Ceftiofur Sodium: what the FDA reviewed for dog products
16 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Ceftiofur Sodium, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Cattle; Cattle (beef and dairy cattle, including lactating dairy cattle); Cattle (beef and non-lactating dairy cattle); Cattle, swine, sheep, goats, dogs, horses, day-old chickens, and day-old turkey poults (supplement relevant to horses); Cattle, swine, sheep, goats, horses, dogs, day-old chickens & day-old turkey poults; Cattle, swine, sheep, goats, horses, dogs, day-old chicks, and day-old turkey poults; Cattle; may be used in lactating dairy cattle; Day-old turkey poults (supplement also revises the day-old chick indication); Goats; Horses; Sheep; Swine; cattle, swine, sheep, goats, dogs, horses, day-old chickens, and day-old turkey poults.
Products
- Ceftiofur Sodium Sterile Powder (NADA/ANADA 200-420)
- Ceftiofur for Injection (NADA/ANADA 200-421)
- Naxcel® Sterile Powder (NADA/ANADA 140-338)
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, April 05, 1990; sponsor Zoetis Inc.; species: Cattle (beef and non-lactating dairy cattle); foi_id 469; FDA PDF
Indication
Treatment of bovine respiratory disease (shipping fever, pneumonia); supplement changes the dose from 0.5 mg/lb to a range of 0.5-1.0 mg/lb.
Dose regimen
0.5 to 1.0 mg/lb of body weight, intramuscular injection, every 24 hours for a total of three treatments (per General Information); additional treatments on days four and five if not recovered, 3 to 5 daily treatments
The Agency concludes that Naxcel Sterile Powder is safe and effective when used for the treatment of bovine respiratory disease in beef and non-lactating dairy cattle at the dosage range of 0.5 to 1.0 mg/lb of body weight.
Target-animal safety
dose multiples 1 mg/lb (1X), 3 mg/lb (3X), 5 mg/lb (5X), 10 mg/lb (up to 10X the highest proposed dose); duration 15 days daily IM (3X the longest proposed duration of use); animals 5M and 5F per treatment group.
The study included 5M and 5F, each at daily doses 0, 1, 3, 5 or 10 mg/lb body weight.
| Finding | Quote |
|---|---|
| No systemic effects | There were no systemic effects attributable to formulated ceftiofur sodium based on clinical signs, hematological, clinical chemistry and urinalysis parameters and on gross and microscopic determinations. |
| Safe IM; slight muscle irritant | Formulated ceftiofur is safe when injected intramuscularly into cattle. The formulation is deemed to be a slight muscle irritant. |
| 5-day tolerance at 25 mg/lb/day (25X of 1.0 mg/lb): well tolerated, no systemic toxicity | In conclusion, formulated ceftiofur diluted in Bacteriostatic Water for Injection, USP with Benzyl Alcohol 0.945% w/v was well tolerated in feeder calves at 25 times the highest recommended dosage of 1.0 mg/lb/day (25 mg/lb/day) for 5 consecutive days. |
| Injection-site pain at 1 mg/lb not significantly more severe than at 0.5 mg/lb | Naxcel causes an immediate and transient local pain at the intramuscular injection site which is not significantly more severe at the 1 mg/lb level. |
Effectiveness
Re-presentation of the original seven-location randomized complete block placebo-controlled feedlot trial (IM ceftiofur 0.5 or 1.0 mg/lb once daily for three to five days; 28-day study); n = 629; primary endpoint: body temperature drop at day 4; clinical success at days 10 and 28; mortality by day 28; result: Each ceftiofur dose significantly better than placebo; the two doses gave similar responses (% clinical success day 10: 29 control, 53 at 0.5 mg/lb, 61 at 1.0 mg/lb; % mortality day 28: 25, 7, 3)
A seven location clinical trial was conducted. This included 629 cattle with spontaneously occurring disease and three treatment groups.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| immediate, transient local pain at IM injection site | Except for an immediate and transient local pain reaction to the intramuscular injection of ceftiofur, there was no evidence of any adverse effect. |
Extraction notes: Supplemental approval (Category II) changing the dose to a 0.5-1.0 mg/lb range; no new studies ('no new data were necessary'). The General Information section still prints the original 0.5 mg/lb regimen, so the dose quote is taken from Agency Conclusions. Effectiveness and TAS re-summarise the 1988 original studies (same 629-cattle trial and the same three cattle safety studies, here described as 25X and 10X of the 1.0 mg/lb dose). n_dogs holds the number of cattle.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, August 04, 1992; sponsor Zoetis Inc.; species: Swine; foi_id 1716; FDA PDF
Indication
Treatment/control of swine bacterial respiratory disease (bacterial pneumonia) associated with Actinobacillus (Haemophilus) pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis and/or Streptococcus suis type 2.
Dose regimen
1.36 to 2.27 mg ceftiofur per pound of body weight (3.0 mg to 5 mg ceftiofur per kilogram), Intramuscular injection, once daily for three consecutive days (per the field and dose-finding studies; General Information does not state the frequency), 1 mL reconstituted solution per 37 to 22 lb (17 to 10 kg) body weight
NAXCEL® Sterile Solution should be administered to swine at a dosage of 1.36 to 2.27 mg ceftiofur per pound of body weight (3.0 mg to 5 mg ceftiofur per kilogram of body weight).
Target-animal safety
dose multiples 1X (5 mg/kg), 3X (15 mg/kg), 5X (25 mg/kg); duration once daily for 15 consecutive days (5X the 3-day label duration); necropsy 24 h after last injection; animals 5 barrows and 5 females per treatment group.
