EXCEDE for Lactating Dairy Cows: Overview of Research Supporting a 2-Dose Regimen for Treatment of Metritis

Transcription

1 EXD12001 February 2012 for Lactatg Dairy Cows: Overview Research Supportg a 2-Dose Regimen for Treatment Metritis Pfizer Animal Health Pfizer Inc. Madison, NJ A 2-dose regimen provides effective treatment acute metritis lactatg dairy cows, with no milk discard. Summary A 2-dose regimen Sterile Suspension (ceftiur) was recently approved for treatment acute metritis (0-10 days postpartum) lactatg dairy cows. A study characterized pharmacoketics 2 treatments given 3 days apart, with each dose admistered at rate 3 mg CE/lb BW. # Two treatments with provided plasma drug concentrations comparable to a 5-day regimen ceftiur (1 mg CE/lb BW/day). The secondary peak plasma levels likely helps achieve higher longer drug concentrations utere tissues. An extensive 15-site clical study evaluated efficacy a 2-dose regimen for treatment metritis lactatg dairy cows. # A significantly greater (P < ) metritis cure rate was achieved cows treated with (74.3%) vs non-medicated control cows (55.3%). # Cows treated with demonstrated significantly lower (P ) rectal temperatures than controls for 5-6 days post-treatment. A milk residue study confirmed that a 2-dose regimen can be safely admistered to lactatg dairy cows with no milk discard. is highly effective for treatment acute postpartum metritis dairy cows. M etritis is an flammation uterus caused by bacterial fection, is a common, costly, even life-threateng disease dairy cows. Clical metritis most commonly occurs first 10 days post-calvg, affected cows may subsequently exhibit poor reproductive performance with irregular estrous cycles, lower conception rates, greater tervals from calvg to pregnancy. Clical metritis is characterized by fever, fetid vulvar discharge, depression, appetence, a uterus with excess fluid lackg tone. The literature demonstrates that fection uterus with Escherichia coli appears to predispose animals for subsequent fection with or bacteria that furr contribute to condition. 1 An average case metritis is estimated to cost dairy producers between $304 $354 due to cullg, reduced milk production fertility/ reproductive performance, treatment costs, milk discard. 2 The disease can be very difficult

2 Dairy producers prefer for antimicrobial rapy because it can be used lactatg cows with no milk discard. A sgle dose would likely be sufficient for treatment acute metritis. to treat, treatment choice has been a 5-day regimen EXCENEL RTU (ceftiur HCl) plus appropriate supportive rapy. Sterile Suspension (ceftiur crystalle free acid) is potent sgle-dose treatment for bove respiratory disease foot rot lactatg dairy cattle. Furrmore, dairy producers ten prefer because it can be used with no milk discard. provides demonstrated efficacy ceftiur a convenient extended-rapy formulation designed for SC admistration at base ear lactatg dairy cows at a dose 3 mg ceftiur equivalents (CE) per lb body weight (BW) (or 1.5 ml /100 lb BW). As result an extensive research development program conducted by Pfizer scientists, a 2-dose regimen has been recently approved for treatment acute metritis (0-10 days postpartum) lactatg dairy cows. Summaries studies that led to new metritis dication for follow, highlightg rationale, efficacy, safety this significant ra peutic advance for dairy veterarians ir clients. Pharmacology The pharmacoketic rationale for usg a 2-dose regimen treatment acute metritis was established by studies that vestigated fate ceftiur dairy cows. Sgle-dose pharmacoketics In an early study, ceftiur concentrations utere tissues (caruncle) were compared after dairy cows received eir a sgle dose (3 mg CE/lb BW) or 5 sequential daily doses conventional ceftiur (EXCENEL RTU, 1 mg CE/lb BW/day). 3 Caruncle tissue was assayed for ceftiur concentration at 1, 3, 5 days after itial dose admistration. A ceftiur mimum hibitory concentration (MIC) 0.2 µg/ml has ten been used for bacterial respiratory pathogens susceptible to ceftiur, a MIC 0.5 µg/ml has been determed for many E. coli isolates volved metritis cases. Results summarized Figure 1 show that ceftiur concentrations caruncle fell below 0.5 µg/g by day 3 for cows treated with a sgle dose, approached Caruncle drug concentration (µg/g) Excede (1 dose) Excenel RTU (5 doses) 0.5 µg/g 0.2 µg/g 1 3 Days after first dose ab P 0.05 Figure 1 Ceftiur/metabolite concentration utere caruncle tissue after a sgle dose (3 mg CE/lb BW) or 5 sequential daily doses EXCENEL RTU (1 mg CE/lb BW). 0.2 µg/g by day 5. In contrast, utere tissue concentrations gradually accumulated cows that received 5 doses ceftiur remaed near or above MIC benchmarks 0.2 to 0.5 µg/g. These outcomes suggested that a sgle dose would likely be sufficient for treatment acute metritis that a second dose after 3 days might provide additional coverage required for efficacy. Results this study or research thus prompted vestigation pharmacoketic behavior a 2-dose regimen for metritis rapy. Two-dose pharmacoketics A study was conducted to characterize pharmacoketics 2 treatments given 3 days apart, with each dose admistered at rate 3 mg CE/lb BW. 4 The study volved 12 lactatg Holste dairy cows that received as a SC jection at base ear, with second dose admistered base opposite ear approximately 72 hours after first jection. Blood samples were obtaed prior to first jection at specified time pots up to 14 days after first jection, assayed to determe concentrations ceftiur active metabolites. Pharmacoketic parameters calculated from collected data are summarized Table 1, Figure 2 shows resultg plasma concentra - tions observed over course study. Figure 2 also cludes projected plasma levels for 5 sequential daily doses conventional ceftiur (EXCENEL RTU) when admistered a b 5 2

3 at 1 mg CE/lb BW. Investigators were most terested estimates maximum drug concentration (Cmax) area under drug depletion curve (AUC). Study results dicated that ceftiur exposure lactatg cows followg 2 doses (3 mg CE/lb BW) admistered 72 hours apart was statistically similar to that provided by 5 sequential daily doses ceftiur (1 mg CE/lb BW). The second dose provided a secondary peak plasma that would likely help achieve higher longer concentrations active drug utere tissues. These results provided pharmacoketic rationale to suggest that 2 doses could provide efficacy agast acute metritis lactatg dairy cows. Table 1 Mean pharmacoketic parameters ceftiur cows when admistered as 2 doses 3 mg CE/lb BW 3 days apart. Plasma drug concentration (µg/ml) Cmax (µg/ml) 5.98 AUC0-LOQ (µg h/ml) 651 tmax 77.1 t1/ t> C max = maximum plasma concentration; AUC 0-LOQ = area under plasma concentration vs time curve from time jection to limit quantitation (LOQ) assay; t max = time after jection when C max occurs; t 1/2 = termal phase biological half life; t >0.2 = time plasma concentrations rema above 0.2 μg. Excede (2 doses) Excenel RTU (5 doses) Days after first dose Figure 2 Ceftiur/metabolite concentration (LS means) plasma after 2 doses (3 mg CE/lb BW, 3 d apart) or 5 sequential daily doses EXCENEL RTU (1 mg CE/lb BW). Metritis Efficacy: Experiment Design An extensive clical field study evaluated effectiveness a 2-dose regimen for treatment acute metritis lactatg dairy cows under commercial production conditions. 5 The multicentric study was conducted at 15 dairies West, Norast, Midwest, Southwest regions US, with an identical experiment protocol followed at each site. The study volved 1023 lactatg Holste dairy cows that had calved with 10 days study itiation. Cows were managed accordg to normal husbry, health, management practices each particular dairy operation. Cows cluded study were housed with cows not enrolled study ten moved between pens consistent with normal animal flow dairy, while at some sites cows remaed fresh-cow pen. Cow were enrolled romized-block study (day 0) when y demonstrated clical signs acute postpartum metritis defed as a fetid vagal discharge (th, serous, or watery, red/pk to brown color, with or without pieces necrotic tissue) rectal temperature 103 F. Pairs qualifyg animals were blocked based on order--entry with dairies without regard to parity, romly assigned to eir 2 treatment groups: (2 doses): 1.5 ml/100 lb BW (3 mg CE/lb BW) admistered SC at base ear on day 0, followed by a second SC dose at base opposite ear 3 days later (day 3) (n=514); Non-medicated control (vehicle; 2 doses): 1.5 ml/100 lb BW admistered SC at base ear on day 0, followed by a second SC dose at base opposite ear 3 days later (day 3) (n=509). Each cow was observed daily on study days 1 to 13 for any abnormal clical signs, rectal temperature was recorded on days 1 to 5 or 6. On study day 5/6, each cow was examed to determe if severe clical signs acute postpartum metritis necessitated removal from study. Cows removed from study for worseng metritis durg days 1 to 14 were classified as a treatment failure were admistered alternate rapy. On day 14, each remag cow was examed, rectal Plasma levels from 2 doses were similar to 5 sequential daily doses EXCENEL RTU. The 2nd dose provides a secondary plasma peak that helps achieve effective drug levels utere tissues. 3

4 Cure rate (%) b ab P Rectal temperature ( F) *P Control Excede Two treatments successfully resolved metritis 74.3% clical cases. Cows treated with had lower rectal temperatures than controls for 5-6 days after treatment a Control Excede Figure 3 Metritis cure rate (back-transformed LS means) 14 days after itial dose; 2 doses (3 mg CE/lb BW, 3 d apart) vs non-medicated vehicle (control). temperature recorded, vagal discharge was scored (0 to 4 scale, 0=no discharge, 4=fetid discharge) to determe metritis cure or treatment failure. The condition cow ears (where treatments were admistered) ease/success base--ear SC admistration procedure were also assessed on days 5/6, 14, 57 (study conclusion). Personnel conductg all clical evaluations were blded to treatment assignments. Data collected durg study were statis - tically analyzed usg appropriate stard methods (cludg computation least squares means), with significance declared when P The primary parameter was cure rate defed as a non-fetid vagal discharge score (<4) rectal temperature <103 F on day 14. Metritis Efficacy: Results A total 41 cows were not cluded statis - tical analyses for treatment efficacy due to medical events unrelated to metritis (25 cows) or protocol deviations (16 cows). Two treatments admistered 3 days apart proved successful resolvg clical metritis. As shown Figure 3, a significantly greater (P < ) metritis cure rate was achieved cows treated with (74.3%) than control cows that received non-medicated vehicle (55.3%). Thus, improved cure rate by 34.4% compared to controls. also favorably impacted rectal temperature cows with clical metritis (Figure * * Study day (days post-treatment) Figure 4 Rectal temperature (LS means) on study days 0 to 5/6; 2 doses (3 mg CE/lb BW, 3 d apart) vs non-medicated vehicle (control). 4). Cows treated with demonstrated significantly lower (P ) rectal temperatures than controls on each days 1 to 5/6. These results suggest that medicated cows rapidly responded to rapy. Data collected regardg treatment admistration at base--ear SC site were also summarized. Equipment routely used to restra cows (neck lock-up halter) was adequate to allow jection at base ear for 97.8% admistered jections, 96.8% all jections were completed without need for re-jection due to animal movement, no post-jection problems (bleedg /or leakback) were observed 78.5% doses admistered. Normal ear carriage (vs droopy ears) was observed about 98% all ears at day 14, no apparent differences existed between treatment groups regard to jection site irritation (mostly swellg) at day 57 (>96% normal). Results this study demonstrate that is effective for treatment acute metritis lactatg dairy cows occurrg with 10 days calvg. The 2-dose regimen admistered SC at base ears quickly lowered rectal temperatures cured metritis 74.3% affected cows. Milk Discard Tissue Residue Studies * 5/6 The advent a 2-dose regimen for lactatg dairy cows raised milk discard tissue residue implications that required vestigation before FDA approval could be attaed. * * 4

