comparative efficacy of draxxin vs zuprevo or micotil high ...is a unique, novel antibiotic for the...

Summary

Zoetis Florham Park, NJ 07932

Arrival administra-

tion of DRAXXIN ®

provided better BRD

control and fewer

combined BRD

mortalities and

chronics than

metaphylaxis using

Zuprevo® or Micotil.®

eedyard veterinarians and managers are

perpetually interested in better ways to lower

the economic impacts of bovine respiratory

disease (BRD) in their operations, particularly

for high-risk cattle. One of the major develop-

ments in BRD management has been the

advent of macrolide antimicrobials that have

greatly expanded the choice of available BRD

medications. Macrolides are typically the

preferred drug class for the control of BRD in

high-risk calves, used to help reduce morbidity

and mortality and improve performance.

Zoetis continues to conduct research to investi-

gate the efficacy and benefits of medication

strategies based on metaphylactic administra-

tion of a macrolide and the post-metaphylactic

interval (PMI)/post-treatment interval (PTI)

concepts. A comparative study1 evaluated the

impacts of three macrolide products –

F

DRX13056

September 2013

Comparative Efficacy of DRAXXIN® vsZuprevo® or Micotil® for Control of BRD inHigh-Risk Feedlot Cattle

• A study1 at a commercial feedlot evaluated three macrolide antibiotics for the control

of bovine respiratory disease (BRD) in high-risk cattle:

# DRAXXIN® (tulathromycin) administered as an antibiotic for the control of BRD

on arrival, followed by EXCEDE® (ceftiofur crystalline free acid) for BRD therapy

upon occurrence following a 10-day post-metaphylaxis interval (PMI).

# A similar protocol but using Zuprevo® (tildipirosin) for arrival control of BRD.

# A similar protocol but using Micotil® (tilmicosin) for arrival control of BRD with a

3-day PMI.

# A 7-day post-treatment interval (PTI) was observed after initial EXCEDE treatment.

• Cattle that received arrival DRAXXIN experienced at least 23% better metaphylaxis

success rates (no BRD) at days 28 and 56 (P < 0.01), at least 76% fewer combined

mortalities and chronics (P < 0.01), and at least 18% better daily gain and feed/gain

(P < 0.01) than cattle that received Zuprevo metaphylaxis.

• DRAXXIN cattle also demonstrated similar or greater health and performance

advantages compared to calves that received metaphylaxis with Micotil.

• DRAXXIN remains the unsurpassed choice for helping optimize the health and

productivity of feedlot cattle at high risk for BRD.

2

DRAXXIN® (tulathromycin), Zuprevo®

(tildipirosin), or Micotil® (tilmicosin) – for the

control component, followed by use of

EXCEDE® (ceftiofur crystalline free acid) for

initial BRD treatment upon occurrence.

DRAXXIN® OverviewDRAXXIN (tulathromycin) Injectable Solution

is a unique, novel antibiotic for the control and

treatment of BRD that conveniently delivers a

full course of therapy in a single dose.

Tulathromycin is a semi-synthetic macrolide

compound developed by Zoetis scientists as a

highly bioavailable, long-acting antimicrobial

for treatment of BRD.2 Admin istered as a single

subcutaneous (SC) injection at 1.1 mL/100 lb

body weight (2.5 mg/kg), DRAXXIN is indi -

cated for the treatment of BRD associated with

4 of the most common bacterial respiratory

pathogens of cattle: Mannheimia haemolytica,

Pasteurella multocida, Histophilus somni, and

Mycoplasma bovis. DRAXXIN is also the only

BRD product approved for the control of respi-

ratory disease in cattle at high risk of develop-

ing BRD associated with the same 4 pathogens.

These indications make DRAXXIN particularly

well-suited for use in control programs for

arriving feedlot cattle, when animals are experi-

encing stress due to transport, commingling,

etc., and are at high risk of BRD pathogen

exposure. DRAXXIN is also indicated for treat-

ment of infectious bovine keratoconjunctivitis

associated with Moraxella bovis, and bovine

foot rot (inter digital necro bacillosis) associated

with Fuso bacterium necrophorum and

Porphyro monas levii.

Experiment DesignThe study involved 1370 crossbred beef steers

sourced from livestock auctions in the south-

eastern US and transported by truck to a major

feedyard in northern Texas. Overall health of

calves was good at the time of purchase, but the

stress of marketing, commingling, and shipping

put these animals at high risk for the develop-

ment of BRD. Calves averaged 626 lb body

weight (BW) when placed on feed for a typical

commercial grow/finish period. Only healthy

cattle were enrolled in the study; animals were

excluded if systemic disease or complicating

physical conditions were observed.

The study was designed to address the follow-

ing hypothesis: treatment success rate for

control of BRD is greater for calves adminis-

tered DRAXXIN vs either Micotil or Zuprevo

upon arrival in the feedyard. The study

employed a split-plot design, with type of

housing (with or without shelter) as the whole-

plot factor and arrival BRD metaphy laxis

treatment (DRAXXIN, Zuprevo, or Micotil) as

the split-plot factor. Cattle arriving on the same

day were commingled before arrival processing

to form arrival lots of at least 234 calves.