Three dosages of ceftiofur sodium; 5, 15 and 25 mg free acid equivalents per kilogram of body weight (2.27, 6.82 and 11.36 mg/pound of body weight) were compared to a placebo (sterile water for injection) treated group.
| Finding | Quote |
|---|---|
| All pigs survived and gained weight; no systemic effects | Throughout the course of this study, all pigs survived and gained weight. There were no systemic effects attributable to formulated ceftiofur sodium based on the parameters measured. |
| Gross injection-site streaks in all groups including controls, more prominent at the two higher doses | Gross necropsy examination revealed only incidental changes in most tissues with some red to reddish-tan streaks at the injection site in all groups including the controls. The more prominent streaks were noted in the group of animals that received the two higher doses. |
| Microscopic injection-site necrosis with hemorrhage in treated and placebo animals | Microscopic evaluations of the injection sites revealed some degree of necrosis with frequently accompanying hemorrhages. This observation was made in some animals in all treated groups as well as the placebo treated controls. |
| Conclusion: safe IM in swine; slight muscle irritant | Formulated ceftiofur sodium (NAXCEL®) is safe when injected intramuscularly into swine. This formulation is deemed to be a slight muscle irritant. |
| Acute tolerance study (125 mg/kg, >25X, 5 days, 4 treated pigs): no overt clinical toxicity | Results of this study indicate that the administration of ceftiofur sodium at exaggerated doses produced no overt clinical signs of toxicity. |
| Acute tolerance study: one treated pig developed marked anemia | One drug treated pig developed a marked anemia as shown by a 3-fold decrease in terminal red blood cell count, hemoglobin and hematocrit values in comparison to the other animals. |
Effectiveness
11-location (10 USA, 1 Canada) randomized complete block field trial in feeder pigs with naturally occurring bacterial pneumonia; IM ceftiofur 3 or 5 mg/kg (1.36 or 2.27 mg/lb) once daily for 3 days vs saline placebo controls within each pen; 14-day trial; n = 1,762; primary endpoint: mortality, lung lesion scores (day 7 necropsy), and gainers (pigs surviving and gaining >5 lb in 14 days); result: Both doses effective; 3 mg/kg significantly reduced mortality and lung lesion scores and improved gainers vs placebo; 5 mg/kg gave non-significant reductions in mortality and lesion scores and significant improvement in gainers. Table 3 rows (dose, pens, lesion score, % mortality, mortality degrees, % gainers, gainers degrees): '0 (0 mg) 30 2.50 7.05 15.59 79.36 64.42', '3 (1.36 mg) 30 1.10 1.92 10.54 86.17 69.11', '0 (0 mg) 30 1.79 9.08 16.51 74.69 60.74', '5 (2.27 mg) 30 1.50 3.91 13.26 83.65 66.08'
A total of 1,762 feeder pigs were used in this clinical trial. Most of the pigs were crossbreds and ranged in weight from 32 pounds to 148 pounds at the time of the first treatment.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| local transient pain at IM injection (dose-finding challenge study) | Some animals showed signs of local transient pain as a result of the intramuscular injection, but no evidence of any adverse effects of ceftiofur was noted. |
Extraction notes: Supplement adding swine (original swine data package with dose-finding challenge study, field trial and two TAS studies). n_dogs holds the number of pigs. Dose-finding study: 120 pigs challenged with A. pleuropneumoniae, 0/1/3/5 mg/kg; mortality 59.17/35.83/30.00/13.33% (Table 1). TAS summary states 881 swine received ceftiofur in the field trial with only transient local pain observed. Adverse-reaction incidences not tabulated.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, August 24, 1995; sponsor Zoetis Inc.; species: Cattle; foi_id 1717; FDA PDF
Indication
New indication: treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus.
Dose regimen
0.5 to 1.0 mg ceftiofur per pound (lb) of body weight (1 to 2 mL per 100 lb), intramuscular injection, every 24 hours for a total of three treatments, additional treatments on Days 4 and 5 for animals not recovered after the first three treatments
NAXCEL® Sterile Solution is to be administered to cattle at the dosage range of 0.5 to 1.0 mg ceftiofur per pound (lb) of body weight (BW); 1 to 2 mL reconstituted sterile solution per 100 lb BW. Treatment should be repeated every 24 hours for a total of three treatments.
Effectiveness
Pivotal multilocation (11 sites: 6 beef feedlots, 5 dairies) placebo-controlled dose confirmation field study in cattle with naturally occurring acute foot rot; 0.5 mg ceftiofur/lb IM once daily for 3 days vs sterile water; veterinarian-assessed cure on Days 4 and 7; n = 47 beef and 41 lactating cows; primary endpoint: cure (reduction in lameness score by 2 points with none to moderate swelling and healed/healing lesions) on Day 4 and Day 7; result: Combined cure rate 62.2% (28/45) ceftiofur vs 14.0% (6/43) placebo, P < 0.003 (beef 69.6% vs 16.7%; dairy 54.6% vs 10.5%); one ceftiofur beef animal relapsed on Day 14
Eighty-eight cattle (47 beef, 41 lactating cows) from 11 different locations were used in a pivotal dose confirmation trial. Animals were randomly assigned to either placebo or 0.5 mg ceftiofur/lb BW for 3 days.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| adverse reactions (field study) | g. Adverse Reactions: None observed during the study. |
Extraction notes: Supplement adding the foot-rot indication in cattle; target animal safety addressed by reference to the 1988 summary (no TAS content). n_dogs holds the number of cattle (88 total; the word 'Eighty-eight' is spelled out so the total is given as its components). Pivotal dose determination study: 39 yearling cattle with induced foot rot, placebo vs 0.5 vs 1.0 mg/lb for 3 days, both doses more effective than placebo (P < 0.0001), no adverse reactions. Cure-rate rows verbatim from Table 4: 'Beef (6) 69.6 (16/23) 16.7 (4/24)', 'Lactating Dairy Cows (5) 54.6 (12/22) 10.5 (2/19)', 'Combined Beef and Dairy (11) 62.2 (28/45) 14.0 (6/43)'.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, December 31, 2003; sponsor Zoetis Inc.; species: cattle, swine, sheep, goats, dogs, horses, day-old chickens, and day-old turkey poults; foi_id 474; FDA PDF
Indication
Multi-species label; dog indication: treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis (other species: BRD/foot rot in cattle, swine respiratory disease, sheep and goat pneumonia, equine respiratory infections, early mortality in chicks and poults).
Dose regimen
1 mg/lb body weight (dog), SC only (dog), not stated in this supplement, other species: cattle 0.5-1.0 mg/lb IM or SC; swine 1.36-2.27 mg/lb IM; sheep and goats 0.5-1.0 mg/lb IM; horses 1-2 mg/lb IM; chicks 0.08-0.20 mg/chick SC; poults 0.17-0.5 mg/poult SC
Dog: 1 mg/lb body weight SC only.
Effectiveness
Labeling supplement only: updated clinical microbiology (MIC) tables, quality-control ranges and NCCLS reference; no new clinical studies; result: MIC tables updated (Table 1 field-study isolates, Table 2 diagnostic-laboratory isolates); canine field-study isolates: E. coli n=18 (1990) MIC90 0.25 µg/mL; Proteus mirabilis n=17 (1990) MIC90 <= 0.06 and n=23 (1992) MIC90 1.0 µg/mL
Updated in vitro minimum inhibitory concentration (MIC) data for cattle, swine, sheep, chicken, and turkey pathogens are presented in tabular format in the labeling for NAXCEL Sterile Powder.