5 The origal labelg for sgle-dose admistration dictated a 13-day pre-slaughter withdrawal period, but no milk discard period (0-day withdrawal). Additional studies were conducted by Pfizer scientists to evaluate depletion ceftiur metabolites milk body tissues followg 2 doses (3 mg CE/lb BW) admistered 3 days apart via SC admistration at base ear lactatg dairy cows. A milk residue study monitored drug levels for up to 216 hours (9 days) after 2 doses 40 lactatg Holste cows. 6 The average peak level ceftiur metabolites milk was ppm at 108 hours post-treatment, less than half tolerance level 0.1 ppm, with all or average levels below this peak value. Sce clearly does not accumulate milk, 2-dose regimen retas no milk discard benefit that pro ducers desire. Thus, 2-dose regimen can be safely admistered to lactatg dairy cows with no milk discard. Anor study addressed ceftiur residues body tissues cattle slaughtered for human consumption. 7 Drug levels kidneys ( target tissue for such evaluations) were monitored for up to 16 days after 2-dose regimen was admistered to 16 lactatg Holste cows. No drug could be detected at 12 or 16 days after admistration second dose. Thus, existg 13-day pre-slaughter withdrawal period was aga deemed appropriate for 2-dose regimen (13 days after admistration second dose). Human Safety As part pre-approval safety evaluation process, FDA considers potential impact on human health antimicrobial drugs used food-producg animals. The FDA believes that human exposure through gestion antimicrobial resistant bacteria from animalderived foods represents most significant pathway for human exposure to bacteria that have emerged or been selected as a consequence antimicrobial drug use animals. Thus, a risk assessment is required for all antimicrobial drugs used food-producg animals. To address se concerns, was given a prescription-only (Rx) marketg status, restricted for parenteral jection only to dividual animals with clically recognizable symptoms metritis, designated for contued monitorg National Antimicrobial Resistance Monitorg System. Based on additional research, FDA found re was no need to determe a microbiological acceptable daily take sce amount microbiologically active residues that reach human colon would most likely not cause adverse effects on testal flora consumers. Important Safety Information: As with all drugs, use Sterile Suspension is contradicated animals previously found to be hypersensitive to drug. Though safe cattle when properly admistered, advertent tra-arterial jection ear is possible is fatal. has a pre-slaughter with - drawal period 13 days. Conclusions An extensive body scientific research has resulted FDA approval a 2-dose regimen for treatment acute postpartum metritis lactatg dairy cows. A pharmaco - ketics study showed that a 2-dose regimen provides a secondary drug peak plasma, supportg rationale for higher longer concentrations ceftiur its metabolites utere tissues. A subsequent 15- site clical field study volvg 1023 lactatg dairy cows demonstrated that a 2-dose regimen quickly reduced rectal temperatures cured metritis 74.3% sick cows compared to a cure rate only 55.3% for non-medicated control animals. Subcutaneous jection via base--ear route was readily accomplished, almost all jection site reactions were transient resolved with time. Additional research confirmed that 2-dose regimen can be used lactatg dairy cows with no milk discard, a 13-day pre-slaughter withdrawal period was reconfirmed. A 2-dose regimen fers dairy practitioners ir clients a valuable new tool for treatg metritis lactatg dairy cows, thus circumventg fancial losses due to poor performance mortality se very highvalue animals. A 2-dose regimen can be safely admistered to dairy cows with no milk discard. A 2-dose regimen fers a valuable new tool for treatg metritis lactatg dairy cows. 5

6 6 (Ceftiur Crystalle Free Acid) Sterile Suspension t CAUTION dairy cattle. Not for use calves to be processed for veal. ear where it attaches to head (base ear) beef non-lactatg middle third posterior to head (base ear) lactatg dairy cattle. For subcutaneous jection For subcutaneous jection posterior aspect ear where it attaches Federal (USA) law restricts this drug to use by or on order a licensed Sterile Suspension ystalle Free Ceftiur Cry (C dairy cattle. Not for use calves to be processed for veal. ear where it attaches to head (base ear) beef non-lactatg aspect ear or posterior aspect to head (base ear) lactatg dairy cattle. For subcutaneous jection posterior aspect ear where it at Federal (USA) law restricts this drug to use by or on order a licensed Sterile Suspension ) id) e Aci massage toward base ear. ear where it attaches to head (base ear) beef non-lactatg posterior aspect to head (base ear) lactatg dairy cattle. For subcutaneous jection ttaches Federal (USA) law restricts this drug to use by or on order a licensed middle third posterior aspect ear. Figure 2. Subcutaneous admistration Sterile Suspension massage toward base ear. middle third posterior aspect ear. Figure 2. Subcutaneous admistration Sterile Suspension Figure 2. Subcutaneous admistration Sterile Suspension sk caudal aspect base ear. admistered rostrally toward eye on same side head to loose Figure 6. Diagram head showg direction for base ear jections sk caudal aspect base ear. admistered rostrally toward eye on same side head to loose Figure 6. Diagram head showg direction for base ear jections sk caudal aspect base ear. admistered rostrally toward eye on same side head to loose Figure 6. Diagram head showg direction for base ear jections admistered rostrally toward eye on same side head to loose Figure 6. Diagram head showg direction for base ear jections DESCRIPTION veterarian. agast Grambroad a is which ceftiur, acid free Sterile Suspension is a ready-to-use formulation that contas crystalle stras. Like or positive Gram-negative bacteria cludg ß-lactamase-producg hibition cell wall synsis. cephalospors, ceftiur is bactericidal, Figure 1. Structure ceftiur crystalle free acid: cottonseed oil based suspension. acid equivalent to 200 mg ceftiur, a caprylic/capric triglyceride (Miglyo Each ml this ready-to-use sterile suspension contas ceftiur crystalle free Federal (USA) law restricts this drug to use by or on order a licensed antibiotic cephalospor spectrum broad Sterile Suspension is a ready-to-use formulation that contas crystalle positive Gram-negative bacteria cludg ß-lactamase-producg cephalospors, ceftiur is bactericidal, vitro, resultg from Figure 1. Structure ceftiur crystalle free acid: acid equivalent to 200 mg ceftiur, a caprylic/capric triglyceride (Miglyo Each ml this ready-to-use sterile suspension contas ceftiur crystalle free active antibiotic Sterile Suspension is a ready-to-use formulation that contas crystalle positive Gram-negative bacteria cludg ß-lactamase-producg, resultg from acid equivalent to 200 mg ceftiur, a caprylic/capric triglyceride (Miglyol ) Each ml this ready-to-use sterile suspension contas ceftiur crystalle free Sterile Suspension to ear arteries is likely to be fatal. posterior ear recommended needle sertion locations. Admistration Figure 3. Diagram approximate locations major arteries Sterile Suspension to ear arteries is likely to be fatal. posterior ear recommended needle sertion locations. Admistration Figure 3. Diagram approximate locations major arteries Sterile Suspension to ear arteries is likely to be fatal. posterior ear recommended needle sertion locations. Admistration Figure 3. Diagram approximate locations major arteries Admistration for Base Ear: Ventral Technique serted to loose sk posterior aspect ear where it attaches to syrge are potg ventrally toward base ear. The needle will be Admistration for Base Ear: Ventral Technique serted to loose sk posterior aspect ear where it attaches to syrge are potg ventrally toward base ear. The needle will be Admistration for Base Ear: Ventral Technique serted to loose sk posterior aspect ear where it attaches to syrge are potg ventrally toward base ear. The needle will be serted to loose sk posterior aspect ear where it attaches to syrge are potg ventrally toward base 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-Amo-4-thiazolyl)-2-(methoxyimo)acetyl]amo]- 3-[[(2-furanylcarbonyl) Chemical name ceftiur crystalle free acid: cattle. Histophilus somni multocida, (BRD, shippg fever, pneumonia) associated with Sterile Suspension is dicated for treatment bove respiratory disease thio] methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene 2-carboxylic acid 7-[[2-(2-Amo-4-thiazolyl)-2-(methoxyimo)acetyl]amo]- 3-[[(2-furanylcarbonyl) Chemical name ceftiur crystalle free acid: lactatg beef, non-lactatg dairy, (BRD, shippg fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella Sterile Suspension is dicated for treatment bove respiratory disease 7-[[2-(2-Amo-4-thiazolyl)-2-(methoxyimo)acetyl]amo]- 3-[[(2-furanylcarbonyl) dairy lactatg Pasteurella Sterile Suspension is dicated for treatment bove respiratory disease base ear. when Figure 7. Diagram head showg direction base ear jections sert needle through cartilage ear. See Figure 7. attaches to head (base ear) while matag needle position. See Figure base ear. ventrally to loose admistered when Figure 7. Diagram head showg direction base ear jections sert needle through cartilage ear. See Figure 7. potg while ear) (base head attaches to head (base ear) while matag needle position. See Figure aspect caudal sk loose Figure 7. Diagram head showg direction base ear jections sert needle through cartilage ear. See Figure 7. not to taken be should Care ventrally. potg attaches to head (base ear) while matag needle position. See Figure 7. not 7. cattle. haemolytica, P. multocida, with M. beef non-lactatg dairy cattle which are at high risk developg BRD associated Sterile Suspension is also dicated for control respiratory disease beef, non-lactatg dairy, lactatg dairy cattle. Porphyromonas levii rot (terdigital necrobacillosis) associated with also is Suspension Sterile Treatment BRD bove foot rot DOSAGE dairy cattle. post-partum) associated