering

well before using.Shake

ADMINISTRATION FOR BASE OF THE EAR

be made by the rostral or ventral injection techniques.





of the ear where it attaches to the head (base of the ear).

subcutaneously Suspension Sterile EXCEDE

complete the read Please well before using.





aspectposterior the in

beforeinsert package

CONTRAINDICATIONS

pre

As with all drugs, the use of EXCEDE Sterile Suspension is contraindicated in animals

WARNINGS

viously found to be hypersensitive to the drug.

CONTRAINDICATIONSAs with all drugs, the use of EXCEDE Sterile Suspension is contraindicated in animals

WARNINGS





100 lb BW).

In beef and non-lactating dairy cattle, EXCEDE

adminis

per 100 lb BW).

mg CE/lb (6.6 mg CE/kg) BW3.0 at a dosage of aspect of the ear

subcutaneous single a as tered

Control of BRD

is observed, the diagnosis should be reevaluated.

Most animals will respond to treatment within three to five days. If no improvement

(1.5 mL sterile suspension per 100 lb BW).(6.6 mg CE/kg) BW

(base of the ear) to beef and non-lactating dairy cattle at a dosage of

aspect of the ear or in the posterior aspect of the ear where it attaches to the head

Administer as a subcutaneous injection either in the middle third of the posterior

at “high risk” of devel

effective for the control of respiratory disease in beef and non-lactating dairy cattle

Clinical studies indicate that administration of EXCEDE Sterile Suspension is

oping BRD. One or more of the following factors typically

In beef and non-lactating dairy cattle, EXCEDE Sterile Suspension may also be

(1.5 mL sterile suspensionmg CE/lb (6.6 mg CE/kg) BW

posteriorthe of third middle the in injection subcutaneous

is observed, the diagnosis should be reevaluated.


(1.5 mL sterile suspension per 100 lb BW).

3.0 mg CE/lb(base of the ear) to beef and non-lactating dairy cattle at a dosage of






Sterile Suspension may also be

(1.5 mL sterile suspension

posterior


3.0 mg CE/lb






ventral techniques. Hold the syringe and needle and insert the needle as described below.

The subcutaneous (SC) injection may be made using the toward the opposite eye, rostral, or

toward the animal’s opposite eye. See Figures 4 and 5.

the direction of an imaginary line that would pass through the headpoint in

Hold the syringe and needle behind the ear to be dosed so the needle and syringe

Administration for the Base of the Ear: Toward the Opposite Eye Technique

Do not administer EXCEDE Sterile Suspension in the neck.

Deliver the entire contents of the syringe.

attaches to the head (base of the ear) while maintaining this angle. See Figure 4.

posterior aspect of the ear where it attaches to the head (base of the ear).Figure 4. Subcutaneous administration of EXCEDE Sterile Suspension in the



toward the animal’s opposite eye. See Figures 4 and 5.

the direction of an imaginary line that would pass through the head



Do not administer EXCEDE Sterile Suspension in the neck.

Deliver the entire contents of the syringe.


posterior aspect of the ear where it attaches to the head (base of the ear).Figure 4. Subcutaneous administration of EXCEDE Sterile Suspension in the



the direction of an imaginary line that would pass through the head




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

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

reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention.

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.



individuals. Repeated allergic reactions in some



exposure to this product.







The material safety data sheet contains more detailed occupational safety

KEEP OUT OF REACH OF CHILDREN.FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE.



exposure may leador prolonged individuals. Repeated











exposure may lead








Cattle are from multiple farm origins,

stops),

transport extended had have cattle

ambient temperature change from origin to arrival of 30° F or more,

cattle have had continued exposure to extremely wet or cold weather conditions,

Treatment of Acute Metritis

procedures (such as castration, dehorning).

cattle have experienced excessive shrink or excessive arrival processing

Table 1. Dosing Schedule for EXCEDE Sterile Suspension.

initial dose.

this dose in the contra-lateral (opposite) ear approximately 72 hours following the

3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 mL sterile suspension per 100 lb BW). Repeat

it attaches to the head (base of the ear) to lactating dairy cattle at a dosage of

Administer as a subcutaneous injection in the posterior aspect of the ear where

Cattle are from multiple farm origins,

any if few included have may (that times transport

ambient temperature change from origin to arrival of 30° F or more,


procedures (such as castration, dehorning).