Extraction notes: Category II labeling supplement (MIC table update, QC ranges, NCCLS reference, freezing/storage clarification). Summary states the supplement does not change target animal safety or human food safety data. Canine MIC rows verbatim from Table 1: 'Escherichia coli 18 1990 0.25 0.13-0.5' and 'Proteus mirabilis 17 1990 ≤ 0.06 ≤ 0.06-0.5 Canine' (columns: Organism, Number Tested, Date Tested, MIC90, MIC Range; the 'Canine' animal label is displaced by extraction). No PK, safety or adverse-reaction data.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, February 27, 2004; sponsor Zoetis Inc.; species: Cattle, swine, sheep, goats, dogs, horses, day-old chickens, and day-old turkey poults (supplement relevant to horses); foi_id 475; FDA PDF
Indication
Horse: treatment of respiratory infections in horses associated with Streptococcus zooepidemicus (indication relevant to this supplement).
Dose regimen
1 to 2 mg/lb body weight (horse), IM only, not stated in this supplement
Recommended Dosage: Horse: 1 to 2 mg/lb body weight IM only
Effectiveness
Labeling supplement only: adds updated equine isolate MIC survey data to Table 2 and NCCLS interpretive criteria for equine isolates; no new clinical studies; result: Equine susceptible-only breakpoint added (zone >= 22 mm, MIC <= 0.25 µg/mL); 2002 isolates: S. equi subsp. equi n=29 MIC90 <= 0.03, S. zooepidemicus n=59 MIC90 <= 0.03, Rhodococcus equi n=42 MIC90 8.0 µg/mL
Based on the pharmacokinetic studies of ceftiofur in horses after a single intramuscular injection of 1 mg ceftiofur equivalents/lb (2.2 mg/kg) BW, clinical effectiveness data and MIC data, the following breakpoint is recommended by NCCLS.
Extraction notes: Category II labeling supplement; summary states target animal safety and human safety data are unchanged. No PK, safety or adverse-reaction data. Equine breakpoint row verbatim: '≥ 22 ≤ 0.25 (S) Susceptible'.
Naxcel® Sterile Powder NADA 140-338, Original approval, January 25, 1988; sponsor Zoetis Inc.; species: Cattle; foi_id 468; FDA PDF
Indication
Treatment of bovine respiratory disease (shipping fever, pneumonia).
Dose regimen
0.5 mg ceftiofur per pound of body weight (1 ml reconstituted sterile solution per 100 lb), intramuscular injection, every 24 hours for a total of three treatments, additional treatments may be given on days four and five for animals which do not show a satisfactory response after the first three treatments
Naxcel Sterile Solution should be administered by intramuscular injection to cattle at the dosage of 0.5 mg ceftiofur per pound of body weight (1 ml reconstituted sterile solution per 100 lb body weight). Treatment should be repeated every 24 hours for a total of three treatments.
Target-animal safety
dose multiples 1 mg/lb, 3 mg/lb, 5 mg/lb, 10 mg/lb (up to 20X the highest proposed dose of 0.5 mg/lb); duration 15 days daily IM (3X the longest proposed duration of use); necropsy on day 16; animals 5 M and 5 F per treatment group.
The study included 5 M and 5 F, each at daily doses 0, 1, 3, 5 or 10 mg/lb body weight.
| Finding | Quote |
|---|---|
| No systemic effects at up to 10 mg/lb/day for 15 days | There were no systemic effects attributable to formulated ceftiofur sodium based on clinical signs, hematological, clinical chemistry and urinalysis parameters and on gross and microscopic determinations. |
| Local injection-site muscle irritation, microscopic only | Local effects of muscle irritation were evidenced by histopathologic evaluation. Lesions were microscopic in size and difficult to find even with the aid of injection site markers. |
| Conclusion of 15-day study: safe IM; slight muscle irritant | Formulated ceftiofur is safe when injected intramuscularly into cattle. The formulation is deemed to be a slight muscle irritant. |
| 5-day study (0, 1, 3, 5 mg/lb, 20 steers): elevated CPK at the high dose correlating with injection-site muscle damage | Significantly elevated CPK values (P ¾ .05) were observed in the high dose animals when compared to the controls. |
| 5-day tolerance study at 25 mg/lb/day (8 feeder calves): well tolerated, no systemic toxicity; transient AST/CPK elevations | In conclusion, formulated ceftiofur diluted in Bacteriostatic Water for Injection, USP with Benzyl Alcohol 0.945% w/v was well tolerated in feeder calves at 50 times the highest recommended dosage of 1.0 mg/lb/day (25 mg/lb/day) for 5 consecutive days. |
| Overall safety conclusion across seven trials | Based on results of these seven trials, ceftiofur is safe when administered intramuscularly at doses up to 1.0 mg. ceftiofur per lb body weight daily for five days. |
Effectiveness
Multi-location (seven feedlots) randomized complete block, placebo-controlled clinical trial in feedlot cattle with spontaneously occurring BRD; IM ceftiofur 0.5 or 1.0 mg/lb or sterile diluent once daily for three days, two more days if not recovered; 28-day study; n = 629; primary endpoint: body temperature drop at day 4; clinical success at day 10 and day 28; mortality by day 28; result: Both ceftiofur doses significantly better than placebo on all four variables and not different from each other. Table (Treatment, No., temp drop day 4, temp day 4, % clinical success day 10, % success day 28, % mortality day 28): control 204 / 1.2 / 104.0 / 29 / 57 / 25; 0.5 mg/lb 201 / 2.1 / 103.1 / 53 / 69 / 7; 1.0 mg/lb 201 / 2.2 / 103.0 / 61 / 69 / 3
Finally, a seven location clinical trial was conducted. This included 629 cattle with spontaneously occurring disease and three treatment groups.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| immediate, transient local pain at IM injection site (all four clinical trials) | Except for an immediate and transient local pain reaction to the intramuscular injection of ceftiofur, there was no evidence of any adverse effect. |
Extraction notes: Species is given as cattle/bovine throughout; no Species/Class field in this 1988 General Information. n_dogs holds the number of cattle. No PK data in this summary. Three TAS studies: (1) 5-day 0/1/3/5 mg/lb in 20 steers, (2) 5-day tolerance at 25 mg/lb in 8 calves (summary calls this both 50X and '50 times the highest recommended dosage of 1.0 mg/lb/day', an internal inconsistency quoted as written), (3) 15-day 0/1/3/5/10 mg/lb in 5M+5F per group, described as 'up to 20X the highest proposed doses for 15 days, which is 3X the longest proposed duration of use' (used for target_animal_safety). Multi-location trial results row quoted verbatim in effectiveness.result; earlier dose-response trials (84, 220 and 235 cattle) supported 0.5 mg/lb as the optimal dose. Adverse-reaction incidence not tabulated.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, July 13, 1994; sponsor Zoetis Inc.; species: Horses; foi_id 470; FDA PDF
Indication
Treatment of respiratory infections in horses associated with Streptococcus zooepidemicus.