Within each arrival lot, calves were randomly

assigned to 1 of 6 pens based on the order they

passed through the chute at arrival processing

until each pen reached the desired capacity of

approximately 40 calves. Blocks consisted of 6

pens, of which 3 pens had shelter/shade and 3

pens had no shelter. Within each block and type

of housing, either of the 3 BRD metaphylaxis

treatments was randomly assigned to pens (all

calves in a pen received the same treatment).

Cattle were processed (study day 0) within

36 hours of arrival according to standard

procedures at the feedyard (vaccinated with

The study investigatedthe efficacy of threedifferent macrolidesfor the control of BRD,and PMI/PTI concepts.

Figure 1 – Experiment design; metaphylaxis and treatment protocols used in the study.

Day 10................................ ..............................

Day 3 ............................................. ............................................Day 0

10 days

Repeat E at any timeXCEDEif needed

7 days

3days

Observe animals for BRD;treat at any time if needed

Observe animals for BRD;treat at any time if needed

Micotil (3-day PMI)

Metaphylaxis

Day 0 (processing)

D or ZuprevoRAXXIN (10-day PMI)

EXCEDE (7-day PTI)

1 Treatmentst (if needed)

Trt+7...................... ......................TrtEnd ofstudy

BOVI-SHIELD GOLD® IBR-BVD and

ULTRACHOICE™ 7, treated for internal and

external parasites with DECTOMAX® Injectable

Solution, implanted with Component® TE-IS,

and identified with identical tags in each ear).

The 3 antibiotics used for the control of BRD

were administered at processing as follows

(Figure 1):

! DRAXXIN Injectable Solution (tulathro-

mycin): 2.5 mg/kg BW (1.1 mL/100 lb)

single dose SC in the lateral neck for

metaphylaxis on day 0, with a 10-day PMI (n=456 across 12 pens);

! Zuprevo 18% Injectable Solution (tildipiro -

sin): 4.0 mg/kg BW (1 mL/100 lb) single

dose SC in the lateral neck for metaphylaxis

on day 0, with a 10-day PMI (n=456 across

12 pens);

! Micotil 300 (tilmicosin): 10 mg/kg BW

(1.5 mL/100 lb) single dose SC in the lateral

neck for metaphylaxis on day 0, with a

3-day PMI (n=458 across 12 pens).

Cattle were observed daily from study day 1

through day 56 for clinical signs of BRD

using a standard clinical appearance score

index (CAS; animals rated using 5 categories,

0-4; 0=normal, 4=moribund). During the PMI

period, any animal with a CAS = 3 was

removed from study and administered

emergency therapy. Calves completing their

treatment group’s respective PMI and then

demonstrating a CAS ≥ 2 (moderate BRD or

worse) were pulled for BRD treatment as

follows:

• EXCEDE® Sterile Suspension: 6.6 mg/kg

BW (1.5 mL/100 lb) single dose SC in the

middle third of the posterior ear or at the

base of the ear for the first therapeutic BRD

treatment, with a 7-day PTI;

• EXCEDE (same dose/route) for the second

BRD treatment (if needed), choice and

timing of any additional re-treatments was

at the discretion of the feedlot.

Calves were returned to their home pens

following treatment. Any additional BRD

episodes occurring after these 2 therapeutic

treatments (assuming at least 1 BRD episode

occurred during the first 28 days) qualified a

calf as a BRD chronic (removed from study

and treated with standard feedlot therapy).

Calves scoring a CAS of 4 at anytime were

removed from study and humanely euthanized.

Feedyard personnel making clinical observa-

tions (pen riders, feed-bunk readers) were

blinded and did not have knowledge of treat-

ment group assignments.

Water was provided ad libitum and cattle

were offered standard rations used at the

feedlot, formulated to meet or exceed nutrient

requirements for their class and weight. Ration

changes were made according to facility

procedures and could include an ionophore and

tylosin (coccidia and liver abscess control), but

did not include antimicrobials affecting BRD

therapy (e.g., tetracyclines, sulfas).

Treatment success rates during the immediate

28 and 56 days after initial BRD metaphylaxis

were the primary parameters of interest.

Success rate was defined as the percentage of

cattle that were alive and did not qualify for

BRD treatment following the PMI (clinical

signs of BRD during the PMI did not constitute

a treatment failure unless severity warranted

removal of the animal from the study). Other

evaluated parameters included BRD mortality

(days 0-28, 56, harvest), chronic rates (days 0-

56, harvest), and the number of BRD treat-

ments. Individual animal weights were obtained

on day 0 and at re-implant (day 71), and pen

weights were obtained at harvest, to allow

computation of average daily gain (ADG) and

feed efficiency (feed/gain, F/G).

Collected data were statistically analyzed by

appropriate methods using pen as the experi-

mental unit. The analysis model included the

fixed effects of treatment, type of housing (with

or without shelter), and interaction of treatment

and type of housing; random effects included

block, block within type of housing, and inter-

action of block within type of housing and

treatment. Data from animals removed from

the study for protocol deviations or reasons/

conditions other than BRD were not included

in analyses. Least squares (LS) means (back-

transformed where appropriate) and 95%

confidence intervals/ranges were calculated for

each treatment, with differences assessed at the

5% level of signifi cance (P ≤ 0.05). No treat-

ment × housing-type interactions were detected

(P > 0.05), so all statistical comparisons were

made across both types of housing. The study

was conducted in accordance with the Zoetis

Institutional Animal Care and Use Committee.

3

Cattle received eitherDRAXXIN,® Zuprevo,® orMicotil ® for the control

of BRD; subsequent treatment regimens withEXCEDE ® were identical.