Table 1. Dosing Schedule for EXCEDE Sterile Suspension.





restany







RESIDUE WARNINGS

likely to result in sudden death of the animal.

towards the opposite eye. Intra-arterial injection of EXCEDE Sterile Suspension is

Suspension via middle third of the ear injection or base of the ear injection directed

Intra-arterial injection may occur during administration of EXCEDE Sterile

RESIDUE WARNINGS





pre-slaughter withdrawal period is required after the last treatment.Following label use as either a single-dose or 2-dose regimen, a 13-day

milk discard period is required for this product.single-dose a either as use Following label

administration by unapUse of dosages in excess of 3.0 mg CE/lb (6.6 mg CE/kg) BW or

the neck or intramuscular injection) may cause violative residues.proved routes (subcutaneous injection in

ruminating calves.A withdrawal period has not been established for this product in pre-

Do not use in calves to be processed for veal.





pre-slaughter withdrawal period is required after the last treatment.Following label use as either a single-dose or 2-dose regimen, a 13-day

milk discard period is required for this product.noregimen, 2-dose or single-dose

Use of dosages in excess of 3.0 mg CE/lb (6.6 mg CE/kg) BW or

the neck or intramuscular injection) may cause violative residues.proved routes (subcutaneous injection in

A withdrawal period has not been established for this product in pre-

Do not use in calves to be processed for veal.




Weight Dose Volume(lb) (mL)

100 1.5

200 3.0

300 4.5

400 6.0

500 7.5

600 9.0

700 10.5

800 12.0

900 13.5

Weight Dose Volume(lb) (mL)

1100 16.5

1200 18.0

1300 19.5

1400 21.0

1500 22.5

1600 24.0

1700 25.5

1800 27.0

1900 28.5

head (base of the ear).Sterile Suspension in Figure 5. Injection location for the subcutaneous administration of EXCEDE

head (base of the ear).ear where it attaches to of the aspect the posterior Sterile Suspension in

Figure 5. Injection location for the subcutaneous administration of EXCEDE

theear where it attaches to Figure 5. Injection location for the subcutaneous administration of EXCEDE

ANTIBACTERIAL WARNINGS

PRECAUTIONS

ment of drug-resistant bacteria.

likely to provide benefit to treated animals and may increase the risk of the develop

Use of antibacterial drugs in the absence of a susceptible bacterial infection is un

minimize their occurrence.

infections may result in

may ear

the ear, thickening and swelling (characterized by aseptic cellular infiltrate) of the

Following subcutaneous injection

open draining lesions in a small percentage of cattle.

Injection of volumes greater than 20 mL, in the middle third of the ear, may result in

least 13 days post administration resulting in trim loss of edible tissue at slaughter.

(base of the ear), areas of discoloration and signs of inflammation may persist at

Following injection in the posterior aspect of the ear where it attaches to the head

ANTIBACTERIAL WARNINGS

PRECAUTIONS

ment of drug-resistant bacteria.



minimize their occurrence.

abscess formation. Attention to hygienic procedures caninfections may result in

injections, parenteral other with As occur. may


in the middle third Following subcutaneous injection








abscess formation. Attention to hygienic procedures can

bacterialpost-injection localized injections,


ofaspect posterior of the in the middle third






-

-

abscess formation. Attention to hygienic procedures can

bacterial


of





ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR

ADMINISTRATION

aspect of the ear, avoiding all blood vessels. See Figures 2 and 3.

subcutaneous single a as Deposit

cattle.

administering EXCEDE Sterile Suspension subcutaneously in the posterior ear of

Please read the complete package insert beforeShake well before using.

tags or ear tag holes. Do not administer intra-arterially.

will appear.