Dose regimen
1.0-2.0 mg per pound of body weight (2.2-4.4 mg/kg), intramuscular injection, every 24 hours, continued for 48 hours after clinical signs resolve (label text truncated by a page break in the summary); field studies treated up to a maximum of 10 days; maximum 10 mL per injection site
Administer by intramuscular injection to horses at a dosage of 1.0-2.0 mg per pound of body weight (2.2-4.4 mg/kg). Treatment should be repeated every 24 hours.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 4.46 +/- 0.93 µg ceftiofur equivalents/mL plasma | single IM dose 1 mg ceftiofur equivalents/lb (2.2 mg/kg); 4 male Quarter Horses and 8 mixed-breed females, 972-1360 lb; ceftiofur plus desfuroylceftiofur metabolites | The average maximum plasma concentration of ceftiofur and desfuroylceftiofur metabolites (Cmax) of 4.46 +/- 0.93 µg ceftiofur equivalents/mL of plasma occurred 1.25 ± 0.46 hours after injection. |
| tmax | 1.25 ± 0.46 hours | single IM dose 1 mg ceftiofur equivalents/lb; 12 horses | The average maximum plasma concentration of ceftiofur and desfuroylceftiofur metabolites (Cmax) of 4.46 +/- 0.93 µg ceftiofur equivalents/mL of plasma occurred 1.25 ± 0.46 hours after injection. |
| other | plasma concentrations 0.99 ± 0.16 (8 h), 0.47 ± 0.15 (12 h), 0.17 ± 0.02 (24 h) µg ceftiofur equivalents/mL | single IM dose 1 mg ceftiofur equivalents/lb; 12 horses; concentrations remained above MIC(90) (<= 0.06 µg/mL) for the 24-hour dosing interval | These concentrations declined to 0.99 ± 0.16, 0.47 ± 0.15, and 0.17 ± 0.02 µg ceftiofur equivalents/mL of plasma at 8, 12, and 24 hours, respectively, after injection. |
| other | mean residence time 4.6 ± 1.0 hours | single IM dose 1 mg ceftiofur equivalents/lb; 12 horses | The mean residence time of ceftiofur and desfuroylceftiofur metabolites was estimated to be 4.6 ± 1.0 hours. |
| other | lung homogenate 1.40 ± 0.36 (1 h), 0.27 ± 0.07 (12 h), 0.15 ± 0.08 (24 h) µg ceftiofur equivalents/g wet weight | single IM dose 1 mg ceftiofur equivalents/lb; groups of four horses euthanized at 1, 12 and 24 hours | The measured total lung homogenate concentrations of ceftiofur and its desfuroylceftiofur metabolites in horses were 1.40 ± 0.36, 0.27 ± 0.07, and 0.15 ± 0.08 µg ceftiofur equivalents/g of lung tissue (wet weight) at 1, 12, and 24 hours after dosing, respectively. |
Target-animal safety
dose multiples 1X (1 mg/lb/day), 3X (3 mg/lb/day), 5X (5 mg/lb/day) of the 1.0 mg/lb dose (0.5X, 1.5X, 2.5X of the 2.0 mg/lb upper dose); duration daily IM for 30 days with a one-month recovery period; animals 20 adult male (gelding) horses (a parallel study used 20 adult female horses).
Twenty (20) adult male (gelding) horses were divided into four groups: six horses in each of the saline control and high dose groups, and four horses in each of the low and intermediate dose groups.
| Finding | Quote |
|---|---|
| Generally well tolerated up to 5 mg/lb/day for 30 days (males) | Ceftiofur sodium was generally well tolerated when administered intramuscularly to male horses at doses up to 5 mg/lb/day for 30 days. |
| Transient decrease in pelleted feed consumption at 3 and 5 mg/lb/day | A very slight to mild decrease in pelleted food consumption was detected in the horses receiving the 3 and 5 mg/lb/day of ceftiofur. |
| Mild injection-site skeletal muscle irritation in all ceftiofur groups, increasing with dosing-solution concentration | Generally, mild skeletal muscle irritation was detected at the injection sites in all dose groups receiving ceftiofur. The incidence and severity of the muscle irritation tended to increase with each successive increase in the concentration of the dosing solution. |
| Increased serum AST and CPK attributed to injection-site muscle damage | Increases in serum concentrations of aspartate aminotransferase(AST, SGOT) and creatine phosphokinase(CPK) were detected in some of the ceftiofur treated horses. |
| Tolerance study (IV 10 and 25 mg/lb/day for 10 days): altered large-intestinal flora, inflammation, diarrhea, colic signs, reduced feed intake | Ceftiofur administered intravenously at a dose of 10 or 25 mg/lb/day changed the bacterial flora of the large intestine leading to inflammation with subsequent diarrhea and other clinical signs. |
| Safety conclusion supporting the 1.0-2.0 mg/lb dose range | The dosage range of 1.0-2.0 mg/lb (2.2-4.4 mg/kg) of body weight given SID intramuscularly was established as being safe for horses. |
Effectiveness
Blinded, placebo-controlled clinical study (Univ. of Illinois) in horses with naturally acquired respiratory infections; ceftiofur 1 mg/lb (2.2 mg/kg) IM SID vs saline, continued 48 h after afebrile and asymptomatic, maximum 10 days; n = 60; primary endpoint: clinical improvement on the last day of treatment; body temperature reduction after two treatments; Day 7 post-treatment evaluation; result: 28 (93%) ceftiofur horses improved vs 6 (20%) placebo; failures 2 (7%) vs 24 (80%); day-3 temperature reduction 1.49 vs 0.03 °F (P<0.01); at Day 7, 26 of the 28 improved ceftiofur horses completely recovered
Sixty (60) horses with naturally acquired respiratory infections were randomly assigned to two study groups: 30 to ceftiofur and 30 to the placebo (saline) group.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| adverse reactions (ceftiofur vs placebo field study) | Ceftiofur was well tolerated by the animals treated. There were no adverse reactions in either treatment group. | ||
| injection-site pain/swelling and diarrhea (ceftiofur vs ampicillin studies) | Both therapies were well tolerated: diarrhea was not observed post-treatment, and neither pain nor swelling was observed at the injection sites. |
Extraction notes: Supplement adding horses. n_dogs holds the number of horses. Result figures quoted from: 'Twenty-eight (93%) of the horses treated with ceftiofur showed clinical improvement and 2 (7%) were classified as failures on the last day of treatment; whereas, only 6 (20%) of the controls improved and 24 (80%) were failures.' A second pivotal study (17 horses, ceftiofur vs ampicillin 3 mg/lb BID) and a corroborative 29-horse study also supported effectiveness. Dose regimen label text in General Information is cut by a page break after 'continued for 48 hours after clinical'. The 2 mg/lb upper dose was not tested in field trials; it was supported by the 5 mg/lb/day 30-day safety studies (margin >2.5X).