4

ResultsHealth outcomesDRAXXIN metaphylaxis provided superior

disease control for calves at high risk of

developing BRD. As shown in Figure 2,

excellent metaphylaxis success rates (no BRD

development) of 79.5% and 72.4% were

achieved by the DRAXXIN treatment group at

days 28 and 56, respectively. These outcomes

were significantly greater (P < 0.01) than

metaphylaxis success rates observed in the

Zuprevo or Micotil groups. In terms of relative

improvements, DRAXXIN success rates were

23.3% to 48.0% better than those achieved by

the other medications.

No significant BRD mortality differences were

observed between treatment groups at 28 and

56 days, or at harvest.

Rates of costly BRD chronics (≥3 therapeutic

BRD treatments, with at least 1 BRD episode

occurring during the first 28 days) were signifi-

cantly (P < 0.01) reduced in DRAXXIN-treated

calves at both 56 days and over the entire study

(Figure 3). Notably, compared to Zuprevo,

DRAXXIN metaphylaxis reduced chronic

rates by 83.6% and 80.0% for days 0-56 and

0-harvest, respectively. Even greater significant

reductions (P < 0.01) in chronic rate were

achieved by DRAXXIN relative to Micotil.

Figure 4 summarizes the rates of both mortality

and chronics at 56 days and harvest, reflecting

perhaps the most costly aspects of BRD. Calves

receiving DRAXXIN metaphylaxis generated

dramatic 4-fold (or more) reductions (P < 0.01)

in mortality+chronics rate compared to either

Zuprevo or Micotil (reductions of 76.3% and

81.0%, respectively, for day 0-harvest). These

outcomes significantly favor DRAXXIN as the

choice agent for BRD metaphylaxis.

The percent of cattle receiving re-treatment for

BRD further demonstrated the excellent BRD

control offered by DRAXXIN. While 76.9% of

calves receiving DRAXXIN at arrival required

no therapeutic BRD treatments during the

course of the feeding period, only 57.7% and

68.3% of Micotil- and Zuprevo-treated animals,

respectively, completed the feeding period

without BRD therapy. Furthermore, DRAXXIN

cattle demonstrated the lowest rates in the other

BRD treatment frequency categories (1, 2, or 3

treatments, data not shown).

Metaphylaxis successrate was at least 23%greater for cattle thatreceived DRAXXIN ®

compared to calvesthat received Zuprevo.®

DRAXXIN ® metaphylaxissuccess rate was about48% greater than thatachieved using Micotil.®

Figure 2 – 28-day and 56-day success rates of BRD metaphylaxis (no BRD cases).

90

80

70

60

50

40

0

53.7

63.8

Micotil Zuprevo

Metaphylaxis success (%)mP � 0.01 vs Micotil

+48.0% 79.5mz

Draxxin

+24.6%

zP � 0.01 vs Zuprevo

28-day Success

49.0

58.7

Micotil Zuprevo

+47.8% 72.4mz

Draxxin

+23.3%

56-day Success

Figure 3 – BRD chronic rates during days 0-56and for the entire feeding period.

12

10

8

6

4

2

0

9.0

6.7

BRD chronics (%)mP � 0.01 vs Micotil

1.1mz

zP � 0.01 vs Zuprevo

10.7

8.0

1.6mz

Micotil Zuprevo Draxxin Micotil Zuprevo Draxxin

Day 0-56 Day 0-harvest

Figure 4 – BRD mortality+chronics during days0-56 and for the entire feeding period.

9.6

7.6

BRD mortality+chronics (%)mP � 0.01 vs Micotil

1.6mz

zP � 0.01 vs Zuprevo11.6

9.3

2.2mz

12

10

8

6

4

2

0Micotil Zuprevo Draxxin Micotil Zuprevo Draxxin

Day 0-56 Day 0-harvest

Metaphylaxis withDRAXXIN ® cut incidenceof deads and chronicsmore than 4-fold compared to Zuprevo.®

Performance outcomesGrowth results summarized in Figure 5,

calculated on a deads-in basis (including

chronics removed from the study), reveal that

DRAXXIN metaphylaxis generated at least

28% better (P < 0.01) ADG during the feeding

period compared to either Zuprevo or Micotil.

Furthermore, F/G for cattle that received

DRAXXIN meta phylaxis was 18.5% better

(P < 0.01) than that of the Zuprevo group over

the entire feeding period, and improved 17.0%

(P < 0.05) compared to F/G experienced by the

Micotil group (Figure 6). No significant differ-

ences were detected between treatment groups

for ADG or F/G when calculated on a deads-

out basis (data not shown).

ConclusionsResults of this study confirm that use of

DRAXXIN for arrival metaphylaxis provided

substantial health and performance benefits

relative to Zuprevo or Micotil for controlling

the negative impacts of BRD in high-risk

calves arriving at a commercial feedyard.

DRAXXIN-medicated cattle experienced

significantly improved metaphylaxis success

rates (no BRD) at both 28 and 56 days after

arrival treatment. In addition to reduced BRD

morbidity, cattle receiving DRAXXIN

metaphylaxis experienced significantly reduced

incidences of BRD mortality and chronics

compared to animals treated metaphylactically

with Zuprevo or Micotil. The DRAXXIN group

also demonstrated signifi cantly improved ADG

and F/G compared to the other medicated

groups.