When administered correctly, a subcutaneous bleb of EXCEDE Sterile Suspension

1000 15.0

ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR

aspect of the ear, avoiding all blood vessels. See Figures 2 and 3.

posteriorthe of third middle the in injection subcutaneous


Please read the complete package insert before

tags or ear tag holes. Do not administer intra-arterially.


2000 30.0

posterior


Please read the complete package insert before


Administration for the Base of Ear: Toward the Same Eye Technique or Rostral Direction

toward the eye on the same side of the head. See Figures 5 and 6.

point in the direction of an imaginary line that would pass through the head

to the head (base of the ear) while maintaining the needle position. See Figure 6.





ctiontion for






ADVERSE EFFECTS

lactation have not been determined.

The effects of ceftiofur on bovine reproductive performance, pregnancy, and

CLINICAL PHARMACOLOGY

antibiotic or formulation during any of the clinical and target animal safety studies.

intra-arterial injection. No other adverse systemic effects were noted for either the

incidence of acute death (see ANIMAL SAFETY) confirmed to be the result of inadvertent

sudden death of the animal. During the conduct of clinical studies, there was a low

opposite eye. Intra-arterial injection of EXCEDE Sterile Suspension is likely to result in

via middle third of the ear injection or base of the ear injection directed towards the

Intra-arterial injection may occur during administration of EXCEDE Sterile Suspension

hydrochloride (EXCENEL

Ceftiofur administered as either ceftiofur sodium (NAXCEL


ADVERSE EFFECTS

lactation have not been determined.


CLINICAL PHARMACOLOGY








RTU Sterile Suspension), or ceftiofur crystalline free acid®hydrochloride (EXCENEL

Ceftiofur administered as either ceftiofur sodium (NAXCEL










RTU Sterile Suspension), or ceftiofur crystalline free acid

Sterile Powder), ceftiofur®Ceftiofur administered as either ceftiofur sodium (NAXCEL








RTU Sterile Suspension), or ceftiofur crystalline free acid

Sterile Powder), ceftiofur

10

g g

(EXCEDE Sterile Suspension) is metabolized rapidly to desfuroylceftiofur, the primary

Single Dose Regimen

not less than 150 hours after a single admin

Mannheimia Pasteurella multocida, encompass 90% of the most susceptible isolates (MIC

metabolites in plasma above the lowest minimum inhibitory concentration to

provides therapeutic concentrations

BOE) of beef, non-lactating dairy, and lactating dairy cattle,head (base of the ear,

non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the

posterior the of third middle

metabolite. Subcutaneous administration of ceftiofur crystalline free acid, either in the

The pharmacokinetic parameters for the two subcutaneous locations of injection


istration (See Figure 8).not less than 150 hours after a single admin

somniHistophilus and haemolyticaMannheimia ) for the labeled BRD pathogens,90encompass 90% of the most susceptible isolates (MIC


of ceftiofur and desfuroylceftiofur-relatedprovides therapeutic concentrations

BOE) of beef, non-lactating dairy, and lactating dairy cattle,


ear, the of third (middle ear the of aspect



pathogensTable 4. Ceftiofur minimum inhibitory concentration (MIC) values* of indicated

Indicatedpathogen

Mannheimia haemolyticaPasteurella multocidaHistophilus somniFusobacterium necrophorumPorphyromonas levii

* The correlation between


, for generallysomni) for the labeled BRD pathogens,


of ceftiofur and desfuroylceftiofur-related

BOE) of beef, non-lactating dairy, and lactating dairy cattle,


andbeef of MOE)



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




proximately 225 kg) were given a single 3.0 mg CE/lb

result in death and must be avoided.