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, June 02, 2006; sponsor Zoetis Inc.; species: Cattle; may be used in lactating dairy cattle; foi_id 477; FDA PDF
Indication
Treatment of BRD associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, and of acute bovine interdigital necrobacillosis; supplement establishes a 4-day pre-slaughter withdrawal.
Dose regimen
0.5 to 1.0 mg ceftiofur per pound of body weight (1-2 mL per 100 lb), Intramuscular (IM) or subcutaneous (SC) injection, at 24-hour intervals for a total of three consecutive days; additional treatments on days four and five if not recovered, 4-day (96-hour) pre-slaughter withdrawal for IM and SC; no milk discard
0.5 to 1.0 mg ceftiofur per pound of body weight (1-2 mL reconstituted sterile solution per 100 lb body weight).
Extraction notes: Supplement establishing a 4-day pre-slaughter withdrawal period for cattle; CVM did not require effectiveness or target animal safety studies (validator warning expected). Pivotal residue study 2000-0427: 38 cattle, IM 2.2 mg CE/kg/day for five days; kidney DCA 5.29 ± 0.79 ppm at 3 h, 0.12 ± 0.02 at 96 h; tolerance limit below the 0.4 ppm kidney tolerance at 93 hours, supporting a 96-hour withdrawal. Frequency sentence not quoted because '24-hour' is hyphen-split across a line in the extracted text.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, June 18, 2004; sponsor Zoetis Inc.; species: Swine; foi_id 476; FDA PDF
Indication
Treatment/control of swine bacterial respiratory disease associated with A. pleuropneumoniae, P. multocida, S. choleraesuis and S. suis type 2; supplement establishes a 4-day pre-slaughter withdrawal.
Dose regimen
1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) of body weight, Intramuscular (IM) injection, at 24 h intervals for a total of three consecutive days, 4-day pre-slaughter withdrawal established by this supplement
1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) of body weight (1 mL of reconstituted sterile solution per 22 to 37 lb of body weight). Treatment should be repeated at 24 h intervals for a total of three consecutive days.
Extraction notes: Supplement establishing a 4-day pre-slaughter withdrawal period for swine; summary states it does not change effectiveness or target animal safety data, so no PK/TAS/effectiveness content (validator warning expected). Pivotal residue study: 36 swine, IM 5 mg CE/kg/day for 3 days; kidney DCA residue 5.4 ± 1.1 µg/g at 3 h, 0.18 ± 0.06 at 72 h, (0.073) at 96 h (kidney tolerance 0.25 ppm; 99th percentile/95% confidence tolerance limit below tolerance at 4 days).
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, March 07, 2001; sponsor Zoetis Inc.; species: Goats; foi_id 472; FDA PDF
Indication
Treatment of caprine respiratory disease (goat pneumonia) associated with Pasteurella haemolytica and Pasteurella multocida.
Dose regimen
0.5 to 1.0 mg/lb body weight, Intramuscular injection, at 24-hour intervals for 3 consecutive days, additional treatments may be given on Days 4 and 5 for animals that do not show a satisfactory response after the initial 3 treatments
Recommended Dosage: 0.5 to 1.0 mg/lb body weight. Treatment should be repeated at 24-hour intervals for 3 consecutive days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | mean 2.66 (SD 1.24) µg/mL | IM single dose 1.1 mg ceftiofur free acid equivalents/kg (0.5 mg/lb), lactating dairy goats, n=6; Table 4.4 row: six individual animals then Mean and Std. Dev. | Cpmax (µg/mL) 1.56 1.74 3.04 4.67 1.66 3.30 2.66 1.24 |
| tmax | mean 69.9 (SD 49.1) min | IM 0.5 mg/lb, lactating dairy goats, n=6; Table 4.4 row | tmax (min) 64.0 127 36.4 28.2 135 29.0 69.9 49.1 |
| half-life | T½ß 163 min (harmonic mean) | IM 0.5 mg/lb, lactating dairy goats, n=6; Table 4.4 row | T½ß (min) 133 195 124 196 288 133 163 (harmonic) |
| auc | AUC 0->inf mean 695 (SD 175) µg•min/mL | IM 0.5 mg/lb, lactating dairy goats, n=6; Table 4.4 row | AUC 0–>inf (µg•min/mL) 420 730 647 698 966 708 695 175 |
| cmax | mean 4.57 (SD 0.96) µg/mL | IM single dose 2.2 mg/kg (1.0 mg/lb), lactating dairy goats, n=6; Table 4.5 row | Cpmax (µg/mL) 5.15 4.53 3.25 4.85 5.94 3.76 4.57 0.96 |
| auc | AUC 0->inf mean 1447 (SD 328) µg•min/mL | IM 1.0 mg/lb, lactating dairy goats, n=6; Table 4.5 row | AUC 0–>inf (µg•min/mL) 1170 1260 1510 1810 1080 1840 1447 328 |
| auc | AUC 0->inf mean 1625 (SD 270) µg•min/mL | IV single dose 2.2 mg/kg (1.0 mg/lb), lactating dairy goats, n=6; Table 4.2 row | AUC 0–>inf (µg•min/mL) 1400 1470 1450 2060 1510 1860 1625 270 |
| auc | AUC 0->inf mean 2036 (SD 383) µg•min/mL | IV single dose 2.2 mg/kg (1.0 mg/lb), non-lactating dairy goats, n=6; Table 4.3 row | AUC 0–>inf (µg•min/mL) 1890 1520 2220 2620 2170 1790 2036 383 |
Target-animal safety
dose multiples 5X (up to 5 times the label dose); duration three times the indicated treatment period.