The use of DRAXXIN for arrival metaphylaxis

offers beef producers a reliable, cost-effective,

and unsurpassed strategy for helping optimize

the health and profitability of feedlot cattle at

high risk for BRD.

5

DRAXXIN ® arrival metaphylaxis providedsubstantial health and performance benefits

relative to Zuprevo®

or Micotil.®

Figure 5 – Average daily gain (lb) during the entire feeding period (day 0-harvest,deads/chronics-in).

3.4

3.0

2.6

2.2

0

ADG (lb)mP � 0.01 vs MicotilzP � 0.01 vs Zuprevo

2.47 2.43

+28.7% 3.18mz+30.9%

Micotil Zuprevo Draxxin

Figure 6 – Average feed/gain during the entirefeeding period (day 0-harvest,deads/chronics-in).

7.5

7.0

6.5

6.0

5.5

0

Feed/GainmP � 0.05 vs MicotilzP � 0.01 vs Zuprevo

7.007.13

5.81mz

Micotil Zuprevo Draxxin

Overall ADG and F/G forcattle on the DRAXXIN ®

protocol was improvedat least 28% and 17%,

respectively, comparedto the other medications.

Important Safety Information: Do not use DRAXXIN in female dairy cattle 20 months

of age or older. Do not use in calves to be processed for veal. DRAXXIN has an 18 day pre-slaughter

withdrawal

Important Safety Information: As with all drugs, the use of EXCEDE is contraindicated

in animals with known allergy to ceftiofur or to the β-lactam group (penicillins and cephalosporins)

of antimicrobials. Though safe in cattle when properly administered, inadvertent intra-arterial

injection is possible and fatal. EXCEDE has a pre-slaughter withdrawal time of 13 days in cattle.

Do not use in calves to be processed for veal.

6

References1. Data on file, Study Report No. A131R-US-12-028, Zoetis Inc.

2. Evans NA. Tulathromycin: an overview of a new triamilide antibiotic for livestock respiratory disease.Vet Ther 2005; 6:83-95.

(Ceftiofur Crystalline Free Acid)Sterile Suspension

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ey rtions maecial inferttion bac-injeced post, localizy oce) of the ear mataellular infiltry aseptic ced biz

t of theior aspecterd of the posttion in the middle thir

elopmenisk of the devease the ry incred animals and mation is unlikecial inferteptible bace of a suscial drugs in the absenc

.esiduese rtivveause violay ction) ma

tion in thecutaneous injeces (subouted rvveo

.

.tducoor this pr

.ttmeneaer the last trted afequird is rerioal p

1100

(lb)

Weight

1.5100

(mL)(lb)

Dose VolumeWeight

ension.erile SusptCEDE Sor EXchedule fable 1. Dosing STTa

.wing the initial doseolloely 72 hours ftximaoear apprt this dose in the cepea). RWile suspension per 100 lb BerW (1.5 mL stBt a dosage of 3.0 mg CE/lb (6.6 mg CE/kg)ttle ay cating dairtao laco the head (base of the ear) tt

ior aspecertion in the poster as a subcutaneous injectdministAitisetre Mcutt of AtmenearT

ning).tion, dehoracastre aressivcxink or ee shressivcxed eiencxpere evttle haca

et or cemely wtrxo ee txposurtinued eone had cvttle hacaal of 30° F or morivro arin tigom ore change frturaempert tambien

e included fvy hat mat times (thaansporended trtxe had evttle haca,insigm orom multiple fare frttle ara C

.eloping BRDdevtactypically charors ttwing factolloe of the f. One or morBRD

ting dairtay disease in beef and non-lactortaespirol of rtronco

16.51100

(mL)(lb)

Dose VolumeWeight

ension.

e)al (oppositerta-latront this dose in the ct a dosage of 3.0 mg CE/lb (6.6 mg CE/kg)

ttachese it at of the ear wheror aspecct

es (such asedurocessing procal privr,onditionsther coeaold wco

,eal of 30° F or morops),est sty rew if ane included f

isk oft high ral aivres on ares calvizertelopingof dev””iskhigh r“t ttle ay cating dair

the ear).

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

Injection 5. Figure

onon


EXCEDE of administration subcutaneous the for location Injection

t of the ear (middle thirthe posttiofur creftion of caSubcutaneous administr

ed rile Suspension) is metabolizertSile Suspension), or certTU S R®CENELide (EXochlordryh

ed as either certiofur administefCOGYOLLOCCOAAL PHARMCLINIC

y of the clinical and taring antion durmulaortibiotic or fantion. No other aial injecterta-artrin

th (see ANIMe deae of acutincidencing the cur. Dth of the animalsudden dea

tion injecial erta-artrnI. eeye opposittion or base of the ear injecd of the ear injecvia middle thir

cur dury oction maial injecerta-artrnISTVERSE EFFECAD

.minedere not been detvhavine rtiofur on boefts of ceche effT

.ttletage of caencsmall perer than 20 mL, in the middle thirtearg

im loss of edible tissue aesulting in trtion rapost administrtion and sigaoloreas of discof the ear), ar

ior aspecertion in the postwing injectolloF

location for


Sterile EXCEDE

, MOE) of beef and non-lacd of the eart of the ear (middle thir, either in the middle thiree acidstalline frytiofur cr

y metaboimar, the prtiofurefylcoo desfurapidly ted rCee acid (EXstalline frytiofur crefile Suspension), or ctioefder), cwoile Pert S®CELXtiofur sodium (NAefed as either c