with bacterial organisms susceptible to ceftiur lactatg Sterile Suspension is also dicated for treatment acute metritis (0-10 where it Admister as a sgle subcutaneous jection posterior aspect ear 100 lb BW). equivalents (CE)/lb (6.6 mg CE/kg) body weight (BW) attaches to head (base ear) to cattle at a dosage 3.0 mg ceftiur H. somni. beef non-lactatg dairy cattle which are at high risk developg BRD associated Sterile Suspension is also dicated for control respiratory disease beef, non-lactatg dairy, lactatg dairy cattle. rot (terdigital necrobacillosis) associated with Fusobacterium necrophorum bove treatment for dicated also Treatment BRD bove foot rot post-partum) associated with bacterial organisms susceptible to ceftiur lactatg Sterile Suspension is also dicated for treatment acute metritis (0-10 Admister as a sgle subcutaneous jection posterior aspect ear (1.5 ml sterile suspension per equivalents (CE)/lb (6.6 mg CE/kg) body weight (BW) ear) to cattle at a dosage 3.0 mg ceftiur beef non-lactatg dairy cattle which are at high risk developg BRD associated Sterile Suspension is also dicated for control respiratory disease Fusobacterium necrophorum foot bove post-partum) associated with bacterial organisms susceptible to ceftiur lactatg Sterile Suspension is also dicated for treatment acute metritis (0-10 days Admister as a sgle subcutaneous jection posterior aspect ear (1.5 ml sterile suspension per ear) to cattle at a dosage 3.0 mg ceftiur ADMINISTRATION FOR BASE OF THE EAR be made by rostral or ventral jection techniques. posterior aspect ear where it attaches to head (base ear) can In lactatg dairy cattle jection techniques for subcutaneous (SC) jection made by rostral, ventral or toward opposite eye jection techniques. In beef non-lactatg dairy cattle SC jection base ear can be ear where it attaches to head (base ear). admisterg well before usg. Shake ADMINISTRATION FOR BASE OF THE EAR be made by rostral or ventral jection techniques. posterior aspect ear where it attaches to head (base ear) can In lactatg dairy cattle jection techniques for subcutaneous (SC) jection made by rostral, ventral or toward opposite eye jection techniques. In beef non-lactatg dairy cattle SC jection base ear can be ear where it attaches to head (base ear). subcutaneously Suspension Sterile complete read Please well before usg. posterior aspect ear where it attaches to head (base ear) can In lactatg dairy cattle jection techniques for subcutaneous (SC) jection made by rostral, ventral or toward opposite eye jection techniques. In beef non-lactatg dairy cattle SC jection base ear can be aspect posterior before sert package CONTRAINDICATIONS pre As with all drugs, use Sterile Suspension is contradicated animals WARNINGS viously found to be hypersensitive to drug. CONTRAINDICATIONS As with all drugs, use Sterile Suspension is contradicated animals WARNINGS viously found to be hypersensitive to drug. As with all drugs, use Sterile Suspension is contradicated animals viously found to be hypersensitive to drug. As with all drugs, use Sterile Suspension is contradicated animals 100 lb BW). In beef non-lactatg dairy cattle, admis per 100 lb BW). aspect ear at a dosage 3.0 mg CE/lb (6.6 mg CE/kg) BW tered as a sgle subcutaneous Control BRD is observed, diagnosis should be reevaluated. Most animals will respond to treatment with three to five days. If no improvement (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). (base ear) to beef non-lactatg dairy cattle at a dosage aspect ear or posterior aspect ear where it attaches to head Admister as a subcutaneous jection eir middle third posterior at high risk devel effective for control respiratory disease beef non-lactatg dairy cattle Clical studies dicate that admistration Sterile Suspension is opg BRD. One or more followg factors typically In beef non-lactatg dairy cattle, Sterile Suspension may also be mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension subcutaneous jection middle third posterior is observed, diagnosis should be reevaluated. Most animals will respond to treatment with three to five days. If no improvement (1.5 ml sterile suspension per 100 lb BW). (base ear) to beef non-lactatg dairy cattle at a dosage 3.0 mg CE/lb aspect ear or posterior aspect ear where it attaches to head Admister as a subcutaneous jection eir middle third posterior effective for control respiratory disease beef non-lactatg dairy cattle Clical studies dicate that admistration Sterile Suspension is opg BRD. One or more followg factors typically Sterile Suspension may also be (1.5 ml sterile suspension posterior Most animals will respond to treatment with three to five days. If no improvement 3.0 mg CE/lb aspect ear or posterior aspect ear where it attaches to head Admister as a subcutaneous jection eir middle third posterior effective for control respiratory disease beef non-lactatg dairy cattle Clical studies dicate that admistration Sterile Suspension is opg BRD. One or more followg factors typically ventral techniques. Hold syrge needle sert needle as described below. The subcutaneous (SC) jection may be made usg toward opposite eye, rostral, or toward animal s opposite eye. See Figures 4 5. direction an imagary le that would pass through head pot Hold syrge needle behd ear to be dosed so needle syrge Admistration for Base Ear: Toward Opposite Eye Technique Do not admister Sterile Suspension neck. Deliver entire contents syrge. attaches to head (base ear) while matag this angle. See Figure 4. posterior aspect ear where it attaches to head (base ear). Figure 4. Subcutaneous admistration Sterile Suspension ventral techniques. Hold syrge needle sert needle as described below. The subcutaneous (SC) jection may be made usg toward opposite eye, rostral, or toward animal s opposite eye. See Figures 4 5. direction an imagary le that would pass through head Hold syrge needle behd ear to be dosed so needle syrge Admistration for Base Ear: Toward Opposite Eye Technique Do not admister Sterile Suspension neck. Deliver entire contents syrge. attaches to head (base ear) while matag this angle. See Figure 4. posterior aspect ear where it attaches to head (base ear). Figure 4. Subcutaneous admistration Sterile Suspension ventral techniques. Hold syrge needle sert needle as described below. The subcutaneous (SC) jection may be made usg toward opposite eye, rostral, or direction an imagary le that would pass through head Hold syrge needle behd ear to be dosed so needle syrge Admistration for Base Ear: Toward Opposite Eye Technique attaches to head (base ear) while matag this angle. See Figure 4. clothg. Sensitization sk may be avoided by wearg protective gloves. to sensitization. Avoid direct contact product with sk, eyes, mouth allergic reactions some Topical exposures to such antimicrobials, cludg ceftiur, may elicit mild to severe Penicills cephalospors can cause allergic reactions sensitized dividuals. exposure to this product. Persons with a known hypersensitivity to penicill or cephalospors should avoid reaction occurs (e.g., sk rash, hives, difficult breathg), seek medical attention. sk exposure, wash with soap water. Remove contamated clothg. If allergic In case accidental eye exposure, flush with water for 15 mutes. In case accidental report any adverse event please call formation. To obta a material safety data sheet please call To The material safety data sheet contas more detailed occupational safety posterior aspect ear where it attaches to head (base ear). Figure 4. Subcutaneous admistration Sterile Suspension KEEP OUT OF REACH OF CHILDREN. FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. clothg. Sensitization sk may be avoided by wearg protective gloves. to sensitization. Avoid direct contact product with sk, eyes, mouth allergic reactions some dividuals. Repeated Topical exposures to such antimicrobials, cludg ceftiur, may elicit mild to severe Penicills cephalospors can cause allergic reactions sensitized dividuals. exposure to this product. Persons with a known hypersensitivity to penicill or cephalospors should avoid reaction occurs (e.g., sk rash, hives, difficult breathg), seek medical attention. sk exposure, wash with soap water. Remove contamated clothg. If allergic In case accidental eye exposure, flush with water for 15 mutes. In case accidental report any adverse event please call formation. To obta a material safety data sheet please call To The material safety data sheet contas more detailed occupational safety KEEP OUT OF REACH OF CHILDREN. FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. clothg. Sensitization sk may be avoided by wearg protective gloves. to sensitization. Avoid direct contact product with sk, eyes, mouth dividuals. Repeated or prolonged exposure may lead Topical exposures to such antimicrobials, cludg ceftiur, may elicit mild to severe Penicills cephalospors can cause allergic reactions sensitized dividuals. Persons with a known hypersensitivity to penicill or cephalospors should avoid reaction occurs (e.g., sk rash, hives, difficult breathg), seek medical attention. sk exposure, wash with soap water. Remove contamated clothg. If allergic In case accidental eye exposure, flush with water for 15 mutes. In case accidental report any adverse event please call formation. To obta a material safety data sheet please call To The material safety data sheet contas more detailed occupational safety to sensitization. Avoid direct contact product with sk, eyes, mouth exposure may lead Topical exposures to such antimicrobials, cludg ceftiur, may elicit mild to severe Penicills cephalospors can cause allergic reactions sensitized dividuals. Persons with a known hypersensitivity to penicill or cephalospors should avoid sk exposure, wash with soap water. Remove contamated clothg. If allergic In case accidental eye exposure, flush with water for 15 mutes. In case accidental formation. To obta a material safety data sheet please call To The material safety data sheet contas more detailed occupational safety Cattle are from multiple farm origs, stops), cattle have had extended transport ambient temperature change from orig to arrival 30 F or more, cattle have had contued exposure to extremely wet or cold wear conditions, Treatment Acute Metritis procedures (such as castration, dehorng). cattle have experienced excessive shrk or excessive arrival processg Table 1. Dosg Schedule for Sterile Suspension. itial dose. this dose contra-lateral (opposite) ear approximately 72 hours followg 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Repeat it attaches to head (base ear) to lactatg dairy cattle at a dosage Admister as a subcutaneous jection posterior aspect ear where Cattle are from multiple farm origs, transport times (that may have cluded few if any ambient temperature change from orig to arrival 30 F or more, cattle have had contued exposure to extremely wet or cold wear conditions, procedures (such as castration, dehorng). cattle have experienced excessive shrk or excessive arrival processg Table 1. Dosg Schedule for Sterile Suspension. this dose contra-lateral (opposite) ear approximately 72 hours followg 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Repeat