EXCEDE Sterile Suspension in the middle auricular



feeder in investigated were Suspension Sterile





proximately 225 kg) were given a single 3.0 mg CE/lb



EXCEDE Sterile Suspension in the middle auricular



cattle.feeder


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


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




*

**

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




susceptibility data and clinical effectiveness is unknown.in vitroThe correlation between

respiratory criteria* interpretive CLSI-accepted





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*





Zone diameter MIC breakpoint(mm) (μg/mL)

R S I R

18 to 20 ≤ 17 ≤ 2.0 4.0 ≥ 8.0

mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE 3.0


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




jugular vein and were monitored for adverse effects following injection.

Sterile Suspension in the

Suspension is an unacceptable route of administration.




increase in thickness is attributed to the space required for the volume








One steerjugular vein and were monitored for adverse effects following injection.

Sterile Suspension in the




of injected





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


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

R – Resistant

days. The 3.0 mg CE/lb (6.6 mg CE/kg) BW EXCEDE Sterile Suspension dose significantly (p

evaluated clinically

subcutaneously in the middle third of the pos

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


Histophilus somni

S – Susceptible

I – Intermediate

EFFECTIVENESS

have not been established.



R – Resistant


and 28 and 14 4, to 2 Days on evaluated

terior aspect of the ear. Cattle weresubcutaneously in the middle third of the pos







studyother all on were observed and

terior aspect of the ear. Cattle were




portions of the carcass around the base of the ear.

CFR 301.2). No signs of irritation were observed on the edibleinedible tissues in the US (9

cattle. The discoloration was markedly reduced in size by the end of the study. Ears are

areas of discoloration and some foci of hemorrhage were observed in ears of injected

injected ear in a drooping position for 7 days post injection. At necropsy, subcutaneous

After Day 14, post injection ear thickness

Sterile EXCEDE

The local tolerance of the ear of cattle to a single subcutaneous injection of

well tolerated and was acceptable under feedlot conditions.

administration of EXCEDE Sterile Suspension in the posterior aspect of the ear was

immediately animals treated the of

Leak back and/or bleeding from the injection site was observed in a small fraction

from this trial due to ear irritation although swelling was noted at some injection sites.

study. None of the 1927 animals treated with EXCEDE Sterile Suspension were removed

also was Suspension

EXCEDE

A study evaluated the 56-day feedlot performance of beef steers administered

Sterile Suspension alone, EXCEDE Sterile Suspension with a growth

portions of the carcass around the base of the ear.

CFR 301.2). No signs of irritation were observed on the edible




decreased in all animals. One animal carried anAfter Day 14, post injection ear thickness


well tolerated and was acceptable under feedlot conditions.


concluded was It administration. after immediately




effectivenessmulti-location large a in evaluated also



CFR 301.2). No signs of irritation were observed on the edible




decreased in all animals. One animal carried an



thatconcluded




effectiveness



either the middle third of the ear or the base of the ear.Pharmacokinetic Beef - Middle

Parameter Third of the EarMean Value ±

Deviation

(μg CE/mL)maxC 6.90 ± 2.68

(h)maxt

0-LOQAUC 376 ± 66.1

(h)>0.2, modelt 183 ± 40.8

(h)>0.2, ncat 246 ± 48.5

(h)1/2t 62.3 ± 13.5

(μg CE/mL)C maximum plasma concentration (in μg CE/mL).

either the middle third of the ear or the base of the ear.Beef - Middle Beef - Base of

Third of the Ear the Ear Base of the EarMean Value ± Mean Value ± Mean Value ±

Standard StandardDeviation Deviation

6.90 ± 2.68 6.39 ± 1.79

12.0 ± 6.2 19.8 ± 5.81

376 ± 66.1 412 ± 67.3

183 ± 40.8 NE

246 ± 48.5 218 ± 45.5

62.3 ± 13.5 40.7 ± 11.2

maximum plasma concentration (in μg CE/mL).

0.05) increased Day 14 treatment success rate, defined as ≤


ancillary any

and had no or mild depression on that day.