.y studiesetget animal safy of the clinical and taror either ed fe noterts wectemic effsterse sytion. No other adv

teresult of inadvo be the rmed tonfir) cYTAL SAFEas a e w, thert of clinical studiesonducting the c

esulro tlikely is Suspension ile ertSCEDE EXof tion d arwoed ttection diron or base of the ear inject

ile SuspensertCEDE Stion of EXaing administrcur dur

tta, and lacynancyeg, premancorfe pertivoducteprvine r

aining lesions esult in open dry r, mad of the earer than 20 mL, in the middle thirolumtion of vnject. Iertt slaughim loss of edible tissue a

t least 13 dy persist ation mans of inflammation and sigo the head (bttaches te it at of the ear wheror aspect

2000

1900

1800

1700

1600

1500

1400

1300

1200

15.01000

13.5900

12.0800

10.5700

9.0600

7.5500

6.0400

4.5300

3.0200

es 2 and 3.iguree F. Sesselsoiding all blood vv, aearr,

erile Suspension subcutaneously in the postertCEDE SEXe packompletead the clease rP. e usingorefell be wwhakS

THE EARTHIRD OF THE MIDDLE TION FORAATADMINISTR

TIONAATADMINISTR

30.02000

28.51900

27.01800

25.51700

24.01600

22.51500

21.01400

19.51300

18.01200


side of the headtion of an iectdir

tion fadministrAA

.ttleior ear of caeringere administort befage insere pack

THE EAR

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 loose

Figure 6. Diagram of head showing the direction for the base of ear injections

e 6.iguree Ftaining the needle position. Sthe head (base of the ear) while main

es 5 and 6.iguree F. Sside of the headd the eyarwoough the head tould pass thrt wy line thainartion of an imag

echnique or RostTTee yyeame Ed the SarwwaoTTo: ase of Earor the Bffo

on

skin in the caudal aspect of the base of the ear.



e 6.

e on the samed the ey

tioneciral Dechnique or Rostr

g g

es (MOE and BOE) demonstrtion sitinjectistical analytaable 2. STTaound in e fand BOE) arers fametinetic parokmache pharT

Single Dose Regimen

e 8).iguree Ftion (Saadministr, ophilus somnii,Histto and ahaemolytic

or the labeled BRD pa) f90es (MICtisolaenoncy corest minimum inhibitwlo

tiofur and desfureftions of catrenonccting dairta, non-lact, BOE) of beefear

ior aspecer, or in the postttley cadairt of the ear (midior aspecterthe post



o the base of the ear (BOE Ltell inas wwe

er administrtes afolited metabtelar

.talenapeutically equive thert they are thataes (MOE and BOE) demonstro subcutanewom these tta frses of the datistical analy

tion (Mtions of injecto subcutaneous locawor the ters f

er a sintally not less than 150 hours afor gener, fcida, Mannheioultella meurastP, thogensor the labeled BRD pa

eptompass 90% of the most susco enction tatrenevaboes in plasma ed metabolittela-rtiofurefylcotiofur and desfur

apevides thero, prttley cating dairta, and lacyting dairo the head (base of ttaches te it at of the ear wherior aspec

tta, MOE) of beef and non-lacd of the eart of the ear (middle thir

.ttleay cting dairtating) in lactaaco the base of the ear (BOE L

eriletCEDE Stion of EXXaer administr

inge and needle and inser. Hold the syrechniquesal ttrenvy be made using the ttion ma) injecthe subcutaneous (SCT

o the head (base of the ear).tior aspecerin the postSuspension subcutaneously ile ertSCEDE EX

e packompletead the clease r P.e usingoreffell be wwehakS

echniquestion te injecte eyd the oppositarwwoal or ttren, valostrrtion in tttle the SC injecty cating dairtan beef and non-lacctI

.echniquestion tal injecttrenal or vostrr(base head the o tttaches ait e wherear the of taspectior erpost

or subcutaneous (SCechniques ftion tttle the injecty cating dairtan lactITHE EARASE OF TION FOR BAATADMINISTR

.d the base of the eararwoowt

.iallyerta-artrer ino not administ. Dtag holes

in in the postskally ttrenting vpoin

tion fadministrAA

.wibed belot the needle as descringe and needle and inser, oralostr, ree eyd the oppositarwoy be made using the t

ttachese it at of the ear wheror aspectingere administort befage insere pack

.echniquesy thetion in the base of the ear can be made b

they bmade be can ear) the of (base tion in the) injector subcutaneous (SC

o the head (base of the ear) while ttaches te it at of the ear wherior aspecerin in the posted inthe needle will be inserT. d the base of the eararwoally t

echniqueTTeal trenVVe: ase of the Earor Bffo

o the head (base of the ear) while o the loose ted in

Co

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f c

eft

iofu

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nd

Day

Two-Dose Regimen

A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required for the treatment of acute metritis in lactating cows. The mean plasma concentration vs. time profile for ceftiofur and desfuroylceftiofur-related metabolites for the 2-dose regimen in 12 cows is shown in Figure 9 below. The pharmacokinetic parameters for the 2-dose regimen are provided in Table 3.