it attaches to head (base ear) to lactatg dairy cattle at a dosage Admister as a subcutaneous jection posterior aspect ear where any rest cattle have had contued exposure to extremely wet or cold wear conditions, cattle have experienced excessive shrk or excessive arrival processg this dose contra-lateral (opposite) ear approximately 72 hours followg 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Repeat it attaches to head (base ear) to lactatg dairy cattle at a dosage Admister as a subcutaneous jection posterior aspect ear where RESIDUE WARNINGS likely to result sudden death animal. towards opposite eye. Intra-arterial jection Sterile Suspension is Suspension via middle third ear jection or base ear jection directed Intra-arterial jection may occur durg admistration Sterile RESIDUE WARNINGS likely to result sudden death animal. towards opposite eye. Intra-arterial jection Sterile Suspension is Suspension via middle third ear jection or base ear jection directed Intra-arterial jection may occur durg admistration Sterile pre-slaughter withdrawal period is required after last treatment. Followg label use as eir a sgle-dose or 2-dose regimen, a 13-day milk discard period is required for this product. sgle-dose a eir as Followg label use admistration by unap Use dosages excess 3.0 mg CE/lb (6.6 mg CE/kg) BW or neck or tramuscular jection) may cause violative residues. proved routes (subcutaneous jection rumatg calves. A withdrawal period has not been established for this product pre- Do not use calves to be processed for veal. likely to result sudden death animal. towards opposite eye. Intra-arterial jection Sterile Suspension is Suspension via middle third ear jection or base ear jection directed Intra-arterial jection may occur durg admistration Sterile pre-slaughter withdrawal period is required after last treatment. Followg label use as eir a sgle-dose or 2-dose regimen, a 13-day milk discard period is required for this product. no regimen, 2-dose or sgle-dose Use dosages excess 3.0 mg CE/lb (6.6 mg CE/kg) BW or neck or tramuscular jection) may cause violative residues. proved routes (subcutaneous jection A withdrawal period has not been established for this product pre- Do not use calves to be processed for veal. towards opposite eye. Intra-arterial jection Sterile Suspension is Suspension via middle third ear jection or base ear jection directed Intra-arterial jection may occur durg admistration Sterile Weight Dose Volume (lb) (ml) Weight Dose Volume (lb) (ml) head (base ear). Sterile Suspension Figure 5. Injection location for subcutaneous admistration head (base ear). Sterile Suspension posterior aspect ear where it attaches to Figure 5. Injection location for subcutaneous admistration ear where it attaches to Figure 5. Injection location for subcutaneous admistration ANTIBACTERIAL WARNINGS PRECAUTIONS ment drug-resistant bacteria. likely to provide benefit to treated animals may crease risk develop Use antibacterial drugs absence a susceptible bacterial fection is un mimize ir occurrence. fections may result ear may ear, thickeng swellg (characterized by aseptic cellular filtrate) Followg subcutaneous jection open drag lesions a small percentage cattle. Injection volumes greater than 20 ml, middle third ear, may result least 13 days post admistration resultg trim loss edible tissue at slaughter. (base ear), areas discoloration signs flammation may persist at Followg jection posterior aspect ear where it attaches to head ANTIBACTERIAL WARNINGS PRECAUTIONS ment drug-resistant bacteria. likely to provide benefit to treated animals may crease risk develop Use antibacterial drugs absence a susceptible bacterial fection is un mimize ir occurrence. abscess formation. Attention to hygienic procedures can fections may result may occur. As with or parenteral jections, ear, thickeng swellg (characterized by aseptic cellular filtrate) Followg subcutaneous jection middle third open drag lesions a small percentage cattle. Injection volumes greater than 20 ml, middle third ear, may result least 13 days post admistration resultg trim loss edible tissue at slaughter. (base ear), areas discoloration signs flammation may persist at Followg jection posterior aspect ear where it attaches to head likely to provide benefit to treated animals may crease risk develop Use antibacterial drugs absence a susceptible bacterial fection is un abscess formation. Attention to hygienic procedures can jections, localized post-jection bacterial ear, thickeng swellg (characterized by aseptic cellular filtrate) aspect middle third posterior open drag lesions a small percentage cattle. Injection volumes greater than 20 ml, middle third ear, may result least 13 days post admistration resultg trim loss edible tissue at slaughter. (base ear), areas discoloration signs flammation may persist at Followg jection posterior aspect ear where it attaches to head - - abscess formation. Attention to hygienic procedures can bacterial ear, thickeng swellg (characterized by aseptic cellular filtrate) Injection volumes greater than 20 ml, middle third ear, may result least 13 days post admistration resultg trim loss edible tissue at slaughter. (base ear), areas discoloration signs flammation may persist at Followg jection posterior aspect ear where it attaches to head ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR ADMINISTRATION aspect ear, avoidg all blood vessels. See Figures 2 3. Deposit as a sgle subcutaneous cattle. admisterg Sterile Suspension subcutaneously posterior ear Shake well before usg. Please read complete package sert before tags or ear tag holes. Do not admister tra-arterially. will appear. When admistered correctly, a subcutaneous bleb Sterile Suspension ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR aspect ear, avoidg all blood vessels. See Figures 2 3. subcutaneous jection middle third posterior admisterg Sterile Suspension subcutaneously posterior ear Please read complete package sert before tags or ear tag holes. Do not admister tra-arterially. When admistered correctly, a subcutaneous bleb Sterile Suspension posterior admisterg Sterile Suspension subcutaneously posterior ear Please read complete package sert before When admistered correctly, a subcutaneous bleb Sterile Suspension Admistration for Base Ear: Toward Same Eye Technique or Rostral Direction toward eye on same side head. See Figures 5 6. pot direction an imagary le that would pass through head to head (base ear) while matag needle position. See Figure 6. Admistration for Base Ear: Toward Same Eye Technique or Rostral Direction toward eye on same side head. See Figures 5 6. pot direction an imagary le that would pass through head to head (base ear) while matag needle position. See Figure 6. ction tion for Admistration for Base Ear: Toward Same Eye Technique or Rostral Direction toward eye on same side head. See Figures 5 6. pot direction an imagary le that would pass through head to head (base ear) while matag needle position. See Figure 6. open drag lesions a small percentage cattle. ADVERSE EFFECTS lactation have not been determed. The effects ceftiur on bove reproductive performance, pregnancy, CLINICAL PHARMACOLOGY antibiotic or formulation durg any clical target animal safety studies. tra-arterial jection. No or adverse systemic effects were noted for eir cidence acute death (see ANIMAL SAFETY) confirmed to be result advertent sudden death animal. Durg conduct clical studies, re was a low opposite eye. Intra-arterial jection Sterile Suspension is likely to result via middle third ear jection or base ear jection directed towards Intra-arterial jection may occur durg admistration Sterile Suspension hydrochloride (EXCENEL Ceftiur admistered as eir ceftiur sodium (NAXCEL open drag lesions a small percentage cattle. ADVERSE EFFECTS lactation have not been determed. The effects ceftiur on bove reproductive performance, pregnancy, CLINICAL PHARMACOLOGY antibiotic or formulation durg any clical target animal safety studies. tra-arterial jection. No or adverse systemic effects were noted for eir cidence acute death (see ANIMAL SAFETY) confirmed to be result advertent sudden death animal. Durg conduct clical studies, re was a low opposite eye. Intra-arterial jection Sterile Suspension is likely to result via middle third ear jection or base ear jection directed towards Intra-arterial jection may occur durg admistration Sterile Suspension RTU Sterile Suspension), or ceftiur crystalle free acid hydrochloride (EXCENEL Ceftiur admistered as eir ceftiur sodium (NAXCEL open drag lesions a small percentage cattle. The effects ceftiur on bove reproductive performance, pregnancy, antibiotic or formulation durg any clical target animal safety studies. tra-arterial jection. No or adverse systemic effects were noted for eir cidence acute death (see ANIMAL SAFETY) confirmed to be result advertent sudden death animal. Durg conduct clical studies, re was a low opposite eye. Intra-arterial jection Sterile Suspension is likely to result via middle third ear jection or base ear jection directed towards Intra-arterial jection may occur durg admistration Sterile Suspension RTU Sterile Suspension), or ceftiur crystalle free acid Ceftiur admistered as eir ceftiur sodium (NAXCEL Sterile Powder), ceftiur The effects ceftiur on bove reproductive performance, pregnancy, tra-arterial jection. No or adverse systemic effects were noted for eir cidence acute death (see ANIMAL SAFETY) confirmed to be result advertent sudden death animal. Durg conduct clical studies, re was a low opposite eye. Intra-arterial jection Sterile Suspension is likely to result via middle third ear jection or base ear jection directed towards Intra-arterial jection may occur durg admistration Sterile Suspension RTU Sterile Suspension), or ceftiur crystalle free acid Sterile Powder), ceftiur