A safety/toxicity study conducted in healthy goats with ceftiofur sodium under PMF 5671 demonstrated no drug related adverse effects even when administered IM at up to 5 times the label dose for three times the indicated treatment period.
| Finding | Quote |
|---|---|
| No local irritation or systemic toxicity | There were no signs of local irritation or systemic toxicity seen in any of the animals. |
Effectiveness
No clinical trial in goats; effectiveness supported by pharmacokinetic studies in goats (PMF 5671) bridged to approved cattle and sheep data; result: Goat PK similar to cattle and sheep; dose-proportional AUC and Cmax after IM and IV; lactation increased elimination (lower exposure in lactating goats)
The purpose of these studies was to show that the pharmacokinetics of the drug in goats are similar to those in cattle and sheep for whom the drug is already approved.
Extraction notes: Minor-species supplement (goats). PK tables 4.1-4.5 were flattened; each quoted row lists six individual animal values followed by Mean and Std. Dev. (harmonic mean for half-lives). Lactation finding: 'Drug exposure appears to be significantly less in lactating as compared to dry goats.' TAS study details (n, doses) are only summarised by reference to PMF 5671. No adverse-reaction data reported. The registered-mark glyph after NAXCEL in the indication sentence was extracted as private-use character U+F6DA and is kept verbatim in the quote.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, March 15, 1991; sponsor Zoetis Inc.; species: Cattle (beef and dairy cattle, including lactating dairy cattle); foi_id 1715; FDA PDF
Indication
Treatment of bovine respiratory disease (shipping fever, pneumonia) in beef and dairy cattle, including lactating dairy cattle (new class of animal added by this supplement).
Dose regimen
0.5 to 1.0 mg ceftiofur per pound of body weight (1 to 2 mL per 100 lb), intramuscular injection, every 24 hours for a total of three treatments, additional treatments on days four and five for animals not recovered after the first three treatments; no milk discard time required
NAXCEL Sterile Solution should be administered by intramuscular injection to cattle at the dosage range of 0.5 to 1.0 mg ceftiofur per pound of body weight (1 to 2 mL reconstituted sterile solution per 100 lb body weight). Treatment should be repeated every 24 hours for a total of three treatments.
Extraction notes: Category II supplement adding lactating dairy cattle; effectiveness and target animal safety are addressed by reference to the January 25, 1988 FOI summary, so no PK/TAS/effectiveness content (validator warning expected). New data are 14C-ceftiofur milk residue studies: peak total milk residue 0.045 ppm at 12 h after a 0.5 mg/lb dose; after five daily 1.0 mg/lb doses milk residues peaked at 0.1154 ppm (D5 + 12 h) vs a 1 ppm calculated safe concentration; no milk discard time required.
Ceftiofur for Injection NADA 200-421, Original approval, March 29, 2012; sponsor Hospira, Inc.; species: Cattle, swine, sheep, goats, horses, dogs, day-old chicks, and day-old turkey poults; foi_id 1150; FDA PDF
Indication
Dogs: treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis (multi-species generic label).
Dose regimen
1.0 mg per pound (2.2 mg/kg) body weight, Subcutaneous injection (dogs), Repeated at 24 hour intervals, 5-14 days
Dogs: 1.0 mg per pound 2.2 mg/kg) of body weight (0.1 mL reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 24 hour intervals for 5-14 days.
Extraction notes: Generic ANADA (Hospira, Inc.). 'CVM did not require effectiveness studies for this approval.' and 'CVM did not require target animal safety studies for this approval.' In vivo bioequivalence study waived on formulation characteristics; RLNAD NAXCEL Sterile Powder, NADA 140-338. Dose quote reproduces the summary's missing parenthesis ('1.0 mg per pound 2.2 mg/kg)'). Route quote: 'For subcutaneous injection only in dogs, day-old chicks, and day-old turkey poults.'
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, May 21, 1996; sponsor Zoetis Inc.; species: Day-old turkey poults (supplement also revises the day-old chick indication); foi_id 471; FDA PDF
Indication
Control of early mortality associated with E. coli organisms susceptible to ceftiofur in day-old chicks and day-old turkey poults.
Dose regimen
0.17 to 0.5 mg per poult, single subcutaneous injection (back of the neck), once, single injection at one day of age
Naxcel® Sterile Powder should be administered to day-old turkey poults at a dosage of 0.17 to 0.5 mg per poult. Treatment should be administered once.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 1.674 ± 0.662 µg/mL | turkey poults, single SC 0.12 mg 14C-ceftiofur/poult; Table 4.2 row order: Dose (mg/poult), Cmax (µg/mL), AUC (µg·hr/mL), Tmic (hr); composite plasma of 3 poults per cage, 6 replicates | 0.12 1.674 ± 0.662 13.84 ± 4.49 8.50 ± 3.70 |
| auc | 13.84 ± 4.49 µg·hr/mL | turkey poults, single SC 0.12 mg/poult; AUC determined to the last time point (12 h); Table 4.2 row | 0.12 1.674 ± 0.662 13.84 ± 4.49 8.50 ± 3.70 |
| other | Tmic 8.50 ± 3.70 hr (time above E. coli MIC) | turkey poults, single SC 0.12 mg/poult; Table 4.2 row | 0.12 1.674 ± 0.662 13.84 ± 4.49 8.50 ± 3.70 |
| cmax | 4.259 ± 1.276 µg/mL | turkey poults, single SC 0.24 mg/poult; Table 4.2 row (Dose, Cmax, AUC, Tmic) | 0.24 4.259 ± 1.276 22.77 ± 4.61 19.99 ± 11.45 |
| auc | 22.77 ± 4.61 µg·hr/mL | turkey poults, single SC 0.24 mg/poult; Table 4.2 row | 0.24 4.259 ± 1.276 22.77 ± 4.61 19.99 ± 11.45 |
| cmax | 9.071 ± 2.564 µg/mL | turkey poults, single SC 0.48 mg/poult; Table 4.2 row (Dose, Cmax, AUC, Tmic) | 0.48 9.071 ± 2.564 46.14 ± 18.86 15.97 ± 7.43 |
| auc | 46.14 ± 18.86 µg·hr/mL | turkey poults, single SC 0.48 mg/poult; Table 4.2 row | 0.48 9.071 ± 2.564 46.14 ± 18.86 15.97 ± 7.43 |
| cmax | 1.665 ± 0.125 µg/mL (chicks, comparator species) | chicks, single SC 0.08 mg 14C-ceftiofur/chick (lowest approved chick dose); Table 4.1 row order: Dose (mg/chick), Cmax, AUC (to 8 h), Tmic | 0.08 1.665 ± 0.125 6.13 ± 1.91 7.59 ± 5.51 |
Target-animal safety
dose multiples 12X (100 mg/kg), 50X (400 mg/kg), 800 mg/kg (multiple not stated); duration single SC injection at 1 day of age, 7-day observation.