Figure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two Subcutaneous

MICROBIOLOGY

Ceftiofur has demonstrated in vitro activity against Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, three major pathogens associated with BRD, and against Fusobacterium necrophorum and Porphyromonas levii associated with bovine foot rot. A summary of the susceptibility of BRD and foot rot pathogens is presented in Table 4. BRD isolates were obtained from cattle enrolled in a field study conducted in the United States that were diagnosed with BRD. Foot rot isolates were obtained from cattle enrolled in a field study conducted in the United States and Canada that were diagnosed with foot rot. Susceptibility testing was conducted according to the Clinical and Laboratory Standards Institute (CLSI) M7-A3 and M11-A6 standards for BRD and foot rot isolates, respectively.

Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a single administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility data, the following breakpoints are recommended for BRD pathogens by CLSI.

EFFECTIVENESS

A field dose confirmation study for the treatment of BRD evaluated the effectiveness of 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 bacterial component of BRD under field conditions. All treatments were administered subcutaneously in the middle third of the posterior aspect of the ear. Cattle were clinically evaluated on Days 2 to 4, 14 and 28 and were observed on all other study days. The 3.0 mg CE/lb (6.6 mg CE/kg) BW EXCEDE Sterile Suspension dose significantly (p ≤0.05) increased Day 14 treatment success rate, defined as animals that did not require any ancillary treatment and had a rectal temperature of <104°F, normal respiration index, and had no or mild depression on that day. The effectiveness of a single dose of EXCEDE Sterile Suspension for the control of BRD in feedlot cattle was evaluated in a nine-location field effectiveness study. In addition to standard processing on arrival at feedlots, cattle (n=3911) considered to be at high risk for BRD were assigned to one of four arrival treatments, including EXCEDE Sterile Suspension at 2.0 or 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) BW or negative control. Effectiveness evaluation was based on the incidence of clinical BRD within 28 days following arrival processing. Administration of a single dose of EXCEDE Sterile Suspension administered subcutaneously in the middle third of the posterior aspect of the ear at arrival processing significantly reduced the incidence of BRD in high-risk feedlot cattle in the 28-day period after arrival processing compared to negative controls. Base of the ear administration (beef and non-lactating dairy cattle) and middle third of the ear administration (lactating dairy cattle) were compared to the middle third of the ear pharmacoki netic data for beef and non-lactating dairy cattle and were found to be therapeutically equivalent. The effectiveness of EXCEDE Sterile Suspension for the treatment of bovine foot rot was evaluated in a six-location field effectiveness study. Cattle diagnosed with bovine foot rot were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg CE/kg) dBW or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days post-treatment for treatment success, which was based on defined decreases in lesion, swelling and lameness scores. A total of 169 beef and dairy cattle were included in the analysis. There was a statistically significant difference (p = 0.0054) in treatment success for EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal discharge and a rectal temperature of ≥ 103 °F were enrolled in the study and treated with either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle control, administered approximately 72 hours apart at the base of opposite ears. At 14 days post-treatment, each cow remaining in the study was examined and rectal temperature and vaginal discharge score were recorded. Cows with a non-fetid discharge, and a rectal temperature < 103 °F, and that did not require alternate (“escape”) therapy during the 14_day observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001) in EXCEDE-treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings determined the probable cause of death to be intra-arterial injection.

ANIMAL SAFETY

Systemic Safety Studies

After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile Suspension), ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate to evaluate the systemic safety of EXCEDE Sterile Suspension. Results from a five-day tolerance study conducted with ceftiofur sodium in normal feeder calves indicated that ceftiofur was well tolerated at 25 mg CE/lb/day for five consecutive days, approx-imately 8 times the approved dose of EXCEDE Sterile Suspension 3.0 mg CE/lb (6.6 mg 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 administered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 or 10 mg CE/lb/day thus, evaluating up to 3.3 times the approved dose of EXCEDE Sterile Suspension of 3.0 mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, indicating that ceftiofur has a wide margin of safety when injected intramuscularly into feeder calves. Local tissue tolerance to subcutaneous injection of EXCEDE Sterile Suspension in the posterior ear of cattle was evaluated in a separate study. The systemic safety of ceftiofur concentrations resulting from product administration at the base of the ear was established via a pharmacokinetic comparison of the two routes of administration (base of the ear versus middle third of the ear). Based upon the results of this relative bioavailability study, it was determined that the two routes of administration are therapeutically equivalent. To support systemic target animal safety for the 2-dose metritis regimen, five projected daily doses of NAXCEL Sterile Powder (ceftiofur sodium) at 2.2 mg/kg BW were compared pharmacokinetically with EXCEDE administered 2 times at a 72 hour interval at 6.6 mg/kg BW. The peak concentration (Cmax) and the extent of exposure (AUC) after two doses of EXCEDE were statistically no higher than the exposure following five daily doses of NAXCEL Sterile Powder in beef cattle.Investigation of Intra-Arterial and Intravenous Injection

In approximately 6000 animals enrolled in the BRD clinical studies, nine animals died following injection of EXCEDE Sterile Suspension. All deaths were within 30 minutes of the time of injection. The exact cause was confirmed in three animals. These deaths resulted from inadvertent intra-arterial injection of this oil-based suspension into one of the two major auricular (ear) arteries. Intra-arterial injection at this location resulted in direct administration of the oil-based formulation into the arterial blood supply of the brain resulting in embolism and death. Since intra-arterial injection was confirmed in three animals that died following injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-arterial injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Two heifers (body weight approximately 225 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE Sterile Suspension in the middle auricular artery. Both heifers collapsed immediately and died within approximately eight minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will result in death and must be avoided. Since subcutaneous injection in the ear may potentially result in inadvertent intravenous administration of an injectable product, the consequences of purposeful intravenous injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Three heifers and three steers (body weight range 197-223 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE Sterile Suspension in the jugular vein and were monitored for adverse effects following injection. One steer and one heifer had transient (2 to 5 minutes) increases in heart rate without any other untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile Suspension is an unacceptable route of administration.Safety Studies in Beef Cattle