7 7 g g ( Sterile Suspension) is metabolized rapidly to desfuroylceftiur, primary Sgle Dose Regimen not less than 150 hours after a sgle adm Pasteurella multocida, Mannheimia encompass 90% most susceptible isolates (MIC metabolites plasma above lowest mimum hibitory concentration to provides rapeutic concentrations head (base ear, BOE) beef, non-lactatg dairy, lactatg dairy cattle, non-lactatg dairy cattle, or posterior aspect ear where it attaches to middle third posterior metabolite. Subcutaneous admistration ceftiur crystalle free acid, eir The pharmacoketic parameters for two subcutaneous locations jection ( Sterile Suspension) is metabolized rapidly to desfuroylceftiur, primary not less than 150 hours after a sgle admistration (See Figure 8). Histophilus somni haemolytica Mannheimia encompass 90% most susceptible isolates (MIC90) for labeled BRD pathogens, metabolites plasma above lowest mimum hibitory concentration to ceftiur desfuroylceftiur-related provides rapeutic concentrations BOE) beef, non-lactatg dairy, lactatg dairy cattle, non-lactatg dairy cattle, or posterior aspect ear where it attaches to aspect ear (middle third ear, metabolite. Subcutaneous admistration ceftiur crystalle free acid, eir The pharmacoketic parameters for two subcutaneous locations jection pathogens Table 4. Ceftiur mimum hibitory concentration (MIC) values* dicated Indicated pathogen Mannheimia haemolytica Pasteurella multocida Histophilus somni Fusobacterium necrophorum Porphyromonas levii * The correlation between ( Sterile Suspension) is metabolized rapidly to desfuroylceftiur, primary somni, for generally ) for labeled BRD pathogens, metabolites plasma above lowest mimum hibitory concentration to ceftiur desfuroylceftiur-related BOE) beef, non-lactatg dairy, lactatg dairy cattle, non-lactatg dairy cattle, or posterior aspect ear where it attaches to MOE) beef metabolite. Subcutaneous admistration ceftiur crystalle free acid, eir The pharmacoketic parameters for two subcutaneous locations jection Table 4. Ceftiur mimum hibitory concentration (MIC) values* dicated Indicated Year Number pathogen isolation isolates Mannheimia haemolytica 1996 to Pasteurella multocida 1996 to Histophilus somni 1996 to Fusobacterium necrophorum 2006 to Porphyromonas levii 2006 to The correlation between vitro susceptibility data clical effectiveness is unknown. Table 4. Ceftiur mimum hibitory concentration (MIC) values* dicated Number ** 50 MIC ** 90 MIC MIC range (μg/ml) (μg/ml) (μg/ml) to to to to > to susceptibility data clical effectiveness is unknown. arterial jection jection Sterile Suspension, consequences purposeful tra- Sce tra-arterial jection was confirmed three animals that died followg Two heifers (body weight Sterile Suspension were vestigated feeder cattle. CE/kg) BW bolus dose mg (6.6 approximately 225 kg) were given a sgle 3.0 mg CE/lb result death must be avoided. mutes jection. Intra-arterial jection Sterile Suspension ear will artery. Both heifers collapsed immediately died with approximately eight travenous Sce subcutaneous jection ear may potentially result advertent Three heifers three steers (body weight range kg) were given a sgle travenous jection Sterile admistration an jectable product, consequences purposeful jection Sterile Suspension, consequences purposeful tra- Sce tra-arterial jection was confirmed three animals that died followg Sterile Suspension were vestigated feeder cattle. proximately 225 kg) were given a sgle 3.0 mg CE/lb result death must be avoided. mutes jection. Intra-arterial jection Sterile Suspension ear will artery. Both heifers collapsed immediately died with approximately eight Sterile Suspension middle auricular Sce subcutaneous jection ear may potentially result advertent Three heifers three steers (body weight range kg) were given a sgle Sterile Suspension were vestigated feeder admistration an jectable product, consequences purposeful jection Sterile Suspension, consequences purposeful tra- Sce tra-arterial jection was confirmed three animals that died followg Sterile Suspension were vestigated feeder cattle. proximately 225 kg) were given a sgle 3.0 mg CE/lb mutes jection. Intra-arterial jection Sterile Suspension ear will artery. Both heifers collapsed immediately died with approximately eight Sterile Suspension middle auricular Sce subcutaneous jection ear may potentially result advertent Three heifers three steers (body weight range kg) were given a sgle feeder cattle. admistration an jectable product, consequences purposeful lactatg dairy cattle. ear (BOE Cattle) beef cattle as well to base ear (BOE Lactatg) two different locations ear, middle third ear (MOE Cattle) base Suspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous jection to one desfuroylceftiur-related metabolites after admistration Sterile Figure 8. Average (n=12/group) plasma concentrations ceftiur equivalent. subcutaneous jection sites (MOE BOE) demonstrate that y are rapeutically (MOE BOE) are found Table 2. Statistical analyses data from se two The pharmacoketic parameters for two subcutaneous locations jection its metabolites (μg/ml) Concentration ceftiur ear (BOE Cattle) beef cattle as well to base ear (BOE Lactatg) two different locations ear, middle third ear (MOE Cattle) base Suspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous jection to one desfuroylceftiur-related metabolites after admistration Sterile Figure 8. Average (n=12/group) plasma concentrations ceftiur subcutaneous jection sites (MOE BOE) demonstrate that y are rapeutically (MOE BOE) are found Table 2. Statistical analyses data from se two The pharmacoketic parameters for two subcutaneous locations jection * ** The correlation between respiratory 5. Table data, followg breakpots are recommended for BRD pathogens by CLSI. sgle admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW MIC susceptibility Based on pharmacoketic clical effectiveness studies ceftiur cattle after a The lowest MIC to encompass 50% 90% most susceptible isolates, respectively. Pathogen Mannheimia haemolytica Pasteurella multocida ear (BOE Cattle) beef cattle as well to base ear (BOE Lactatg) two different locations ear, middle third ear (MOE Cattle) base Suspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous jection to one desfuroylceftiur-related metabolites after admistration Sterile Figure 8. Average (n=12/group) plasma concentrations ceftiur subcutaneous jection sites (MOE BOE) demonstrate that y are rapeutically (MOE BOE) are found Table 2. Statistical analyses data from se two The pharmacoketic parameters for two subcutaneous locations jection The correlation between vitro susceptibility data clical effectiveness is unknown. respiratory criteria* terpretive CLSI-accepted data, followg breakpots are recommended for BRD pathogens by CLSI. sgle admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW MIC susceptibility Based on pharmacoketic clical effectiveness studies ceftiur cattle after a The lowest MIC to encompass 50% 90% most susceptible isolates, respectively. pathogens. Pathogen Disk Zone diameter potency (mm) S I Mannheimia haemolytica Pasteurella multocida 30 μg to 20 susceptibility data clical effectiveness is unknown. agast cattle ceftiur for criteria* data, followg breakpots are recommended for BRD pathogens by CLSI. sgle admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW MIC susceptibility Based on pharmacoketic clical effectiveness studies ceftiur cattle after a The lowest MIC to encompass 50% 90% most susceptible isolates, respectively. Zone diameter MIC breakpot (mm) (μg/ml) R S I R 18 to mg CE/lb (6.6 mg CE/kg) BW bolus dose 3.0 Three heifers three steers (body weight range kg) were given a sgle untoward signs se or or cattle. Intravenous jection Sterile one heifer had transient (2 to 5 mutes) creases heart rate without any or jugular ve were monitored for adverse effects followg jection. Safety Studies Beef Cattle Suspension is an unacceptable route admistration. Middle ear jection: to when Sterile Suspension was admistered as a sgle subcutaneous jection A study was designed conducted to specifically address tissue tolerance cattle material. Additional creases thickness were observed through Day 14 after jection. crease thickness is attributed to space required for volume cattle is well tolerated characterized by a biphasic thickeng ear. The itial Sterile Suspension to middle third posterior aspect ear (6.6 mg CE/kg) BW. Results from this study dicate that subcutaneous jection posterior aspect ear cattle at recommended dose 3.0 mg CE/lb mg CE/lb (6.6 mg CE/kg) BW bolus dose Three heifers three steers (body weight range kg) were given a sgle untoward signs se or or cattle. Intravenous jection Sterile one heifer had transient (2 to 5 mutes) creases heart rate without any or jugular ve were monitored for adverse effects followg jection. Sterile Suspension Suspension is an unacceptable route admistration. when Sterile Suspension was admistered as a sgle subcutaneous jection A study was designed conducted to specifically address tissue tolerance cattle material. Additional creases thickness were observed through Day 14 after jection. crease thickness is attributed to space required for volume cattle is well tolerated characterized by a biphasic thickeng ear. The itial Sterile Suspension to middle third posterior aspect ear (6.6 mg CE/kg) BW. Results from this study dicate that subcutaneous jection posterior aspect ear cattle at recommended dose 3.0 mg CE/lb Three heifers three steers (body weight range kg) were given a sgle untoward signs se or or cattle. Intravenous jection Sterile one heifer had transient (2 to 5 mutes) creases heart rate without any or jugular ve were monitored for adverse effects followg jection. One steer Sterile Suspension when Sterile Suspension was admistered as a sgle subcutaneous jection A study was designed conducted to specifically address tissue tolerance cattle material. Additional creases thickness were observed through Day 14 after jection. jected cattle is well tolerated characterized by a biphasic thickeng ear. The itial Sterile Suspension to middle third posterior aspect ear (6.6 mg CE/kg) BW. Results from this study dicate that subcutaneous jection posterior aspect ear cattle at recommended dose 3.0 mg CE/lb admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW Sterile Suspension desfuroylceftiur metabolites calculated after a sgle subcutaneous Table 2. Average (n = 12/group) pharmacoketic parameters for ceftiur its metabolites (μg/ml) Concentration ceftiur admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW Sterile Suspension desfuroylceftiur metabolites calculated after a sgle subcutaneous Table 2. Average (n = 12/group) pharmacoketic parameters for ceftiur Day Histophilus somni S Susceptible I Intermediate EFFECTIVENESS have not been established. used to determe antimicrobial susceptibility. Interpretive criteria for bove foot rot pathogens * These terpretive criteria are only tended for use when CLSI M31-A2 performance stards are R Resistant clically evaluated subcutaneously middle third pos bacterial component BRD under field conditions. All treatments were admistered sgle doses mg CE/lb (4.4 or 6.6 mg CE/kg) BW for treatment A field dose confirmation study for treatment BRD evaluated effectiveness admistration 3.0 mg CE/lb (6.6 mg CE/kg) BW Sterile Suspension desfuroylceftiur metabolites calculated after a sgle subcutaneous Table 2. Average (n = 12/group) pharmacoketic parameters for ceftiur Histophilus somni S Susceptible I Intermediate EFFECTIVENESS have not been established. used to determe antimicrobial susceptibility. Interpretive criteria for bove foot rot pathogens * These terpretive criteria are only tended for use when CLSI M31-A2 performance stards are R Resistant evaluated on Days 2 to 4, subcutaneously middle third posterior aspect ear. Cattle were bacterial component BRD under field conditions. All treatments were admistered sgle doses mg CE/lb (4.4 or 6.6 mg CE/kg) BW for treatment A field dose confirmation study for treatment BRD evaluated effectiveness used to determe antimicrobial susceptibility. Interpretive criteria for bove foot rot pathogens * These terpretive criteria are only tended for use when CLSI M31-A2 performance stards are were observed on all or study terior aspect ear. Cattle were bacterial component BRD under field conditions. All treatments were admistered sgle doses mg CE/lb (4.4 or 6.6 mg CE/kg) BW for treatment A field dose confirmation study for treatment BRD evaluated