Suspension administered subcutaneously in the middle third of the poste

following arrival processing. Administration of a

Effectiveness evaluation was based on the

Suspension Sterile

at high risk for BRD were assigned to one of four arrival treatments, including EXCEDE

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

controls.

cattle feedlot

of the ear at arrival processing significantly reduced the incidence of BRD in high-risk

Base of the ear administration (beef and non-lactating dairy cattle) and middle third of

Dairy Cow -Base of the EarMean Value ±

StandardDeviation

4.44 ± 1.65

19.00 ± 8.02

313 ± 85.5

NE

205 ± 35.7

43.92 ± 9.84

0.05) increased Day 14 treatment success rate, defined as


of temperature rectal a had and treatment ancillary

and had no or mild depression on that day.


following arrival processing. Administration of a

incidence of clinical BRD within 28 daysEffectiveness evaluation was based on the

mg CE/kg) 6.6 or (4.4 CE/lb mg 3.0 or 2.0 at Suspension


addition to standard processing on arrival at feedlots, cattle (



processing arrival after period 28-day the in cattle



0.05) increased Day 14 treatment success rate, defined as


respiration normal 104°F, <of

animals that did not require

index,


single dose of EXCEDE Sterile

incidence of clinical BRD within 28 days

negative control.or BWmg CE/kg)


3911) considered to ben=addition to standard processing on arrival at feedlots, cattle (



negativeto compared processing


rior aspect


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


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


the boundaries of the middle third of the ear in some


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



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


=

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


pharmacokinetic The below. 9 Figure in shown

metabolites desfuroylceftiofur-related and




occurs (in hours).maxthe time after injection when C

to the limit of quantitation of the assay (0.15 μg CE/mL).


the time plasma concentrations remain above 0.2 μ



terminal phase biological half life (in hours)

Not estimated

forparameters pharmacokinetic

2-dosethe for metabolites



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


g 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


significant difference statistically a was There


based was which success, treatment for post-treatment


injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg



effectiveness of EXCEDE Sterile Suspension for the


°F were enrolled in the study and treated with 103 discharge and a rectal temperature of ≥



administration (lactating dairy cattle) were compared to the middle third of the


beto found were and cattle dairy non-lactating


forsuccess treatment in 0.0054) = (p


lesion,in decreases defined on based


BWE/kg) Cinjection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg



foot rot wastreatment of bovine effectiveness of EXCEDE Sterile Suspension for the


°F were enrolled in the study and treated with



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



swelling and drooping, and evaluated grossly at necropsy, using skin


. 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


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






the animals showed ear drooping. At necropsy, signs of



ning andswelling and drooping, and evaluated grossly at necropsy, using skin


. Injection sites

base of the ear with EXCEDE


and firmness of tissue) and presence of drug

inedible portions of the base of the ear






(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


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


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





temperature < 103 °F, and that did not require alternate (“escape”) therapy during the



control, administered approximately 72 hours apart at the base of opposite ears. At 14



Suspension. Results from a five-dayto evaluate the systemic safety of EXCEDE Sterile

conducted with ceftiofur sodium are adequatedesfuroylceftiofur. Therefore, studies







14_day temperature < 103 °F, and that did not require alternate (“escape”) therapy during the



days control, administered approximately 72 hours apart at the base of opposite ears. At 14



Suspension. Results from a five-day

conducted with ceftiofur sodium are adequate



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.




days after injection. At necropsy, all six cows showed evidence of injection site


signs of swelling atdrooping ears at any time after treatment but all animals had

animals No Suspension. Sterile EXCEDE 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






signs of swelling at

exhibitedanimals


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


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

tered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5

the posterior ear of cattle was evaluated in a separate study

The systemic safety of ceftiofur concentrations

two routes of administration are therapeutically equivalent.