Middle of the ear injection: A study was designed and conducted to specifically address tissue tolerance in cattle when EXCEDE Sterile Suspension was administered as a single subcutaneous injection into the posterior aspect of the ear of cattle at the recommended dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Results from this study indicate that the subcutaneous injection of EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial increase in thickness is attributed to the space required for the volume of injected material. Additional increases in thickness were observed through Day 14 after injection. After Day 14, post injection ear thickness decreased in all animals. One animal carried an injected ear in a drooping position for 7 days post injection. At necropsy, subcutaneous areas of discoloration and some foci of hemorrhage were observed in ears of injected cattle. The discoloration was markedly reduced in size by the end of the study. Ears are inedible tissues in the US (9 CFR 301.2). No signs of irritation were observed on the edible portions of the carcass around the base of the ear. The local tolerance of the ear of cattle to a single subcutaneous injection of EXCEDE Sterile Suspension was also evaluated in a large multi-location effectiveness study. None of the 1927 animals treated with EXCEDE Sterile Suspension were removed from this trial due to ear irritation although swelling was noted at some injection sites. Leak back and/or bleeding from the injection site was observed in a small fraction of the treated animals immediately after administration. It was concluded that administration of EXCEDE Sterile Suspension in the posterior aspect of the ear was well tolerated and was acceptable under feedlot conditions. A study evaluated the 56-day feedlot performance of beef steers administered EXCEDE Sterile Suspension alone, EXCEDE Sterile Suspension with a growth promoting implant, growth promoting implant alone, or neither product, in a total of 207 Angus and Angus

cross-bred steers. The administration of EXCEDE Sterile Suspension in the posterior aspof the ear with or without growth promoting implants was well tolerated by cattle andnot adversely affect feedlot cattle performance. Based upon the results of this study, location of implants administered after EXCEDE Sterile Suspension may need toadjusted slightly within the boundaries of the middle third of the ear in some animals. Base of the ear injection: The local tolerance of the ear to a single subcutaneous injection at the base of the eaEXCEDE Sterile Suspension was evaluated in a multi-location field study in 2926 beef catNormal restraint was adequate for adminis tration of EXCEDE Sterile Suspension for 99of cattle. No post injection problems (exces sive bleeding or leak back) were obserin 99.8% of cattle. On Days 28 and 56 post-injec tion, 97.8% and 98.9% of the cattle “normal” (no observed swelling) ears. In a residue study, 72 beef cattle were injected in the base of the ear with EXCEDE SteSuspension at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Injection sites were obserdaily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for swelling drooping, and evaluated grossly at necropsy, using skinning and trimming procedusimilar to slaughterhouse practices. All animals had injection site swelling during study; swelling resolved prior to euthanasia in 23 of 72 animals. None of the animshowed ear drooping. At necropsy, signs of inflammation (hemorrhage, congestion, firmness of tissue) and presence of drug material were seen in the area around injection site and on the carcass. At 13 days post-injection, gross lesions were found in inedible portions of the base of the ear in all 18 animals, and in the exposed carcass tisin 11 of 18 animals. The ventral base of the ear injection technique was evaluated in a conditions of study in 200 beef cattle. Each animal received a single injection of EXCEDE SteSuspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral injecttechnique. Normal restraint was adequate for 95.5% of animals in the study. Injection scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28, respectively. Oanimal had an unusually large swelling on Day 7 which reduced to a size comparableother study animals by Day 14. Safety Studies in Lactating Dairy Cattle

The local tolerance of the ear to a single subcutaneous injec tion at the base of the eaEXCEDE Sterile Suspension was evaluated in a multi-location field study in 114 adult dcattle. Successful injection in the base of the ear was achieved in 97.4% of cattle using norfacilities and restraint equipment. No leak back or excessive bleeding was observed fol lowinjection for 99.1% of cattle, with injection volumes ranging from 15 to 30 mL. On Daysand 56 following injection of EXCEDE Sterile Suspension in the base of the ear, 95.6% 100% of ears, respectively, were observed as normal with no injection site swelling. In a residue study, six dairy cows were injected in the base of the ear at a dose rate ofmg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension. No animals exhibited droopears at any time after treatment but all animals had signs of swelling at the injection sitall observation times after treatment. Cows were slaughtered 10 days after injectionnecropsy, all six cows showed evidence of injection site inflammation (discoloration oftissue/fascia) and four of six cows had discoloration of tissue dor sal and posterior to thecanal on the carcass. In addition to discoloration, tan nodules and a milky white fexudate were also present at the sectioned surface. Injection site safety for base of the ear administration was evaluated in the meteffectiveness study described above. Normal restraint was adequate for ≥ 97.8%injections administered. Injection site scores were normal in 50.3%, 73.2%, and 96.4% or 3, 11, and 54±3 days after the second injection, respectively. The ventral and rostral base of the ear injection techniques were compared with toward the opposite eye technique in a conditions of use study in 197 lactating dairy catNormal restraint was adequate for 89.8% (ventral), 98% (rostral), and 100% (opposite eof animals in the study. Injection site scores were normal for 32% (rostral), 46.9% (ventand 47.9% (opposite eye) of cattle on Day 14, and 73% (rostral), 87.8% (ventral), and 64(opposite eye) of cattle on Day 28, respectively.