effectiveness portions carcass around base ear. edible tissues US (9 CFR 301.2). No signs irritation were observed on edible cattle. The discoloration was markedly reduced size by end study. Ears are areas discoloration some foci hemorrhage were observed ears jected jected ear a droopg position for 7 days post jection. At necropsy, subcutaneous After Day 14, post jection ear thickness Sterile The local tolerance ear cattle to a sgle subcutaneous jection well tolerated was acceptable under feedlot conditions. admistration Sterile Suspension posterior aspect ear was immediately animals treated Leak back /or bleedg from jection site was observed a small fraction from this trial due to ear irritation although swellg was noted at some jection sites. study. None 1927 animals treated with Sterile Suspension were removed Suspension was also A study evaluated 56-day feedlot performance beef steers admistered portions carcass around base ear. CFR 301.2). No signs irritation were observed on edible cattle. The discoloration was markedly reduced size by end study. Ears are areas discoloration some foci hemorrhage were observed ears jected jected ear a droopg position for 7 days post jection. At necropsy, subcutaneous After Day 14, post jection ear thickness decreased all animals. One animal carried an The local tolerance ear cattle to a sgle subcutaneous jection well tolerated was acceptable under feedlot conditions. admistration Sterile Suspension posterior aspect ear was concluded was It admistration. after immediately Leak back /or bleedg from jection site was observed a small fraction from this trial due to ear irritation although swellg was noted at some jection sites. study. None 1927 animals treated with Sterile Suspension were removed also evaluated a large multi-location effectiveness A study evaluated 56-day feedlot performance beef steers admistered CFR 301.2). No signs irritation were observed on edible cattle. The discoloration was markedly reduced size by end study. Ears are areas discoloration some foci hemorrhage were observed ears jected jected ear a droopg position for 7 days post jection. At necropsy, subcutaneous decreased all animals. One animal carried an The local tolerance ear cattle to a sgle subcutaneous jection admistration Sterile Suspension posterior aspect ear was that concluded Leak back /or bleedg from jection site was observed a small fraction from this trial due to ear irritation although swellg was noted at some jection sites. study. None 1927 animals treated with Sterile Suspension were removed effectiveness A study evaluated 56-day feedlot performance beef steers admistered eir middle third ear or base ear. Pharmacoketic Beef - Middle Parameter Third Ear Mean Value ± Deviation (μg CE/mL) max C 6.90 ± 2.68 t max 0-LOQ AUC 376 ± 66.1 >0.2, model t 183 ± 40.8 >0.2, nca t 246 ± /2 t 62.3 ± 13.5 (μg CE/mL) C maximum plasma concentration ( μg CE/mL). eir middle third ear or base ear. Beef - Middle Beef - Base Third Ear Ear Base Ear Mean Value ± Mean Value ± Mean Value ± Stard Stard Deviation Deviation 6.90 ± ± ± ± ± ± ± 40.8 NE 246 ± ± ± ± 11.2 maximum plasma concentration ( μg CE/mL). 0.05) creased Day 14 treatment success rate, defed as any ancillary had no or mild depression on that day. Suspension admistered subcutaneously middle third poste followg arrival processg. Admistration a Effectiveness evaluation was based on Sterile Suspension at high risk for BRD were assigned to one four arrival treatments, cludg addition to stard processg on arrival at feedlots, cattle ( BRD feedlot cattle was evaluated a ne-location field effectiveness study. In The effectiveness a sgle dose Sterile Suspension for control controls. cattle feedlot ear at arrival processg significantly reduced cidence BRD high-risk Base ear admistration (beef non-lactatg dairy cattle) middle third Dairy Cow - Base Ear Mean Value ± Stard Deviation 4.44 ± ± ± 85.5 NE 205 ± ± ) creased Day 14 treatment success rate, defed as ancillary treatment had a rectal temperature had no or mild depression on that day. Suspension admistered subcutaneously middle third poste followg arrival processg. Admistration a Effectiveness evaluation was based on cidence clical BRD with 28 days Suspension at 2.0 or 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) at high risk for BRD were assigned to one four arrival treatments, cludg addition to stard processg on arrival at feedlots, cattle ( BRD feedlot cattle was evaluated a ne-location field effectiveness study. In The effectiveness a sgle dose Sterile Suspension for control processg arrival after period 28-day cattle ear at arrival processg significantly reduced cidence BRD high-risk Base ear admistration (beef non-lactatg dairy cattle) middle third 0.05) creased Day 14 treatment success rate, defed as < 104 F, normal respiration animals that did not require dex, Suspension admistered subcutaneously middle third poste sgle dose Sterile cidence clical BRD with 28 days mg CE/kg) BW or negative control. at high risk for BRD were assigned to one four arrival treatments, cludg addition to stard processg on arrival at feedlots, cattle (n=3911) considered to be BRD feedlot cattle was evaluated a ne-location field effectiveness study. In The effectiveness a sgle dose Sterile Suspension for control negative to compared processg ear at arrival processg significantly reduced cidence BRD high-risk rior aspect Base ear admistration (beef non-lactatg dairy cattle) middle third implants was well tolerated by cattle did not Suspension posterior aspect ear 207 Angus Angus cross-bred steers. The admistration Sterile promotg implant, growth promotg implant with boundaries middle third ear some admistered after Sterile Suspension may need to be adjusted slightly performance. Based upon results this study, location Base ear jection: Suspension Sterile ear The local tolerance ear to 2926 beef cattle. Normal restrat was adequate for admis Suspension for 99.8% cattle. No post jection problems (exces leak back) were observed 99.8% cattle. On Days post-jec 98.9% cattle had normal (no observed swellg) ears. In a residue study, 72 beef cattle were jected implants was well tolerated by cattle did not Suspension posterior aspect ear with or without growth promotg bred steers. The admistration Sterile promotg implant alone, or neir product, boundaries middle third ear some admistered after Sterile Suspension may need to be adjusted slightly performance. Based upon results this study, location affect feedlot cattle adversely animals. was Suspension jection at base a sgle subcutaneous 2926 beef cattle. Normal restrat was adequate for admis field multi-location a evaluated Suspension for 99.8% cattle. No post jection problems (exces tration Sterile leak back) were observed 99.8% cattle. On Days post-jec sive bleedg or 98.9% cattle had normal (no observed swellg) ears. tion, In a residue study, 72 beef cattle were jected base ear with with or without growth promotg bred steers. The admistration Sterile product, a total admistered after Sterile Suspension may need to be adjusted slightly implants performance. Based upon results this study, location affect feedlot cattle base study field tration Sterile sive bleedg or tion, 97.8% base ear with g Two-Dose Regimen 2-dose regimen are provided Table 3. regimen 12 cows is shown vs. time prile for ceftiur for treatment acute metritis lactatg cows. The mean plasma concentration A two-dose regimen 6.6 mg CE/kg BW admistered 72 hours apart is required (μg CE/mL) max C = tmax maximum plasma concentration ( μg CE/mL). = AUC 0-LOQ time after jection when C model t>0.2, to limit quantitation assay (0.15 μg CE/mL). = t>0.2, nca estimated usg compartmental pharmacoketic techniques. time plasma concentrations rema above 0.2 μ = t1/2 estimated usg noncompartmental pharmacoketic techniques. time plasma concentrations rema above 0.2 μg CE/mL ( hours), = NE termal phase biological half life ( hours) = Not estimated 2-dose regimen are provided Table 3. shown Figure 9 below. The pharmacoketic desfuroylceftiur-related metabolites for treatment acute metritis lactatg cows. The mean plasma concentration A two-dose regimen 6.6 mg CE/kg BW admistered 72 hours apart is required maximum plasma concentration ( μg CE/mL). occurs ( hours). time after jection when Cmax to limit quantitation assay (0.15 μg CE/mL). estimated usg compartmental pharmacoketic techniques. time plasma concentrations rema above 0.2 μ estimated usg noncompartmental pharmacoketic techniques. time plasma concentrations rema above 0.2 μg CE/mL ( hours), termal phase biological half life ( hours) Not estimated pharmacoketic parameters for metabolites for 2-dose for treatment acute metritis lactatg cows. The mean plasma concentration A two-dose regimen 6.6 mg CE/kg BW admistered 72 hours apart is required ear pharmacoki ear admistration (lactatg dairy cattle) were compared to middle third rapeutically equivalent. -treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). analysis. There swellg lameness scores. A total 169 beef dairy cattle were cluded post-treatment or an equivalent volume a vehicle control. Cattle were clically evaluated 7 days jection base ear as a sgle dose 3.0 mg CE/lb (6.6 mg were enrolled treated with Sterile Suspension, admistered by subcutaneous evaluated a six-location field effectiveness study. Cattle diagnosed with bove foot rot The effectiveness Sterile Suspension for eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle discharge a rectal temperature evaluated a 15-location field effectiveness study. A total 1023 cows with a fetid vagal The effectiveness Sterile Suspension for treatment acute metritis was estimated usg compartmental pharmacoketic techniques. g CE/mL ( hours), estimated usg noncompartmental pharmacoketic techniques. time plasma concentrations rema above 0.2 μg CE/mL ( hours), pharmacoki admistration (lactatg dairy cattle) were compared to middle third rapeutically equivalent. netic data for beef non-lactatg -treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). There was a statistically significant difference swellg lameness scores. A total 169 beef dairy cattle were cluded based was which success, treatment for post-treatment or an equivalent volume a vehicle control. Cattle were clically evaluated 7 days jection base ear as a sgle dose 3.0 mg CE/lb (6.6 mg were enrolled treated with Sterile Suspension, admistered by subcutaneous evaluated a six-location field effectiveness study. Cattle diagnosed with bove foot rot effectiveness Sterile Suspension for eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle discharge a rectal temperature 103 F were enrolled study treated with evaluated a 15-location field effectiveness study. A total 1023 cows with a fetid vagal The effectiveness Sterile Suspension for treatment acute metritis was admistration (lactatg dairy cattle) were compared to middle third Base ear admistration (beef non-lactatg dairy cattle) middle third non-lactatg dairy cattle were found to be -treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). (p = ) treatment success for swellg lameness scores. A total 169 beef dairy cattle were cluded lesion, decreases defed on based or