Based upon the results of this relative bioavailability study, it was determined that the

two the of

administration at the base of the ear was established via a pharmacokinetic comparison

BWmg CE/kg) mg CE/lb (6.6 Table 3. Average (n = 12) Pharmacokinetic Parameters Following Two Subcutaneous

Mean ± Standard Deviation


that ceftiofur was well tolerated at 25 mg CE/lb/day for five con



In a 15-day safety/toxicity study, five steer and five heifer calves per group were admin

calves. Local tissue tolerance to


mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, indicating


tered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5

the posterior ear of cattle was evaluated in a separate study

subcutaneous injection of EXCEDE Sterile Suspension in




ear the of (base administration of routes



secutive days, approx-that ceftiofur was well tolerated at 25 mg CE/lb/day for five con



mg3.0 mg CE/lb (6.6 Suspension

In a 15-day safety/toxicity study, five steer and five heifer calves per group were admin-


mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, indicating


or 10 mg CE/lb/daytered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5

.the posterior ear of cattle was evaluated in a separate study

subcutaneous injection of EXCEDE Sterile Suspension in




of the ear).middle third versus ear


ing from productresult

inflammation (discoloration of fat

days after injection. At necropsy, all six cows showed evidence of injection site10

of tissue dor

tissue/fascia) and four of six cows had discoloration

.sectioned surface

discoloration, tan nodules and a

sal and posterior to the ear canal on the carcass. In addition to

at 2 or 3, 11, and 54±3 days after the second injection, respectively.

injections administered. Injection site scores were normal in 50.3%, 73.2%, and 96.4%

above. study described effectiveness

Injection site safety for base of the ear administration was evaluated in the metritis

TISSUE AND MILK RESIDUE DEPLETION

(rostral), 87.8% (ventral), and 64.6% (opposite eye) of cattle on Day 28, respectively.

(rostral), 46.9% (ventral), and 47.9% (opposite eye) of cattle on Day 14, and 73%

(opposite eye) of animals in the study. Injection site scores were normal for 32%

cattle. Normal restraint was adequate for 89.8% (ventral), 98% (rostral), and 100%

eye technique opposite toward the

The ventral and rostral base of the ear injection techniques were compared with the



milky white fluid exudate were also present at the


at 2 or 3, 11, and 54±3 days after the second injection, respectively.


adequate for ≥ was restraint Normal above.







lactating dairy197 study in of use in a conditions eye technique




milky white fluid exudate were also present at the



of97.8% adequate for ≥






lactating dairy


(h)maxT

(μg/mL)maxC

MICROBIOLOGY

with bovine foot rot.

Fusobacterium necrophorumagainst and BRD,

Histophilus somni, and Pasteurella multocida,Ceftiofur has demonstrated

foot rot isolates, respectively.

and Laboratory Standards Institute (CLSI) M7-A3 and M11-A6 standards for BRD and

diagnosed with foot rot. Susceptibility testing was conducted according to the Clinical

cattle enrolled in a field study conducted in the United States and Canada that were

the United States that were diagnosed with BRD. Foot rot isolates were obtained from

4. BRD isolates were obtained from cattle enrolled in a field study conducted inTable

A summary of the susceptibility of BRD and foot rot pathogens is presented in

77.1 ± 33.4

5.98 ± 2.51

Porphyromonas leviiand Fusobacterium necrophorum three major pathogens associated withHistophilus somni,

Mannheimia haemolytica, activity against in vitroCeftiofur has demonstrated

foot rot isolates, respectively.





4. BRD isolates were obtained from cattle enrolled in a field study conducted in



Investigation of Intra-Arterial and Intravenous Injectionfollowing five daily doses of NAXCEL Sterile Powder in beef cattle.

after two doses of EXCEDE were statistically no higher than (AUC)

interval at 6.6 mg/kg BW. The peak concentration (C

were compared pharmacokinetically with EXCEDE administered 2 times at a 72 hour

projected daily doses of NAXCEL Sterile Powder (ceftiofur sodium) at 2.2 mg/kg BW

To support systemic target animal safety for the 2-dose metritis regimen, five

of the two major auricular (ear) arteries.

resulted from inadvertent intra-arterial injection of this oil-based suspension into one

the time of injection. The exact cause was confirmed in three animals. These deaths

following injection of EXCEDE Sterile Suspension.