TISSUE AND MILK RESIDUE DEPLETION

A radiolabeled residue metabolism study established tolerances for ceftiofur residin cattle kidney, liver and muscle. A separate study established the tolerance for ceftioresidues in milk. The tolerances for ceftiofur residues are 0.4 ppm in kidney, 2.0 ppm in li1.0 ppm in muscle and 0.1 ppm in milk. A pivotal tissue residue decline study was conducted in dairy cattle. In this study, coreceived a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur residues in tisswere less than the tolerances for ceftiofur residues in tissues such as the kidney, liver muscle by 13 days after dosing. These data collectively support a 13-day pre-slaughwithdrawal period. A pivotal milk residue decline study was conducted in lactating dairy cattle. In study, cows received a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftioresidues in milk were less than tolerances at all time points after treatment. These dcollectively support that no milk discard period is required for this product.Two-Dose Residue Decline Studies A pivotal tissue residue decline study was conducted in dairy cattle. In this study, coreceived two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval betwinjections. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residin the kidney by 13 days after the second dose. These data collectively continue to suppa 13-day pre-slaughter withdrawal period after the last dose. A pivotal milk residue decline study was conducted in lactating dairy cattle. In study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hinterval between injections. Milk residue decline data from this study supports that no mdiscard period is required for this product.

STORAGE CONDITIONS

Store at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before us Contents should be used within 12 weeks after the first dose is removed.

HOW SUPPLIED

EXCEDE Sterile Suspension is available in the following package sizes: 100 mL vial 250 mL vial

NADA #141-209, Approved by FDA

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

Revised: December 2011

Co

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desfuroylceftiofur metabolites calculated after a single subcutaneous administration

third of the ear or the base of the ear.

Cmax (μg CE/mL) = maximum plasma concentration (in μg CE/mL).tmax (h) = the time after injection when Cmax occurs (in hours).AUC0-LOQ

of injection to the limit of quantitation of the assay (0.15 μg CE/mL).t>0.2,

model (h) = the time plasma concentrations remain above 0.2 μg CE/mL

(in hours), estimated using compartmental pharmacokinetic techniques.

t>0.2, nca (h) = the time plasma concentrations remain above 0.2 μg CE/mL (in hours), estimated using noncompartmental pharmacokinetic techniques.

t1/2 (h) = terminal phase biological half life (in hours)NE = Not estimated

Pharmacokinetic

Parameter

Beef - Middle Third

of the Ear Mean

Value ± Standard

Deviation

Beef - Base

of the Ear Mean

Value ± Standard

Deviation

Dairy Cow - Base

of the Ear Mean

Value ± Standard

Deviation

Cmax (μg CE/mL) 6.90 ± 2.68 6.39 ± 1.79 4.44 ± 1.65

tmax (h) 12.0 ± 6.2 19.8 ± 5.81 19.00 ± 8.02

AUC0-LOQ 376 ± 66.1 412 ± 67.3 313 ± 85.5

t>0.2, model (h) 183 ± 40.8 NE NE

t>0.2, nca (h) 246 ± 48.5 218 ± 45.5 205 ± 35.7

t½ (h) 62.3 ± 13.5 40.7 ± 11.2 43.92 ± 9.84

PK Parameter Mean ± Standard Deviation

AUC0-LOQ 651 ± 119

t½ (h) 55.7 ± 4.84

t>0.2 (h) 341 ± 34.0

Tmax (h) 77.1 ± 33.4

Cmax (μg/mL) 5.98 ± 2.51

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

pathogens isolated from cattle with naturally occurring BRD or foot rot.

Indicated pathogenYear of

isolation

Number of

isolates

MIC ** MIC ** MIC range

Mannheimia haemolytica 1996 to 1997 75 0.008 0.015 0.001 to 0.015

Pasteurella multocida 1996 to 1997 43 0.004 0.004 0.001 to 0.015

Histophilus somni 1996 to 1997 11 0.004 0.004 0.002 to 0.015

Fusobacterium necrophorum 2006 to 2007 148 ≤ 0.25 0.5 ≤ 0.25 to >128

Porphyromonas levii 2006 to 2007 141 ≤ 0.25 2.0 ≤ 0.25 to 16

* The correlation between in vitro susceptibility data and clinical effectiveness is unknown.** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.

Table 5. CLSI-accepted interpretive criteria* for ceftiofur against cattle

respiratory pathogens.

PathogenDisk

potency

Zone diameter

(mm)

MIC breakpoint

S I R S I R

Mannheimia haemolytica Pasteurella multocida Histophilus somni

30 μg ≥ 21 18 to 20 ≤ 17 ≤ 2.0 4.0 ≥ 8.0

S – Susceptible I – Intermediate R – Resistant

* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to determine antimicrobial susceptibility. Interpretive criteria for b i f t t th h t b t bli h d

Distributed byPharmacia & Upjohn CompanyDivision of Pfizer Inc, NY, NY 10017

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