an equivalent volume a vehicle control. Cattle were clically evaluated 7 days BW CE/kg) jection base ear as a sgle dose 3.0 mg CE/lb (6.6 mg were enrolled treated with Sterile Suspension, admistered by subcutaneous evaluated a six-location field effectiveness study. Cattle diagnosed with bove foot rot effectiveness Sterile Suspension for treatment bove foot rot was eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle F were enrolled study treated with evaluated a 15-location field effectiveness study. A total 1023 cows with a fetid vagal The effectiveness Sterile Suspension for treatment acute metritis was flammation (hemorrhage, conges animals. None animals showed ear droopg. At necropsy, signs 72 site swellg durg study; swellg resolved prior to euthanasia 23 trimmg procedures similar to slaughterhouse practices. All animals had jection swellg droopg, evaluated grossly at necropsy, usg sk were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-jection) for Sterile Suspension at a dose rate 3.0 mg CE/lb (6.6 mg CE/kg) BW In a residue study, 72 beef cattle were jected post-jection, gross lesions were found material were seen area around jection site on carcass. At 13 days all 18 animals, exposed carcass tissue animals. Injection site scores were normal for 65.3% 92.5% cattle on Days 14 28, jection technique. Normal restrat was adequate for 95.5% animals study. Suspension at a dose 6.6 mg CE/kg BW at base ear usg ventral study 200 beef cattle. Each animal received a sgle jection Sterile The ventral base ear jection technique was evaluated a conditions use flammation (hemorrhage, conges animals showed ear droopg. At necropsy, signs site swellg durg study; swellg resolved prior to euthanasia 23 trimmg procedures similar to slaughterhouse practices. All animals had jection swellg droopg, evaluated grossly at necropsy, usg sk were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-jection) for Sterile Suspension at a dose rate 3.0 mg CE/lb (6.6 mg CE/kg) BW. Injection sites In a residue study, 72 beef cattle were jected base ear with post-jection, gross lesions were found material were seen area around jection site on carcass. At 13 days tion, firmness tissue) presence drug all 18 animals, exposed carcass tissue animals. edible portions base ear Injection site scores were normal for 65.3% 92.5% cattle on Days 14 28, jection technique. Normal restrat was adequate for 95.5% animals study. Suspension at a dose 6.6 mg CE/kg BW at base ear usg ventral study 200 beef cattle. Each animal received a sgle jection Sterile The ventral base ear jection technique was evaluated a conditions use animals showed ear droopg. At necropsy, signs site swellg durg study; swellg resolved prior to euthanasia 23 trimmg procedures similar to slaughterhouse practices. All animals had jection swellg droopg, evaluated grossly at necropsy, usg skng were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-jection) for. Injection sites base ear with material were seen area around jection site on carcass. At 13 days firmness tissue) presence drug edible portions base ear Injection site scores were normal for 65.3% 92.5% cattle on Days 14 28, jection technique. Normal restrat was adequate for 95.5% animals study. Suspension at a dose 6.6 mg CE/kg BW at base ear usg ventral study 200 beef cattle. Each animal received a sgle jection Sterile The ventral base ear jection technique was evaluated a conditions use (6.6 mg CE/kg) BW 12 lactatg cows. Subcutaneous Injections 72 hours apart at a Dose 3.0 mg CE/lb Figure 9. LS-Mean DCA Plasma Concentration Time Prile Followg Two 2-dose regimen are provided Table 3. its metabolites (μg/ml) Concentration ceftiur (6.6 mg CE/kg) BW 12 lactatg cows. Subcutaneous Injections 72 hours apart at a Dose 3.0 mg CE/lb Figure 9. LS-Mean DCA Plasma Concentration Time Prile Followg Two Subcutaneous Injections 72 hours apart at a Dose 3.0 mg CE/lb Figure 9. LS-Mean DCA Plasma Concentration Time Prile Followg Two Systemic Safety Studies ANIMAL SAFETY determed probable cause death to be tra-arterial jection. cow died 15 to 20 mutes after second admistration. Necropsy fdgs -treated cows (362/493, 74.3%) than vehicle-treated cows (271/489, 55.3%). One observation period were classified as a cure. The cure rate was significantly higher (p < ) temperature < 103 F, that did not require alternate ( escape ) rapy durg vagal discharge score were recorded. Cows with a non-fetid discharge, a rectal post-treatment, each cow remag study was examed rectal temperature control, admistered approximately 72 hours apart at base opposite ears. At 14 eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle tolerance study conducted with ceftiur sodium normal feeder calves dicated to evaluate systemic safety Sterile desfuroylceftiur. Therefore, studies Suspension), ceftiur sodium ceftiur hydrochloride are rapidly metabolized to After parenteral admistration, ceftiur crystalle free acid (as Sterile Systemic Safety Studies ANIMAL SAFETY determed probable cause death to be tra-arterial jection. cow died 15 to 20 mutes after second admistration. Necropsy fdgs -treated cows (362/493, 74.3%) than vehicle-treated cows (271/489, 55.3%). One observation period were classified as a cure. The cure rate was significantly higher (p < ) temperature < 103 F, that did not require alternate ( escape ) rapy durg vagal discharge score were recorded. Cows with a non-fetid discharge, a rectal post-treatment, each cow remag study was examed rectal temperature control, admistered approximately 72 hours apart at base opposite ears. At 14 eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle tolerance study conducted with ceftiur sodium normal feeder calves dicated to evaluate systemic safety Sterile Suspension. Results from a five-day desfuroylceftiur. Therefore, studies conducted with ceftiur sodium are adequate Suspension), ceftiur sodium ceftiur hydrochloride are rapidly metabolized to After parenteral admistration, ceftiur crystalle free acid (as Sterile determed probable cause death to be tra-arterial jection. cow died 15 to 20 mutes after second admistration. Necropsy fdgs -treated cows (362/493, 74.3%) than vehicle-treated cows (271/489, 55.3%). One observation period were classified as a cure. The cure rate was significantly higher (p < ) temperature < 103 F, that did not require alternate ( escape ) rapy durg 14_day vagal discharge score were recorded. Cows with a non-fetid discharge, a rectal post-treatment, each cow remag study was examed rectal temperature control, admistered approximately 72 hours apart at base opposite ears. At 14 days eir a two-dose regimen (6.6 mg CE/BW) or an equivalent volume vehicle tolerance study conducted with ceftiur sodium normal feeder calves dicated Suspension. Results from a five-day conducted with ceftiur sodium are adequate Suspension), ceftiur sodium ceftiur hydrochloride are rapidly metabolized to After parenteral admistration, ceftiur crystalle free acid (as Sterile Safety Studies Lactatg Dairy Cattle size comparable to or study animals by Day 14. respectively. One animal had an unusually The local tolerance ear to a sgle subcutaneous jec cattle usg nor adult dairy cattle. Successful jection base ear was achieved 97.4% ear Sterile Suspension was evaluated a multi-location field study 114 bleedg was observed fol facilities restrat equipment. No leak back or excessive mal as normal with no jection site swellg. Suspension base ear, 95.6% 100% ears, respectively, were observed rangg from 15 to 30 ml. On Days followg jection Sterile lowg jection for 99.1% cattle, with jection volumes days after jection. At necropsy, all six cows showed evidence jection site 10 jection site at all observation times after treatment. Cows were slaughtered droopg ears at any time after treatment but all animals had 3.0 mg CE/lb (6.6 mg CE/kg) BW In a residue study, six dairy cows were jected base ear at a dose rate Safety Studies Lactatg Dairy Cattle size comparable to or study animals by Day 14. unusually large swellg on Day 7 which reduced The local tolerance ear to a sgle subcutaneous jec cattle. Successful jection base ear was achieved 97.4% Sterile Suspension was evaluated a multi-location field study 114 tion at base facilities restrat equipment. No leak back or excessive as normal with no jection site swellg. Suspension base ear, 95.6% 100% ears, respectively, were observed rangg from 15 to 30 ml. On Days followg jection Sterile lowg jection for 99.1% cattle, with jection volumes days after jection. At necropsy, all six cows showed evidence jection site jection site at all observation times after treatment. Cows were slaughtered droopg ears at any time after treatment but all animals had signs swellg at Sterile Suspension. No animals In a residue study, six dairy cows were jected base ear at a dose rate reduced to a cattle. Successful jection base ear was achieved 97.4% Sterile Suspension was evaluated a multi-location field study 114 tion at base facilities restrat equipment. No leak back or excessive Suspension base ear, 95.6% 100% ears, respectively, were observed rangg from 15 to 30 ml. On Days followg jection Sterile lowg jection for 99.1% cattle, with jection volumes days after jection. At necropsy, all six cows showed evidence jection site jection site at all observation times after treatment. Cows were slaughtered signs swellg at animals exhibited In a residue study, six dairy cows were jected base ear at a dose rate at a 72 Hour Interval. Injections Sterile Table 3. Average (n = 12) Pharmacoketic Parameters Followg Two Subcutaneous PK Parameter 0-LOQ AUC t ½ t> 0.2 T max Concentration ceftiur Sterile Suspension at a Dose 3.0 mg CE/lb (6.6 Table 3. Average (n = 12) Pharmacoketic Parameters Followg Two Subcutaneous Mean ± Stard Deviation 55.7 ± ± ± 33.4 imately 8 times approved dose Sterile that ceftiur was well tolerated at 25 mg CE/lb/day for five con tolerance study conducted with ceftiur sodium normal feeder calves dicated CE/kg) BW. Ceftiur admistered parenterally had no adverse systemic effects. In a 15-day safety/toxicity study, five steer five heifer calves per group were adm is calves. Local tissue tolerance to that ceftiur has a wide marg safety when jected tramuscularly to feeder 3.0 mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, dicatg thus, evaluatg up to 3.3 times approved dose Sterile Suspension tered ceftiur sodium tramuscularly at 0 (vehicle control), 1, 3, 5 posterior ear cattle was evaluated a separate study The systemic safety ceftiur concentrations two routes admistration are rapeutically equivalent. Based upon results this relative bioavailability study, it was determed that two admistration at base ear was established via a pharmacoketic comparison mg CE/lb (6.6 mg CE/kg) BW Table 3. Average (n = 12) Pharmacoketic Parameters Followg Two Subcutaneous Mean ± Stard Deviation imately 8 times approved dose Sterile that ceftiur was well tolerated at 25 mg CE/lb/day for five con tolerance study conducted with ceftiur sodium normal feeder calves dicated CE/kg) BW. Ceftiur admistered parenterally had no adverse systemic effects. In a 15-day safety/toxicity study, five steer five heifer calves per group were