This was a 7-day study in turkeys in which a single injection of Naxcel® Sterile Powder at a dose of 0, 100, 400, or 800 mg/kg of body weight was administered subcutaneously at 1 day of age followed by a 7-day observation period.
| Finding | Quote |
|---|---|
| Clinical signs of toxicity only at 800 mg/kg | Of the three dosages tested, only the 800 mg/kg dose produced clinical signs of toxicity, including depression, ataxia and prostration. |
| Drug-related mortality only in the 800 mg/kg group | The only mortalities that appeared to be drug related occurred in the high dose group. |
| Total 7-day mortality by group (Table 5.1 TOTAL row; columns 0, 100, 400, 800 mg/kg, each M then F) | TOTAL 1/29 0/29 0/20 1/20 0/20 0/20 14/29 6/29 |
| Reduced weight gain at 800 mg/kg only | Poults from the 800-mg/kg dose group showed reduced gains at Day 4, probably due to toxicity. |
| No hematology effects | There was no evidence of treatment effects on red blood cell count, hemoglobin or hematocrit. |
| No treatment-related histology at 100 or 400 mg/kg | There were no histological observations that were treatment related in the 100- or 400-mg/kg treatment groups. |
Effectiveness
Multi-location (8 sites; 7 US, 1 Canada) dose confirmation/field trial, randomized complete block with 12 blocks per site, 2 x 2 factorial (control vs ceftiofur 0.17 mg/poult single SC; male vs female); pen of 50 poults as experimental unit; 14 days; n = 19,189; primary endpoint: cumulative 14-day morbidity/mortality associated with E. coli (moribund plus dead poults per pen / poults placed); result: Ceftiofur 0.17 mg/poult significantly (p = 0.038) reduced E. coli-associated morbidity/mortality vs control (Table 4.8: total 6.7% (565/8387) control vs 4.0% (336/8352) ceftiofur; E. coli-positive 4.1% (341/8387) vs 1.9% (158/8352); one site excluded for technical problems)
The design included a total of 19,200 poults (9,600 males and 9,600 females); the actual number of poults placed was 19,189 (9,589 males and 9,600 females).
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| adverse reactions (field trial) | Adverse Reactions: No adverse reactions were observed. |
Extraction notes: Supplement adding day-old turkey poults; dose derived by PK bridging from chicks (Cmax regression). n_dogs holds the number of poults placed. TAS study used 258 poults in total ('A total of 258 one-day-old Nicholas broad-breasted white turkey poults were used for this study.'), 29/sex initial plus 10/sex repeated per group; n_animals left null because the design quote does not contain the figure. Table 4.8 rows verbatim: '0 6.7 (565/8387) 4.1 (341/8387)' and '0.17 4.0 (336/8352) 1.9 (158/8352)'. TAS conclusion sentence spans a page break and is not quoted.
Ceftiofur Sodium Sterile Powder NADA 200-420, Original approval, May 27, 2009; sponsor Dechra Veterinary Products LLC; species: Cattle, swine, sheep, goats, horses, dogs, day-old chickens & day-old turkey poults; foi_id 2859; FDA PDF
Indication
Dogs: treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis (multi-species generic label; other species carry respiratory/foot-rot/early-mortality indications).
Dose regimen
1.0 mg ceftiofur per pound (2.2 mg/kg) body weight, Subcutaneous injection, Repeated at 24-hour intervals, 5-14 days; only the 1 gram vial is approved for use in dogs (no vial closure entered more than 20 times)
Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 mL reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 24-hour intervals for 5-14 days.
Extraction notes: Generic ANADA (sponsor at approval: Cephazone Pharma, LLC; catalogue sponsor now Dechra). No new safety or effectiveness studies; an in vivo bioequivalence study was waived on formulation characteristics: 'Based on the formulation characteristics of the generic product, Cephazone Pharma, LLC, was granted a waiver from the requirement of an in vivo bioequivalence study for the generic product Ceftiofur Sodium Sterile Powder.' Pioneer: NAXCEL Sterile Powder, NADA 140-338. Summary covers eight species; only the dog regimen/indication is recorded above.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, May 29, 2001; sponsor Zoetis Inc.; species: Cattle; foi_id 473; FDA PDF
Indication
Treatment of BRD associated with P. multocida, P. haemolytica and H. somnus, and of acute bovine interdigital necrobacillosis (foot rot); supplement adds the subcutaneous route.
Dose regimen
0.5 to 1.0 mg ceftiofur per pound (lb) of body weight (1 to 2 mL per 100 lb), intramuscular (IM) or subcutaneous (SC) injection, every 24 hours for a total of three treatments, additional treatments on Days 4 and 5 if not recovered; do not inject more than 15 mL per IM site; SC neck injection may leave discoloration beyond five days
NAXCEL® Sterile Solution is to be administered IM or SC to cattle at the dosage range of 0.5 to 1.0 mg ceftiofur per pound (lb) of body weight (BW); 1 to 2 mL reconstituted sterile solution per 100 lb BW. Treatment should be repeated every 24 hours for a total of three treatments.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | SC vs IM equivalence criteria satisfied for AUC0-LOQ and t>0.2 | 2.2 mg ceftiofur free acid equivalents/kg (1.0 mg/lb), 12 crossbred beef cattle, three-period two-treatment crossover, 72-hour plasma disposition; 90% CI required within ± 20% of reference mean | Both decision criteria for acceptance of equivalence of ceftiofur sodium by the two routes of administration were satisfied (AUC0-LOQ and t>0.2). |
Target-animal safety
dose multiples 1X (2.2 mg/kg, the maximum label dose, SC); duration once daily for five consecutive days.