In approximately 6000 animals enrolled in the BRD clinical studies, nine animals died

in direct administration of the oil-based formula

the brain resulting in embolism and death.

associatedPorphyromonas levii three major pathogens associated with

Mannheimia haemolytica,





4. BRD isolates were obtained from cattle enrolled in a field study conducted in




after two doses of EXCEDE were statistically no higher than

interval at 6.6 mg/kg BW. The peak concentration (C




of the two major auricular (ear) arteries.



All deaths were within 30 minutes offollowing injection of EXCEDE Sterile Suspension.


in direct administration of the oil-based formula

Intra-arterial injection at this location resulted

the brain resulting in embolism and death.

tion



the exposureafter two doses of EXCEDE were statistically no higher than

) and the extent of exposuremaxinterval at 6.6 mg/kg BW. The peak concentration (C






All deaths were within 30 minutes of


Intra-arterial injection at this location resulted

into the arterial blood supply oftion


kidney, 2.0 ppm in liver, 1.0 ppm in muscle and 0.1 ppm in milk.

for ceftiofur residues in milk. The tolerances for ceftiofur residues are 0.4 ppm in

residues in cattle kidney, liver and muscle. A separate study established the tolerance

A radiolabeled residue metabolism study established tolerances for ceftiofur

13

days after dosing. These data collectively support a13kidney, liver and muscle by

in tissues were less than the tolerances for ceftiofur residues in tissues such as the

cows received a single injection of

A pivotal tissue residue decline study was conducted in dairy cattle. In this study,

-day pre-slaughter withdrawal period.

collectively support that no milk discard period is required for this product.

residues in milk were less than tolerances at all time points after treatment. These data

study, cows received a single injection of

study decline milk residue pivotal A


kidney, 2.0 ppm in liver, 1.0 ppm in muscle and 0.1 ppm in milk.




days after dosing. These data collectively support a


. Ceftiofur 3.0 mg CE/lb (6.6 mg CE/kg) BWcows received a single injection of


day pre-slaughter withdrawal period.



3.0 mg CE/lb (6.6 mg CE/kg) BWstudy, cows received a single injection of

cattle. dairy conducted in lactating was study




days after dosing. These data collectively support a


residues. Ceftiofur




. Ceftiofur3.0 mg CE/lb (6.6 mg CE/kg) BW

thisIn cattle.

11

Two-Dose Residue Decline Studies

last dose.

collectively continue to support a 13-day pre-slaughter withdrawal period after the

residues ceftiofur

between injections. Ceftiofur residues in tissues were less than the tolerances for

cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval


STORAGE CONDITIONS

milk discard period is required for this product.

interval between injections. Milk residue decline data from this study supports that no

study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour

A pivotal milk residue decline study was conducted in lactating dairy cattle. In this

Two-Dose Residue Decline Studies


the after days 13 by kidney the in residues




STORAGE CONDITIONS

milk discard period is required for this product.





dataThese dose. second







STORAGE CONDITIONS

using.

Store at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before

HOW SUPPLIED

Contents should be used within 12 weeks after the first dose is removed.

250 mL vial

100 mL vial

EXCEDE Sterile Suspension is available in the following package sizes:

www.EXCEDE.com or call 1-866-387-2287

NADA #141-209, Approved by FDA

Pharmacia & Upjohn CompanyDistributed by

Division of Pfizer Inc, NY, NY 10017

STORAGE CONDITIONSStore at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before




NADA #141-209, Approved by FDA

Pharmacia & Upjohn CompanyDivision of Pfizer Inc, NY, NY 10017

Store at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before



Revised: December 2011


Revised: December 2011


All brands are the property of their respective owners.©2012 Pfizer Inc. All rights reserved. EXD12002

OBSERVE LABEL DIRECTIONS

TAKE TIME

References1. Data on file, Study Report No. 1437C-60-09-768, Pfizer Inc.

2. Data on file, Study Report No. 1437C-60-09-769, Pfizer Inc.

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