adm calves. Local tissue tolerance to that ceftiur has a wide marg safety when jected tramuscularly to feeder mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, dicatg thus, evaluatg up to 3.3 times approved dose Sterile Suspension tered ceftiur sodium tramuscularly at 0 (vehicle control), 1, 3, 5 posterior ear cattle was evaluated a separate study subcutaneous jection Sterile Suspension The systemic safety ceftiur concentrations two routes admistration are rapeutically equivalent. Based upon results this relative bioavailability study, it was determed that ear (base admistration routes admistration at base ear was established via a pharmacoketic comparison imately 8 times approved dose Sterile that ceftiur was well tolerated at 25 mg CE/lb/day for five consecutive days, approxtolerance study conducted with ceftiur sodium normal feeder calves dicated CE/kg) BW. Ceftiur admistered parenterally had no adverse systemic effects. Suspension 3.0 mg CE/lb (6.6 mg In a 15-day safety/toxicity study, five steer five heifer calves per group were admthat ceftiur has a wide marg safety when jected tramuscularly to feeder mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, dicatg thus, evaluatg up to 3.3 times approved dose Sterile Suspension tered ceftiur sodium tramuscularly at 0 (vehicle control), 1, 3, 5 or 10 mg CE/lb/day posterior ear cattle was evaluated a separate study. subcutaneous jection Sterile Suspension The systemic safety ceftiur concentrations two routes admistration are rapeutically equivalent. Based upon results this relative bioavailability study, it was determed that middle third ear). versus ear admistration at base ear was established via a pharmacoketic comparison g from product result flammation (discoloration fat days after jection. At necropsy, all six cows showed evidence jection site 10 tissue dor tissue/fascia) four six cows had discoloration sectioned surface. discoloration, tan nodules a sal posterior to ear canal on carcass. In addition to at 2 or 3, 11, 54±3 days after second jection, respectively. jections admistered. Injection site scores were normal 50.3%, 73.2%, 96.4% study described above. effectiveness Injection site safety for base ear admistration was evaluated metritis TISSUE AND MILK RESIDUE DEPLETION (rostral), 87.8% (ventral), 64.6% (opposite eye) cattle on Day 28, respectively. (rostral), 46.9% (ventral), 47.9% (opposite eye) cattle on Day 14, 73% (opposite eye) animals study. Injection site scores were normal for 32% cattle. Normal restrat was adequate for 89.8% (ventral), 98% (rostral), 100% toward opposite eye technique The ventral rostral base ear jection techniques were compared with days after jection. At necropsy, all six cows showed evidence jection site tissue/fascia) four six cows had discoloration milky white fluid exudate were also present at sal posterior to ear canal on carcass. In addition to at 2 or 3, 11, 54±3 days after second jection, respectively. jections admistered. Injection site scores were normal 50.3%, 73.2%, 96.4% adequate for was restrat Normal above. Injection site safety for base ear admistration was evaluated metritis TISSUE AND MILK RESIDUE DEPLETION (rostral), 87.8% (ventral), 64.6% (opposite eye) cattle on Day 28, respectively. (rostral), 46.9% (ventral), 47.9% (opposite eye) cattle on Day 14, 73% (opposite eye) animals study. Injection site scores were normal for 32% cattle. Normal restrat was adequate for 89.8% (ventral), 98% (rostral), 100% eye technique a conditions use study 197 lactatg dairy The ventral rostral base ear jection techniques were compared with days after jection. At necropsy, all six cows showed evidence jection site tissue/fascia) four six cows had discoloration milky white fluid exudate were also present at sal posterior to ear canal on carcass. In addition to jections admistered. Injection site scores were normal 50.3%, 73.2%, 96.4% 97.8% adequate for Injection site safety for base ear admistration was evaluated metritis (rostral), 87.8% (ventral), 64.6% (opposite eye) cattle on Day 28, respectively. (rostral), 46.9% (ventral), 47.9% (opposite eye) cattle on Day 14, 73% (opposite eye) animals study. Injection site scores were normal for 32% cattle. Normal restrat was adequate for 89.8% (ventral), 98% (rostral), 100% lactatg dairy The ventral rostral base ear jection techniques were compared with T max (μg/ml) C max MICROBIOLOGY with bove foot rot. Fusobacterium necrophorum agast BRD, Histophilus somni, Pasteurella multocida, Ceftiur has demonstrated foot rot isolates, respectively. Laboratory Stards Institute (CLSI) M7-A3 M11-A6 stards for BRD diagnosed with foot rot. Susceptibility testg was conducted accordg to Clical cattle enrolled a field study conducted United States Canada that were United States that were diagnosed with BRD. Foot rot isolates were obtaed from Table 4. BRD isolates were obtaed from cattle enrolled a field study conducted A summary susceptibility BRD foot rot pathogens is presented 77.1 ± ± 2.51 Porphyromonas levii Fusobacterium necrophorum three major pathogens associated with Histophilus somni, activity agast Mannheimia haemolytica, Ceftiur has demonstrated vitro foot rot isolates, respectively. Laboratory Stards Institute (CLSI) M7-A3 M11-A6 stards for BRD diagnosed with foot rot. Susceptibility testg was conducted accordg to Clical cattle enrolled a field study conducted United States Canada that were United States that were diagnosed with BRD. Foot rot isolates were obtaed from 4. BRD isolates were obtaed from cattle enrolled a field study conducted A summary susceptibility BRD foot rot pathogens is presented two routes admistration are rapeutically equivalent. Investigation Intra-Arterial Intravenous Injection followg five daily doses NAXCEL Sterile Powder beef cattle. after two doses were statistically no higher than (AUC) terval at 6.6 mg/kg BW. The peak concentration (C were compared pharmacoketically with admistered 2 times at a 72 hour projected daily doses NAXCEL Sterile Powder (ceftiur sodium) at 2.2 mg/kg BW To support systemic target animal safety for 2-dose metritis regimen, five two major auricular (ear) arteries. resulted from advertent tra-arterial jection this oil-based suspension to one time jection. The exact cause was confirmed three animals. These deaths followg jection Sterile Suspension. In approximately 6000 animals enrolled BRD clical studies, ne animals died direct admistration oil-based formula bra resultg embolism death. associated Porphyromonas levii three major pathogens associated with Mannheimia haemolytica, Laboratory Stards Institute (CLSI) M7-A3 M11-A6 stards for BRD diagnosed with foot rot. Susceptibility testg was conducted accordg to Clical cattle enrolled a field study conducted United States Canada that were United States that were diagnosed with BRD. Foot rot isolates were obtaed from 4. BRD isolates were obtaed from cattle enrolled a field study conducted A summary susceptibility BRD foot rot pathogens is presented two routes admistration are rapeutically equivalent. Investigation Intra-Arterial Intravenous Injection followg five daily doses NAXCEL Sterile Powder beef cattle. after two doses were statistically no higher than terval at 6.6 mg/kg BW. The peak concentration (C were compared pharmacoketically with admistered 2 times at a 72 hour projected daily doses NAXCEL Sterile Powder (ceftiur sodium) at 2.2 mg/kg BW To support systemic target animal safety for 2-dose metritis regimen, five two major auricular (ear) arteries. resulted from advertent tra-arterial jection this oil-based suspension to one time jection. The exact cause was confirmed three animals. These deaths All deaths were with 30 mutes followg jection Sterile Suspension. In approximately 6000 animals enrolled BRD clical studies, ne animals died direct admistration oil-based formula Intra-arterial jection at this location resulted bra resultg embolism death. tion two routes admistration are rapeutically equivalent. Investigation Intra-Arterial Intravenous Injection followg five daily doses NAXCEL Sterile Powder beef cattle. after two doses were statistically no higher than exposure terval at 6.6 mg/kg BW. The peak concentration (Cmax) extent exposure were compared pharmacoketically with admistered 2 times at a 72 hour projected daily doses NAXCEL Sterile Powder (ceftiur sodium) at 2.2 mg/kg BW To support systemic target animal safety for 2-dose metritis regimen, five resulted from advertent tra-arterial jection this oil-based suspension to one time jection. The exact cause was confirmed three animals. These deaths All deaths were with 30 mutes In approximately 6000 animals enrolled BRD clical studies, ne animals died Intra-arterial jection at this location resulted tion to arterial blood supply TISSUE AND MILK RESIDUE DEPLETION kidney, 2.0 ppm liver, 1.0 ppm muscle 0.1 ppm milk. for ceftiur residues milk. The tolerances for ceftiur residues are 0.4 ppm residues cattle kidney, liver muscle. A separate study established tolerance A radiolabeled residue metabolism study established tolerances for ceftiur 13 days after dosg. These data collectively support a kidney, liver muscle by 13 tissues were less than tolerances for ceftiur residues tissues such as cows received a sgle jection A pivotal tissue residue decle study was conducted dairy cattle. In this study, -day pre-slaughter withdrawal period. collectively support that no milk discard period is required for this product. residues milk were less than tolerances at all time pots after treatment. These data study, cows received a sgle jection A pivotal milk residue decle study TISSUE AND MILK RESIDUE DEPLETION kidney, 2.0 ppm liver, 1.0 ppm muscle 0.1 ppm milk. for ceftiur residues milk. The tolerances for ceftiur residues are 0.4 ppm residues cattle kidney, liver muscle. A separate study established tolerance A radiolabeled residue metabolism study established tolerances for ceftiur days after dosg. These data collectively support a tissues were less than tolerances for ceftiur residues tissues such as cows received a sgle jection 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiur A pivotal tissue residue decle study was conducted dairy cattle. In this study, day pre-slaughter withdrawal period. collectively support that no milk discard period is required for this product. residues milk were less than tolerances at all time pots after treatment. These data study, cows received a sgle jection 3.0 mg CE/lb (6.6 mg CE/kg) BW study was conducted lactatg dairy cattle. for ceftiur residues milk. The tolerances for ceftiur residues are 0.4 ppm residues cattle kidney, liver muscle. A separate study established tolerance A radiolabeled residue metabolism study established tolerances for ceftiur days after dosg. These data collectively support a tissues were less than tolerances for ceftiur residues tissues such as. Ceftiur residues A pivotal tissue residue decle study was conducted dairy cattle. In this study, collectively support that no milk discard period is required for this product. residues milk were less than tolerances at all time pots after treatment. These data 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiur cattle. In this