Injection site and kidney residue evaluation and gross pathology after SC administration of ceftiofur sodium (NAXCEL Sterile Powder) at a dose of 2.2 mg ceftiofur equivalents/kg BW administered once daily for five consecutive days in cattle.
| Finding | Quote |
|---|---|
| SC injection well tolerated | The injection of NAXCEL Sterile Powder at the recommended dose administered SC in the neck of cattle was well tolerated. |
| Persistent yellow-red discoloration at SC injection sites beyond 4.5 days | However, a several square centimeter area of yellow-red discoloration resulting from a single SC injection persisted in many of the cattle beyond 4.5 days post-injection. |
| One abscess near an injection site | Also, one of the animals developed an abscess near the injection site. |
Effectiveness
Bioequivalence study (TR 788-7926-96-014), not a clinical trial: three-period, two-treatment crossover (ABB/BAA) of SC vs IM ceftiofur sodium at 2.2 mg CFAE/kg with 14-day washout; n = 12; primary endpoint: AUC0-LOQ and time above 0.2 µg/mL (t>0.2); 90% CI within ± 20% of reference mean; result: SC route bioequivalent to IM; routes interchangeable for efficacy, systemic safety and food safety (except SC injection-site blemishes)
Experimental Animals: Twelve (12) crossbred beef cattle (6 males and 6 females) 224 to 254 kg BW at start of study.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| injection-site discoloration after SC injection (persisting beyond 4.5 days) | However, a several square centimeter area of yellow-red discoloration resulting from a single SC injection persisted in many of the cattle beyond 4.5 days post-injection. |
Extraction notes: Supplement adding the SC route in cattle; effectiveness supported only by the IM-vs-SC bioequivalence study (n_dogs holds the number of cattle). TAS is an injection-site/residue study (SR a0058234) in 6 heifers, 6 steers plus 1 control heifer; n_animals left null because the design quote lacks the figures. Section parser placed the whole body in 'preamble'; quotes taken from raw text. In this summary the registered-mark glyph after NAXCEL was extracted as private-use character U+F6DA, which is kept verbatim in the TAS quotes.
Naxcel® Sterile Powder NADA 140-338, Supplemental approval, October 25, 1996; sponsor Zoetis Inc.; species: Sheep; foi_id 3693; FDA PDF
Indication
Treatment of sheep respiratory disease (sheep pneumonia) associated with Pasteurella haemolytica and Pasteurella multocida.
Dose regimen
0.5 to 1.0 mg/lb body weight (1 to 2 mL per 100 lb), intramuscular (I.M.) injection, at 24-hour intervals for 3 consecutive days, additional treatments may be given on Days 4 and 5 for animals without a satisfactory response after the initial 3 treatments
Administer NAXCEL Sterile Powder to sheep at the dosage of 0.5 to 1.0 mg/lb body weight (1 to 2 mL reconstituted sterile solution per 100 lb body weight). Treatment should be repeated at 24-hour intervals for 3 consecutive days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 4.33 ± 1.21 µg/mL (sheep); 4.12 ± 0.84 µg/mL (cattle comparator) | sheep: single IM 0.5 mg/lb (TR 815-7926-94-007); cattle: single IM 0.45 mg/lb (TR 788-9760-88-018); Table 4.2 row order: parameter, sheep, cattle | Cmax (µg/mL) 4.33 ± 1.21 4.12 ± 0.84 |
| other | C(24) 0.18 ± 0.06 µg/mL (sheep); 0.29 ± 0.08 µg/mL (cattle) | plasma concentration 24 h after single IM 0.5 mg/lb (sheep) or 0.45 mg/lb (cattle); Table 4.2 row | C(24) (µg/mL) 0.18 ± 0.06 0.29 ± 0.08 |
| auc | AUC(0-24) 20.2 ± 3.58 µg·h/mL (sheep); 29.4 ± 5.56 µg·h/mL (cattle) | single IM 0.5 mg/lb (sheep) or 0.45 mg/lb (cattle); Table 4.2 row | AUC(0-24) (µg °h/mL) 20.2 ± 3.58 29.4 ± 5.56 |
| tmax | 0.167 - 1.0 h range (sheep); 0.5 - 1.0 h range (cattle) | single IM 0.5 mg/lb (sheep) or 0.45 mg/lb (cattle); Table 4.2 row | tmax (h, range) 0.167 - 1.0 0.5 - 1.0 |
| clearance | increased total body clearance in sheep vs cattle (no numeric value given) | qualitative statement from the PK comparison | Due to an increased total body clearance in sheep as compared to cattle, the maximum serum concentrations in sheep was less than maximum serum concentrations in cattle. |
Target-animal safety
dose multiples 5x the maximum recommended dose of 1.0 mg/lb; duration 3x the recommended duration of treatment.
A safety/toxicity study conducted in sheep with ceftiofur sodium under PMF 5544 demonstrated wide margin of safety when administered IM to sheep at doses up to 5x the maximum recommended dose of 1.0 mg/lb of body weight and for 3x the recommended duration of treatment.
| Finding | Quote |
|---|---|
| Wide margin of safety at up to 5x dose for 3x duration (PMF 5544) | A safety/toxicity study conducted in sheep with ceftiofur sodium under PMF 5544 demonstrated wide margin of safety when administered IM to sheep at doses up to 5x the maximum recommended dose of 1.0 mg/lb of body weight and for 3x the recommended duration of treatment. |
Effectiveness
Minor-species extrapolation under 21 CFR 514.1(d): literature comparison of pneumonic pasteurellosis in sheep and cattle, PK bridging (sheep vs historical cattle data) and in vitro MIC survey; no clinical trial in sheep; result: Plasma concentrations at 24 h several-fold above MIC90 (<0.06 µg/mL) in both species; sheep isolates MIC90 0.031 µg/mL for P. multocida (n=23) and 0.125 µg/mL for P. haemolytica (n=39); NAXCEL considered effective in sheep at 0.5-1.0 mg/lb IM once daily for 3 to 5 days
A combination of data from sheep (a minor species) and a closely-related approved major species (cattle) were used to support the determination of effectiveness, consistent with the Guidelines for the Preparation of Data to Satisfy the Requirements of Section 512 of the Act Regarding Minor Use of Animal Drugs (FDA/CVM April 1986).
Extraction notes: Minor-species supplement (sheep); effectiveness by extrapolation and PK bridging, TAS summarised by reference to PMF 5544 (no n or design details). Table 4.2 rows are flattened (sheep value then cattle value). MIC sentence verbatim: 'The MIC90 of ceftiofur against P. multocida isolates (n = 23) was 0.031 µg/mL and against P. haemolytica isolates (n = 39) was 0.125 µg/mL.' No adverse-reaction data reported.
Reproduce: foi_structured_search(query="Ceftiofur Sodium") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).